NCCN.org

NCCN Guidelines for Patients

available at www.nccn.org/patients

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines

)

Non-Small Cell Lung

Cancer

Version 5.2021 — June 15, 2021

Continue

NCCN Guidelines Panel Disclosures

*David S. Ettinger, MD/Chair †

The Sidney Kimmel Comprehensive

Cancer Center at Johns Hopkins

*Douglas E. Wood, MD/Vice Chair ¶

Fred Hutchinson Cancer Research Center/

Seattle Cancer Care Alliance

Dara L. Aisner, MD, PhD ≠

University of Colorado Cancer Center

Wallace Akerley, MD †

Huntsman Cancer Institute

at the University of Utah

Jessica R. Bauman, MD ‡ †

Fox Chase Cancer Center

Ankit Bharat, MD ¶

Robert H. Lurie Comprehensive Cancer

Center of Northwestern University

Debora S. Bruno, MD, MS †

Case Comprehensive Cancer Center/

University Hospitals Seidman Cancer

Center and Cleveland Clinic Taussig

Cancer Institute

Joe Y. Chang, MD, PhD §

The University of Texas

MD Anderson Cancer Center

Lucian R. Chirieac, MD ≠

Dana-Farber/Brigham and Women’s

Cancer Center

Thomas A. D’Amico, MD ¶

Duke Cancer Institute

Thomas J. Dilling, MD, MS §

Moffitt Cancer Center

Jonathan Dowell, MD †

UT Southwestern Simmons Comprehensive

Cancer Center

Scott Gettinger, MD † Þ

Yale Cancer Center/Smilow Cancer Hospital

Travis E. Grotz, MD ¶

Mayo Clinic Cancer Center

Matthew A. Gubens, MD, MS †

UCSF Helen Diller Family

Comprehensive Cancer Center

Aparna Hegde, MD †

O'Neal Comprehensive Cancer Center at UAB

Mark Hennon, MD ¶

Roswell Park Comprehensive Cancer Center

Rudy P. Lackner, MD ¶

Fred & Pamela Buffett Cancer Center

Michael Lanuti, MD ¶

Massachusetts General Hospital Cancer Center

Ticiana A. Leal, MD †

University of Wisconsin Carbone Cancer Center

Jules Lin, MD ¶

University of Michigan Rogel Cancer Center

Billy W. Loo, Jr., MD, PhD §

Stanford Cancer Institute

Christine M. Lovly, MD, PhD †

Vanderbilt-Ingram Cancer Center

Renato G. Martins, MD, MPH †

Fred Hutchinson Cancer Research Center/

Seattle Cancer Care Alliance

Erminia Massarelli, MD †

City of Hope National Medical Center

Daniel Morgensztern, MD †

Siteman Cancer Center at Barnes-Jewish Hospital

and Washington University School of Medicine

Thomas Ng, MD ¶

The University of Tennessee Health Science

Center

Gregory A. Otterson, MD †

The Ohio State University Comprehensive

Cancer Center - James Cancer Hospital

and Solove Research Institute

Jose M. Pacheco, MD †

University of Colorado Cancer Center

Sandip P. Patel, MD ‡ † Þ

UC San Diego Moores Cancer Center

Gregory J. Riely, MD, PhD † Þ

Memorial Sloan Kettering Cancer Center

Steven E. Schild, MD §

Mayo Clinic Cancer Center

Theresa A. Shapiro, MD, PhD ¥

The Sidney Kimmel Comprehensive

Cancer Center at Johns Hopkins

Aditi P. Singh, MD †

Abramson Cancer Center at the

University of Pennsylvania

James Stevenson, MD †

Case Comprehensive Cancer Center/

University Hospitals Seidman Cancer

Center and Cleveland Clinic Taussig

Cancer Institute

Alda Tam, MD

The University of Texas

MD Anderson Cancer Center

Tawee Tanvetyanon, MD, MPH †

Moffitt Cancer Center

Jane Yanagawa, MD ¶

UCLA Jonsson Comprehensive Cancer Center

Stephen C. Yang, MD ¶

The Sidney Kimmel Comprehensive

Cancer Center at Johns Hopkins

NCCN

Kristina Gregory, RN, MSN, OCN

Miranda Hughes, PhD

‡ Hematology/Hematology oncology

Þ Internal medicine

† Medical oncology

≠ Pathology

¥ Patient advocacy

§ Radiation oncology/Radiotherapy

¶ Surgery/Surgical oncology

ф Diagnostic/Interventional

radiology

* Discussion Section Writing

Committee

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

Clinical Trials: NCCN believes that

the best management for any patient

with cancer is in a clinical trial.

Participation in clinical trials is

especially encouraged.

To nd clinical trials online at NCCN

Member Institutions, click here:

nccn.org/clinical_trials/member_

institutions.aspx.

NCCN Categories of Evidence and

Consensus: All recommendations

are category 2A unless otherwise

indicated.

See NCCN Categories of Evidence

and Consensus.

NCCN Categories of Preference:

All recommendations are considered

appropriate.

See NCCN Categories of Preference.

NCCN Non-Small Cell Lung Cancer Panel Members

Summary of Guidelines Updates

Lung Cancer Prevention and Screening (PREV-1)

Clinical Presentation and Risk Assessment (DIAG-1)

Initial Evaluation and Clinical Stage (NSCL-1)

Evaluation and Treatment:

• Stage IA (T1abc, N0) (NSCL-2)

• Stage IB (peripheral T2a, N0), Stage I (central T1abc-T2a, N0),

Stage II (T1abc-2ab, N1; T2b, N0), Stage IIB (T3, N0), and Stage IIIA (T3, N1) (NSCL-3)

• Stage IIB (T3 invasion, N0) and Stage IIIA (T4 extension, N0-1; T3, N1; T4, N0-1) (NSCL-5)

• Stage IIIA (T1-2, N2); Stage IIIB (T3, N2); Separate Pulmonary Nodule(s) (Stage IIB, IIIA, IV) (NSCL-8)

• Multiple Lung Cancers (N0-1) (NSCL-11)

• Stage IIIB (T1-2, N3); Stage IIIC (T3, N3) (NSCL-12)

• Stage IIIB (T4, N2); Stage IIIC (T4, N3); Stage IVA, M1a: Pleural or Pericardial Eusion (NSCL-13)

• Stage IVA, M1b (NSCL-14)

Surveillance After Completion of Denitive Therapy (NSCL-16)

Therapy for Recurrence and Metastasis (NSCL-17)

Systemic Therapy for Advanced or Metastatic Disease (NSCL-18)

Principles of Pathologic Review (NSCL-A)

Principles of Surgical Therapy (NSCL-B)

Principles of Radiation Therapy (NSCL-C)

Principles of Image-Guided Thermal Ablation Therapy (NSCL-D)

Systemic Therapy Regimens for Neoadjuvant and Adjuvant Therapy (NSCL-E)

Concurrent Chemoradiation Regimens (NSCL-F)

Cancer Survivorship Care (NSCL-G)

Principles of Molecular and Biomarker Analysis (NSCL-H)

Emerging Biomarkers to Identify Novel Therapies for Patients with Metastatic NSCLC (NSCL-I)

Targeted Therapy or Immunotherapy for Advanced or Metastatic Disease (NSCL-J)

Systemic Therapy for Advanced or Metastatic Disease (NSCL-K)

The NCCN Guidelines

are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment.

Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical

circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network

(NCCN

) makes no representations or

warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN

Guidelines are copyrighted by National Comprehensive Cancer Network

Staging (ST-1)

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

UPDATES

Continued

Updates in Version 5.2021 of the NCCN Guidelines for Non-Small Cell Lung Cancer from Version 4.2021 include:

NSCL-18

• Biomarker Testing

KRAS added

NSCL-19

• The following modied: Sensitizing

EGFR mutation positive (eg, exon 19 deletion or L858R) (also applies to NSCL-20, NSCL-21, NSCL-22)

• The following added

EGFR exon 20 insertion mutation positive

KRAS G12C mutation positive

NSCL-23

• New page added for EGFR exon 20 insertion mutation positive, including amivantamab-vmjw as a subsequent therapy option for patients

that progressed on or after platinum-based chemotherapy ± immunotherapy. This is a category 2A recommendation.

• The following footnotes added: (also applies to NSCL-24)

Footnote pp: For performance status 0–2. Best supportive care for PS 3-4.

Footnote bbb: Monitoring During Initial Therapy: Response assessment after 2 cycles, then every 2–4 cycles with CT of known sites of

disease with or without contrast or when clinically indicated. Timing of CT scans within Guidelines parameters is a clinical decision.

Footnote ccc: In general, 4 cycles of initial systemic therapy (ie, with carboplatin or cisplatin) are administered prior to maintenance

therapy. However, if patient is tolerating therapy well, consideration can be given to continue to 6 cycles.

Footnote ddd: Monitoring During Subsequent Therapy: Response assessment with CT of known sites of disease with or without contrast

every 6–12 weeks. Timing of CT scans within Guidelines parameters is a clinical decision.

NSCL-24

• New page added for KRAS G12C mutation positive, including sotorasib as a subsequent therapy option for patients that progressed on or

after platinum-based chemotherapy ± immunotherapy. This is a category 2A recommendation.

NSCL-J

• EGFR exon 20 insertion mutation positive; subsequent therapy

Amivantamab-vmjw added with reference 10 on NCSL-J 2 of 2

• KRAS G12C mutation positive; subsequent therapy

Sotorasib added with reference 11 on NSCL-J 2 of 2

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

Updates in Version 3.2021 of the NCCN Guidelines for Non-Small Cell Lung Cancer from Version 2.2021 include:

NSCL-3

• Footnote q modied: Consider

Testing for EGFR mutation on surgical tissue or biopsy in stages IB–IIIA.

(also applies to NSCL-6, NSCL-7)

NSCL-4

• Stage IB-IIIA, negative margins: Consider removed before osimertinib. (also applies to NSCL-E)

NSCL-6

• T3-4, N0-1; adjuvant treatment: Recommendation changed to include "and osimertinib" (also applies to NSCL-7)

• Footnote w added: For patients with EGFR mutation-positive NSCLC who received previous adjuvant chemotherapy or are ineligible to

receive platinum-based chemotherapy. (also applies to NSCL-7)

NSCL-29

• First-line therapy

Tepotinib added as a preferred treatment option.

NSCL-31

• First-line therapy

Adenocarcinoma, large cell, NSCLC NOS: Nivolumab + ipilimumab + pemetrexed + (carboplatin or cisplatin).

◊ category 2A changed to category 1 (also applies to NSCL-32)

Squamous cell carcinoma: Nivolumab + ipilimumab + paclitaxel + carboplatin (also applies to NSCL-32)

◊ category 2A changed to category 1 (also applies to NSCL-32)

UPDATES

Continued

Updates in Version 4.2021 of the NCCN Guidelines for Non-Small Cell Lung Cancer from Version 3.2021 include:

NSCL-31

• First-line therapy for PD-L1 ≥50% and negative for actionable molecular markers

Cemiplimab-rwlc added as a preferred, category 1, treatment option.

NSCL-J 1 of 2

• PD-L1 ≥50%; rst-line therapy

Cemiplimab-rwlc added with reference

NSCL-J 2 of 2

• Reference 48 added.

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

UPDATES

Continued

Updates in Version 2.2021 of the NCCN Guidelines for Non-Small Cell Lung Cancer from Version 1.2021 include:

NSCL-23

• Lorlatinib added as a rst-line, preferred treatment option for patients with advanced or metastatic, ALK rearrangement positive NSCLC.

This is a category 1 recommendation.

NSCL-F

• Dosing modication: Durvalumab 10 mg/kg IV every 2 weeks or 1500 mg every 4 weeks (patients with a body weight of ≥30 kg) for up to 12

months (category 1 for stage III; category 2A for stage II)

NSCL-J 1 of 2

• ALK rearrangement positive; rst-line therapy

Lorlatinib added with reference.

Updates in Version 3.2021 of the NCCN Guidelines for Non-Small Cell Lung Cancer from Version 2.2021 include:

NSCL-H 2 of 5

• EGFR Gene Mutations

Bullet 2 modied: Consider adding

Molecular testing for EGFR mutation to be performed on diagnostic biopsy or post-surgical resection

sample to ensure the EGFR mutation results are available for adjuvant treatment decisions for patients with stage IB to IIIA

stage IIB-IIIA or

high-risk stage IB-IIA NSCLC.

NSCL-J 1 of 2

• MET Exon 14 Skipping Mutation; rst-line therapy/subsequent therapy

Tepotinib added with reference.

NSCL-J 2 of 2

• Reference 32 added, 46 updated

NSCL-K 1 of 5

• Systemic Therapy for Advanced or Metastatic Disease

Initial Therapy Options; Adenocarcinoma, Large cell, NSCLC NOS (PS 0-1)

◊ Nivolumab/ipilimumab/pemetrexed/(carboplatin or cisplatin); category 2A changed to category 1

Footnote c modied: Contraindications for treatment with PD-1/PD-L1 inhibitors may include active or previously documented autoimmune

disease and/or current use of immunosuppressive agents, or presence of an oncogene (eg, EGFR [exon 19 deletions, p.L858R point

mutation in exon 21], ALK rearrangements, RET rearrangements), which would predict lack of benet. (also applies to NSCL-K 2 of 5)

Footnote d modied: If progression on PD-1/PD-L1 inhibitor, switching to another

using a PD-1/PD-L1 inhibitor is not recommended. (also

applies to NSCL-K 2 of 5, NSCL-K 4 of 5)

NSCL-K 2 of 5

• Systemic Therapy for Advanced or Metastatic Disease

Initial Therapy Options; Squamous cell carcinoma (PS 0-1)

◊ Nivolumab/ipilimumab/paclitaxel/carboplatin; category 2A changed to category 1

NSCL-K 5 of 5

• Reference 6 updated.

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

UPDATES

Updates in Version 1.2021 of the NCCN Guidelines for Non-Small Cell Lung Cancer from Version 8.2020 include:

DIAG-2

• Footnote j modied: Patients require tissue conrmation of lung cancer before any nonsurgical therapy.

If empiric therapy is contemplated

without tissue conrmation, multidisciplinary evaluation that at least includes interventional radiology, thoracic surgery, and interventional

pulmonology is recommended

required to determine the safest and most ecient approach for biopsy, or to provide consensus that a

biopsy is too risky or dicult and that the patient can proceed with therapy without tissue conrmation. (IJsseldijk MA, et al. J Thorac Oncol

2019;14:583-595.) (also applies to DIAG-3; same footnote added as footnote n on NSCL-2, NSCL-3)

DIAG-3

• Solitary pure ground-glass nodules; ≥6 mm:

CT at 6–12 mo to conrm no growth or change in

development of a solid component, then CT every 2 y until 5 y

DIAG-A 1 of 3

• Footnote 1 added: Patients require tissue conrmation of non-small cell lung cancer (NSCLC) before a lobectomy, bilobectomy, or

pneumonectomy. If a preoperative or intraoperative tissue diagnosis appears risky or unreliable, multidisciplinary evaluation that at least

includes interventional radiology, thoracic surgery, and interventional pulmonology is recommended to determine the safest and most

ecient approach for biopsy, or to provide consensus that a biopsy is too risky or dicult and that the patient can proceed with anatomic

resection without tissue conrmation.

NSCL-2

• Negative mediastinal nodes; Medically inoperable: Denitive RT, preferably including

stereotactic ablative radiotherapy (SABR) (also applies

to NSCL-3)

• Footnote m modied: Image-guided thermal ablation therapy (eg, cryotherapy, microwave, radiofrequency) is an option for selected

patients may be an option for select patients not receiving SABR or denitive RT. See Principles of Image-Guided Thermal Ablation Therapy

(NSCL-D). (also applies to NSCL-15, NSCL-17, NSCL-21, NSCL-22, NSCL-24, and NSCL-25; added to NSCL-11)

NSCL-3

• Medically inoperable; N1, Durvalumab after denitive chemoradiation: Durvalumab claried as a category 1 for stage III and a category 2A for

stage II.

• Footnote q added: Consider testing for EGFR mutation on surgical tissue or biopsy in stages IB–IIIA. (also applies to NSCL-6, NSCL-7)

NSCL-4

• Stage IB-IIIA, negative margins: Consider osimertinib added as a treatment option.

• Footnote w added: For patients with EGFR mutation-positive NSCLC who received previous adjuvant chemotherapy or are ineligible to

receive platinum-based chemotherapy.

NSCL-6

• Superior sulcus tumor; unresectable after surgical reevaluation: Complete denitive RT + chemotherapy

chemoradiation

NSCL-10

• Footnote aa modied: Lesions with dierent cell types (eg, squamous cell carcinoma, adenocarcinoma) may be

are usually dierent primary

tumors. This analysis may be limited by small biopsy samples. However, lesions of the same cell type are not necessarily metastases.

Single contralateral lung nodules with clinical, radiologic, or pathologic features suggestive of a synchronous primary lung cancer (eg,

long disease-free survival, ground glass components, dierent histologic characteristics) that are amenable to local therapy should be

considered as probable separate primary cancers and eligible for local therapy, see NSCL-11.

NSCL-11

• Footnote dd modied with the addition of interventional oncology to the multidisciplinary setting.

Continued

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

UPDATES

Continued

Updates in Version 1.2021 of the NCCN Guidelines for Non-Small Cell Lung Cancer from Version 8.2020 include:

NSCL-13

• Stage IVA, M1a; Pretreatment Evaluation

Added: FDG PET/CT scan (if not previously done)

Added: Brain MRI with contrast

Added: Molecular testing (also applies to NSCL-14)

NSCL-14

• The performance category designations modied: PS 0–1 changed to PS 0–2 and PS 2–4 changed to PS 3–4.

NSCL-15

• T1–3, N1: Chemoradiation noted as preferred.

• Footnote hh modied: Typically, RT (including SABR) or surgical resection. Image-guided thermal ablation therapy (eg, cryotherapy,

microwave, radiofrequency) may be an option for select patients not receiving RT or surgery.

NSCL-16

• Brain MRI claried with contrast.

NSCL-18

• Squamous cell carcinoma: the qualiers of never smokers, small biopsy specimens, and mixed histology removed.

• Footnote nn updated: Paik PK, et al. Mol Cancer Ther 2012;11:2535-2540.

Lam VK, et al. Clin Lung Cancer 2019;20:30-36.e3; Sands JM, et al.

Lung Cancer 2020;140:35-41.

• Footnote removed: In patients with squamous cell carcinoma, the observed incidence of EGFR mutations is 2.7% with a condence that the

true incidence of mutations is less than 3.6%. This frequency of EGFR mutations does not justify routine testing of all tumor specimens.

Forbes SA, Bharma G, Bamford S, et al. The catalogue of somatic mutations in cancer (COSMIC). Curr Protoc Hum Genet 2008;chapter

10:unit 10.11.

NSCL-19

• Testing results moved from page NSCL-18 to NSCL-19.

• Listing of molecular markers in the testing result categories consolidated to negative for actionable molecular markers.

NSCL-20

• Erlotinib + bevacizumab changed from a category 2B recommendation to a category 2A recommendation. It was also changed from Useful in

Certain Circumstances to Other Recommended.

NSCL-21

• Isolated lesion changed to Limited metastases. (also applies to NSCL-22, NSCL-24, NSCL-25)

• Footnote uu added: Limited number is undened but clinical trials have included 3 to 5 metastases. (also applies to NSCL-22, NSCL-24,

NSCL-25)

NSCL-22

• Footnote zz modied: Consider osimertinib (regardless of T790M status) for progressive CNS disease or leptomeningeal disease. In the

Bloom study, osimertinib was used at 160 mg for patients with leptomeningeal disease.

NSCL-23

• Brigatinib changed from Other Recommended to Preferred.

NSCL-26

• Subsequent Therapy: Entrectinib added.

• Footnote eee added: Entrectinib may be better for patients with brain metastases.

• Footnote f added: Entrectinib is primarily for patients with CNS progression after crizotinib.

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

UPDATES

Continued

Updates in Version 1.2021 of the NCCN Guidelines for Non-Small Cell Lung Cancer from Version 8.2020 include:

NSCL-27

• Single-agent dabrafenib removed as a treatment option.

• Vemurafenib changed from Other Recommended to Useful in Certain Circumstances

NSCL-29

• Footnote tt added: Beware of are phenomenon in subset of patients who discontinue TKI. If disease are occurs, restart TKI. (also applies

to NSCL-30)

NSCL-31

• First-line therapy

Nivolumab + ipilimumab changed from a category 2A to a category 1. (also applies to NSCL-32)

Atezolizumab changed from a category 2A to a category 1.

• Continuation Maintenance

Nivolumab + ipilimumab added. (also applies to NSCL-32)

NSCL-33

• Page name claried for PD-L1 <1% and Negative for Molecular Markers and includes Adenocarcinoma, Large Cell, NSCLC NOS, and

Squamous Cell Carcinoma.

• Content for Monitoring During Initial Therapy and Monitoring During Subsequent Therapy added as footnotes.

NSCL-A 1 of 4

• Pathologic Evaluation; bullet 2, sub-bullet 2, the following removed:

The AJCC, Union for International Cancer Control (UICC), and International Association for the Study of Lung Cancer (IASLC) recommend

that at least six nodes are removed during surgical resection, three from N1 and three from N2 stations (ie, a representative node from each

station) for accurate staging.

NSCL-A 2 of 4

• NSCLC Classication; Adenocarcinoma

Dash 3 modied with the removal of this sentence: After comprehensive histologic subtyping in 5%–10% increments, the tumors are

classied according to their predominant pattern.

Dash 5 added: Refer to College of American Pathologists Protocols for additional information.

NSCL-B 1 of 4

• Evaluation; bullet 6 modied: Surgeons should not deny surgery to patients solely due to smoking status, as surgery provides the

predominant therapy opportunity for prolonged survival in

for patients with early-stage lung cancer.

NSCL-C 1 of 10

• General Principles; bullet 6 added: The interaction of strong VEGF inhibitors with prior or subsequent dose-intensive RT (SABR or denitive

dose accelerated fractionation) involving the proximal bronchial tree, hilar vessels, or esophagus can lead to serious toxicity. Careful

coordination of medical and radiation oncology on the therapeutic strategy is important, including the choice and sequencing of systemic

agents with strong VEGF inhibitors and the dose and fractionation of radiation, especially for patients with metastatic disease.

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

Continued

UPDATES

Updates in Version 1.2021 of the NCCN Guidelines for Non-Small Cell Lung Cancer from Version 8.2020 include:

NSCL-C 3 of 10

• Early-Stage NSCLC; bullet 3 modied: For institutions without an established SABR program,

More modestly hypofractionated or dose-

intensied conventionally fractionated 3D-CRT regimens are less preferred alternatives and may be considered if referral for SABR is not

feasible.

• SABR for Node-Negative Early-Stage NSCLC; bullet 2, last sentence of sub-bullet 1 modied: The maximum tolerated dose for 5-fraction

regimens was studied prospectively in RTOG 0813 evaluated the toxicity of 5-fraction regimens and found; preliminary results demonstrate

no high-grade toxicities at 50 Gy in 5 fractions.

NSCL-C 4 of 10

• Conventionally Fractionated RT for Locally Advanced NSCLC; bullet 1; sentence 2 modied: Two

Three randomized trials found improved

survival for IFI versus ENI, possibly because it enabled dose escalation.

NSCL-C 5 of 10

• Advanced/Metastatic NSCLC (Stage IV); bullet 2, sentence 3 modied: In two randomized phase II trials, signicantly improved progression-

free survival and overall survival in one trial...

• Palliative RT for Advanced/Metastatic NSCLC; bullet 2 added: Single-fraction stereotactic RT of 12–16 Gy produced better control of pain

response and local control of non-spine bone metastases compared to standard 30 Gy in 10 fractions in a randomized phase II trial, and may

be promising for patients with longer expected survival.

NSCL-C 8 of 10

• Table 5; Footnote * modied: These constraints represent doses that generally should not be exceeded, based on a consensus survey of

NCCN Member Institutions.

NSCL-C 9 and NSCL-C 10

• Reference 41 updated.

• The following references added: 29, 34, 74, 106.

NSCL-D

• New page added for Principles of Image-Guided Thermal Ablation Therapy.

NSCL-E

• The following added: Previous Adjuvant Chemotherapy or Ineligible for Platinum-Based Chemotherapy

• Osimertinib 80 mg daily

Consider osimertinib for patients with completely resected Stage IB–IIIA EGFR mutation-positive NSCLC who received previous adjuvant

chemotherapy or are ineligible to receive platinum-based chemotherapy.

• Reference 10 added.

NSCL-F

• Durvalumab recommendation modied to include stage II with a category 2A.

• Footnote € added: For patients with superior sulcus tumors, the recommendation is for 2 cycles concurrent with radiation therapy and 2

more cycles after surgery. Rusch VW, Giroux DJ, Kraut MJ, et al. Induction chemoradiation and surgical resection for superior sulcus non-

small-cell lung carcinomas: long-term results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Clin Oncol 2007;25:313-318.

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

UPDATES

Updates in Version 1.2021 of the NCCN Guidelines for Non-Small Cell Lung Cancer from Version 8.2020 include:

NSCL-H 2 of 5

• EGFR: Diamond 2 added

Consider adding molecular testing for EGFR mutation to be performed on diagnostic biopsy or post-surgical resection sample to ensure the

EGFR mutation results are available for adjuvant treatment decisions for patients with stage IB to IIIA NSCLC.

• Section removed:

Some mutations in EGFR are associated with lack of responsiveness to EGFR TKI therapy, including most EGFR exon 20 insertions, and

p.T790M.

Most EGFR exon 20 insertion mutations predict resistance to clinically achievable levels of TKIs. The exception is a rare EGFR exon 20

insertion variant, p.A763_Y764insFQEA, which is associated with responsiveness to EGFR TKI therapy. Therefore, knowledge of an EGFR

exon 20 insertion must be included in the specic sequence alteration.

The nding of p.T790M is most commonly associated with relapse following initial therapy with EGFR TKI, which is a known mechanism

of resistance. If identied prior to TKI exposure, genetic counseling should be considered, because germline p.T790M is associated with

familial lung cancer predisposition and additional testing is warranted.

• Section added:

EGFR exon 20 (EGFRex20) mutations are a heterogeneous group, some of which are responsive to targeted therapy and that require

detailed knowledge of the specic alteration.

◊ EGFR p.T790M is most commonly observed as a mutation that arises in response to and as a mechanism of resistance to rst- and

second-generation EGFR TKI. In patients with progression on rst- or second-generation TKI with p.T790M as the primary mechanism

of resistance, third-generation TKIs are typically ecacious. If p.T790M is observed in the absence of prior EGFR TKI therapy, genetic

counseling and possible germline genetic testing is warranted.

◊ Most other EGFRex20 alterations are a diverse group of in-frame duplication or insertion mutations.

– These are generally associated with lack of response to EGFR TKI therapy, with select exceptions:

p.A763_Y764insFQEA is associated with sensitivity to TKI therapy

p. A763_Y764insLQEA may be associated with sensitivity to TKI therapy

– For this reason, the specic sequence of EGFRex20 insertion mutations is important, and some assays will identify the presence of an

EGFRex20 insertion without specifying the sequence. In this scenario, additional testing to further clarify the EGFRex20 insertion is indicated.

NSCL-H 3 of 5

• ALK Gene Rearrangements; diamond 2 modied: The presence of an ALK rearrangement is associated with responsiveness to oral ALK

TKIs, with recent studies demonstrating improved ecacy of alectinib over crizotinib in the rst-line setting

NSCL-H 4 of 5

• Molecular Targets for Analysis; the following added:

MET (mesenchymal-epithelial transition) exon 14 (METex14) skipping variants: MET is a receptor tyrosine kinase. A mutation that results in

loss of exon 14 can occur in NSCLC. Loss of METex14 leads to dysregulation and inappropriate signaling.

◊ The presence of METex14 skipping mutation is associated with responsiveness to oral MET TKIs.

◊ A broad range of molecular alterations lead to METex14 skipping.

◊ Testing methodologies: NGS-based testing is the primary method for detection of METex14 skipping events, with RNA-based NGS

demonstrating improvement in detection. IHC is not a method for detection of METex14 skipping.

Continued

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

Updates in Version 1.2021 of the NCCN Guidelines for Non-Small Cell Lung Cancer from Version 8.2020 include:

NSCL-H 4 of 5

• Molecular Targets for Analysis; the following added:

RET (rearranged during transfection) Gene Rearrangements: RET is a receptor tyrosine kinase that can be rearranged in NSCLC, resulting

in dysregulation and inappropriate signaling through the RET kinase domain.

◊ Common fusion partners are KIF5B, NCOA4, and CCDC6; however, numerous other fusion partners have been identied.

The presence of a RET rearrangement is associated with responsiveness to oral RET TKIs

Testing methodologies: FISH break-apart probe methodology can be deployed; however, it may under-detect some fusions. Targeted real-

time reverse-transcriptase PCR assays are utilized in some settings, although they are unlikely to detect fusions with novel partners. NGS-

based methodology has a high specicity, and RNA-based NGS is preferable to DNA-based NGS for fusion detection.

• NTRK1/2/3 section, the following added:

Sub-bullet 4 added: Point mutations in NTRK1/2/3 are generally non-activating and have not been studied in association with targeted

therapy.

• Bullet 2 added: In the event that a complete assessment for all biomarkers cannot be reasonably accomplished prior to initiation of therapy,

consider repeat panel testing or selected biomarker testing at progression on rst-line therapy if a lesion can be accessed for sampling and

testing.

NSCL-H 5 of 5

• Plasma Cell-Free/Circulating Tumor DNA Testing

Sub-bullet 6; Diamond 2 modied: In the initial diagnostic setting, if following pathologic conrmation of a NSCLC diagnosis there is

insucient material for molecular analysis, cell-free/circulating tumor DNA should be used only if follow-up tissue-based analysis is

planned for all patients in which an oncogenic driver is not identied (see NSCL-18 for oncogenic drivers with available targeted therapy

options)

NSCL-I

• High-level MET amplication: Capmatinib added as an available targeted agent with activity against the driver event.

• ERBB2 (HER2) mutations: Fam-trastuzumab deruxtecan-nxki added as an available targeted agent with activity against the driver event.

• Tumor mutational burden removed as an immune biomarker, including the following available immunotherapy agents.

Nivolumab + ipilimumab removed

Nivolumab removed

• References 3 and 5 added.

NSCL-K 1 of 5

• Footnote c modied: Contraindications for treatment with PD-1/PD-L1 inhibitors may include active or previously documented autoimmune

disease and/or current use of immunosuppressive agents, or presence of an oncogene (eg, EGFR [exon 19 deletions, p.L858R point

mutation in exon 21], ALK rearrangements), which would predict lack of benet. (also applies to NSCL-K 2 of 5)

NSCL-K 3 of 5

• Maintenance Therapy options moved from algorithm pages.

NSCL-K 4 of 5

• Subsequent Systemic Therapy Options moved from algorithm pages.

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

PREV-1

LUNG CANCER PREVENTION AND SCREENING

• Lung cancer is a unique disease in that the major etiologic agent is an addictive product that is made and promoted by an industry.

Approximately 85% to 90% of cases are caused by voluntary or involuntary (second-hand) cigarette smoking. Reduction of lung cancer

mortality will require eective public health policies to prevent initiation of smoking, U.S. Food and Drug Administration (FDA) oversight of

tobacco products, and other tobacco control measures.

• Persistent smoking is associated with second primary cancers, treatment complications, drug interactions, other tobacco-related medical

conditions, diminished quality of life, and reduced survival.

• Reports from the Surgeon General on both active smoking (http://www.cdc.gov/tobacco/data_statistics/sgr/2004/pdfs/executivesummary.pdf)

and second-hand smoke show that both cause lung cancer. The evidence shows a 20% to 30% increase in the risk for lung cancer from

second-hand smoke exposure associated with living with a smoker (http://www.ncbi.nlm.nih.gov/books/NBK44324/).

Every person should be informed of the health consequences, addictive nature, and mortal threat posed by tobacco consumption and

exposure to tobacco smoke, and eective legislative, executive, administrative, or other measures should be contemplated at the appropriate

governmental level to protect all persons from exposure to tobacco smoke (www.who.int/tobacco/framework/nal_text/en/).

• Further complicating this problem, the delivery system of lung carcinogens also contains the highly addictive substance, nicotine.

Reduction of lung cancer mortality will require widespread implementation of Agency for Healthcare Research and Quality (AHRQ)

Guidelines (http://www.ahrq.gov/professionals/clinicians-providers/guidelines-recommendations/tobacco/index.html) to identify, counsel,

and treat patients with nicotine habituation.

• Patients who are current or former smokers have signicant risk for the development of lung cancer; chemoprevention agents are not yet

established for these patients. When possible, these patients should be encouraged to enroll in chemoprevention trials.

• Lung cancer screening using low-dose CT (LDCT) is recommended in select high-risk smokers and former smokers (see the NCCN

Guidelines for Lung Cancer Screening).

• See the NCCN Guidelines for Smoking Cessation.

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

DIAG-1

Multidisciplinary evaluation including thoracic surgeons, thoracic radiologists, and pulmonologists to determine the likelihood of a cancer diagnosis and the optimal

diagnostic or follow-up strategy.

Risk calculators can be used to quantify individual patient and radiologic factors but do not replace evaluation by a multidisciplinary diagnostic team with substantial

experience in the diagnosis of lung cancer.

See Principles of Diagnostic Evaluation (DIAG-A 1 of 3).

The most important radiologic factor is change or stability compared with a previous imaging study.

CLINICAL PRESENTATION RISK ASSESSMENT

Incidental

nding of nodule

suspicious for

lung cancer

• Multidisciplinary

evaluation

• Smoking cessation

counseling

Patient factors

• Age

• Smoking history

• Previous cancer history

• Family history

• Occupational exposures

• Other lung disease (chronic obstructive pulmonary

disease [COPD], pulmonary brosis)

• Exposure to infectious agents (eg, endemic areas

of fungal infections, tuberculosis) or risk factors or

history suggestive of infection (eg, immune

suppression, aspiration, infectious respiratory

symptoms)

Radiologic factors

c,d

• Size, shape, and density of the pulmonary nodule

• Associated parenchymal abnormalities (eg,

scarring or suspicion of inammatory changes)

• Fluorodeoxyglucose (FDG) avidity on PET imaging

Solid nodules

See Follow-up

(DIAG-2)

Subsolid nodules

See Follow-up

(DIAG-3)

Lung nodules in

asymptomatic, high-risk

patients detected during lung

cancer screening with LDCT

See NCCN Guidelines for

Lung Cancer Screening

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

DIAG-2

FINDINGS FOLLOW-UP

c,d,g,h

See Principles of Diagnostic Evaluation (DIAG-A 1 of 3).

The most important radiologic factor is change or stability compared with a previous

imaging study.

Low risk = minimal or absent history of smoking or other known risk factors.

High risk = history of smoking or other known risk factors. Known risk factors include

history of lung cancer in a first-degree relative; exposure to asbestos, radon, or

uranium.

Non-solid

(ground-glass)

nodules may require longer follow-up to exclude indolent

adenocarcinoma.

Adapted from Fleischner Society Guidelines: MacMahon H, Naidich DP, Goo

JM, et al. Guidelines for management of incidental pulmonary nodules detected

on CT images: From the Fleischner Society 2017. Radiology 2017;284:228-243.

Radiological Society of North America. Fleischner Society Guidelines do not direct

whether or not contrast is necessary or if an LDCT is appropriate. LDCT is preferred

unless there is a reason for contrast enhancement for better diagnostic resolution.

PET/CT performed skull base to knees or whole body. A positive PET result is defined

as a standardized uptake value (SUV) in the lung nodule greater than the baseline

mediastinal blood pool. A positive PET scan finding can be caused by infection or

inflammation, including absence of lung cancer with localized infection, presence

of lung cancer with associated (eg, postobstructive) infection, and presence of lung

cancer with related inflammation (eg, nodal, parenchymal, pleural). A false-negative

PET scan can be caused by a small nodule, low cellular density (nonsolid nodule or

ground-glass opacity [GGO]), or low tumor avidity for FDG (eg, adenocarcinoma in

situ [previously known as bronchoalveolar carcinoma], carcinoid tumor).

If empiric therapy is contemplated without tissue confirmation, multidisciplinary

evaluation that at least includes interventional radiology, thoracic surgery, and

interventional pulmonology is required to determine the safest and most efficient

approach for biopsy, or to provide consensus that a biopsy is too risky or difficult and

that the patient can proceed with therapy without tissue confirmation. (IJsseldijk MA,

et al. J Thorac Oncol 2019;14:583-595.)

Incidental

nding: solid

nodule(s) on

chest CT

High risk

Low risk

<6 mm

6–8 mm

>8 mm

<6 mm

6–8 mm

>8 mm

No routine follow-up

CT at 6–12 mo

Stable

Consider CT

at 18–24 mo

Consider CT at 3 mo,

PET/CT,

or biopsy

CT at 12 mo

(optional)

Stable

CT at 6–12 mo

Stable

Repeat CT at

18–24 mo

No routine follow-up

Consider CT at 3 mo,

PET/CT,

or biopsy

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

See Principles of Diagnostic Evaluation (DIAG-A 1 of 3).

The most important radiologic factor is change or stability compared with a previous

imaging study.

Non-solid (ground-glass) nodules may require longer follow-up to exclude indolent

adenocarcinoma.

Adapted from Fleischner Society Guidelines: MacMahon H, Naidich DP, Goo

JM, et al. Guidelines for management of incidental pulmonary nodules detected

on CT images: From the Fleischner Society 2017. Radiology 2017;284:228-243.

Radiological Society of North America. Fleischner Society Guidelines do not direct

whether or not contrast is necessary or if an LDCT is appropriate. LDCT is preferred

unless there is a reason for contrast enhancement for better diagnostic resolution.

PET/CT performed skull base to knees or whole body.

A positive PET result is defined

as a SUV in the lung nodule greater than the baseline mediastinal blood pool. A

positive PET scan finding can be caused by infection or inflammation, including

absence of lung cancer with localized infection, presence of lung cancer with

associated (eg, postobstructive) infection, and presence of lung cancer with related

inflammation (eg, nodal, parenchymal, pleural). A false-negative PET scan can be

caused by a small nodule, low cellular density (nonsolid nodule or GGO), or low tumor

avidity for FDG (eg, adenocarcinoma in situ [previously known as bronchoalveolar

carcinoma], carcinoid tumor).

If empiric therapy is contemplated without tissue confirmation, multidisciplinary

evaluation that at least includes interventional radiology, thoracic surgery, and

interventional pulmonology is required to determine the safest and most efficient

approach for biopsy, or to provide consensus that a biopsy is too risky or difficult and

that the patient can proceed with therapy without tissue confirmation. (IJsseldijk MA,

et al. J Thorac Oncol 2019;14:583-595.)

Incidental

nding:

subsolid

nodule(s)

on chest CT

Solitary pure

ground-glass

nodules

<6 mm

≥6 mm

No routine follow-up

DIAG-3

Solitary

part-solid

nodules

Multiple

subsolid

nodules

<6 mm

≥6 mm

CT at 6–12 mo to conrm no growth or

development of a solid component, then

CT every 2 y until 5 y

• CT at 3–6 mo to conrm no growth or change in solid

component, then annual CT for 5 y

• If solid component ≥6 mm, consider PET/CT

or biopsy

<6 mm

• CT at 3–6 mo

If stable, consider CT at 2 and 4 y

≥6 mm

• CT at 3–6 mo

• Subsequent management

based on most

suspicious nodule(s)

No routine follow-up

FINDINGS FOLLOW-UP

c,d,g,h

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

DIAG-A

1 OF 3

PRINCIPLES OF DIAGNOSTIC EVALUATION

• Patients with a strong clinical suspicion of stage I or II lung cancer (based on risk factors and radiologic appearance) do not require a biopsy

before surgery.

A biopsy adds time, costs, and procedural risk and may not be needed for treatment decisions.

A preoperative biopsy may be appropriate if a non-lung cancer diagnosis is strongly suspected that can be diagnosed by core biopsy or

ne-needle aspiration (FNA).

A preoperative biopsy may be appropriate if an intraoperative diagnosis appears dicult or very risky.

If a preoperative tissue diagnosis has not been obtained, then an intraoperative diagnosis (ie, wedge resection, needle biopsy) is necessary

before lobectomy, bilobectomy, or pneumonectomy.

• Bronchoscopy should preferably be performed during the planned surgical resection, rather than as a separate procedure.

Bronchoscopy is required before surgical resection (see NSCL-2).

A separate bronchoscopy may not be needed for treatment decisions before the time of surgery and adds time, costs, and procedural risk.

A preoperative bronchoscopy may be appropriate if a central tumor requires pre-resection evaluation for biopsy, surgical planning (eg,

potential sleeve resection), or preoperative airway preparation (eg, coring out an obstructive lesion).

• Invasive mediastinal staging is recommended before surgical resection for most patients with clinical stage I or II lung cancer (see NSCL-2).

Patients should preferably undergo invasive mediastinal staging (mediastinoscopy) as the initial step before the planned resection

(during the same anesthetic procedure), rather than as a separate procedure. For patients undergoing endobronchial ultrasound (EBUS)/

endoscopic ultrasound (EUS) staging, this may require a separate procedure to allow evaluation if onsite rapid cytology interpretation is

not available.

A separate staging procedure adds time, costs, coordination of care, inconvenience, and an additional anesthetic risk.

Preoperative invasive mediastinal staging may be appropriate for a strong clinical suspicion of N2 or N3 nodal disease or when

intraoperative cytology or frozen section analysis is not available.

Patients require tissue confirmation of non-small cell lung cancer (NSCLC) before a lobectomy, bilobectomy, or pneumonectomy. If a preoperative or intraoperative

tissue diagnosis appears risky or unreliable, multidisciplinary evaluation that at least includes interventional radiology, thoracic surgery, and interventional pulmonology

is recommended to determine the safest and most efficient approach for biopsy, or to provide consensus that a biopsy is too risky or difficult and that the patient can

proceed with anatomic resection without tissue confirmation.

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

DIAG-A

2 OF 3

• In patients with suspected non-small cell lung cancer (NSCLC), many techniques are available for tissue diagnosis.

Diagnostic tools that should be routinely available include:

◊ Sputum cytology

◊ Bronchoscopy with biopsy and transbronchial needle aspiration (TBNA)

◊ Image-guided transthoracic needle core biopsy (preferred) or FNA

◊ Thoracentesis

◊ Mediastinoscopy

◊ Video-assisted thoracic surgery (VATS) and open surgical biopsy

Diagnostic tools that provide important additional strategies for biopsy include:

◊ EBUS–guided biopsy

◊ EUS–guided biopsy

◊ Navigational bronchoscopy

• The preferred diagnostic strategy for an individual patient depends on the size and location of the tumor, the presence of mediastinal or

distant disease, patient characteristics (such as pulmonary pathology and/or other signicant comorbidities), and local experience and

expertise.

Factors to be considered in choosing the optimal diagnostic step include:

◊ Anticipated diagnostic yield (sensitivity)

◊ Diagnostic accuracy including specicity and particularly the reliability of a negative diagnostic study (ie, true negative)

◊ Adequate volume of tissue specimen for diagnosis and molecular testing

◊ Invasiveness and risk of procedure

◊ Eciency of evaluation

– Access and timeliness of procedure

– Concomitant staging is benecial, because it avoids additional biopsies or procedures. It is preferable to biopsy the pathology that

would confer the highest stage (ie, to biopsy a suspected metastasis or mediastinal lymph node rather than the pulmonary lesion).

Therefore, PET imaging is frequently best performed before a diagnostic biopsy site is chosen in cases of high clinical suspicion for

aggressive, advanced-stage tumors.

◊ Technologies and expertise available

◊ Tumor viability at proposed biopsy site from PET imaging

Decisions about the optimal diagnostic steps for suspected stage I to III lung cancer should be made by thoracic radiologists,

interventional radiologists, and thoracic surgeons who devote a signicant portion of their practice to thoracic oncology. Multidisciplinary

evaluation should also include a pulmonologist or thoracic surgeon with expertise in advanced bronchoscopic techniques for diagnosis.

PRINCIPLES OF DIAGNOSTIC EVALUATION

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

DIAG-A

3 OF 3

The least invasive biopsy with the highest yield is preferred as the rst diagnostic study.

◊ Patients with central masses and suspected endobronchial involvement should undergo bronchoscopy.

◊ Patients with peripheral (outer one-third) nodules may benet from navigational bronchoscopy, radial EBUS, or transthoracic needle

aspiration (TTNA).

◊ Patients with suspected nodal disease should be biopsied by EBUS, EUS, navigational bronchoscopy, or mediastinoscopy.

– EBUS provides access to nodal stations 2R/2L, 4R/4L, 7, 10R/10L, and other hilar nodal stations if necessary.

– An EBUS-TBNA negative for malignancy in a clinically (PET and/or CT) positive mediastinum should undergo subsequent

mediastinoscopy prior to surgical resection.

– EUS–guided biopsy provides additional access to stations 5, 7, 8, and 9 lymph nodes if these are clinically suspicious.

– TTNA and anterior mediastinotomy (ie, Chamberlain procedure) provide additional access to anterior mediastinal (stations 5 and 6)

lymph nodes if these are clinically suspicious. If TTNA is not possible due to proximity to aorta, VATS biopsy is also an option.

◊ EUS also provides reliable access to the left adrenal gland.

◊ Lung cancer patients with an associated pleural eusion should undergo thoracentesis and cytology. A negative cytology result on

initial thoracentesis does not exclude pleural involvement. An additional thoracentesis and/or thoracoscopic evaluation of the pleura

should be considered before starting curative intent therapy.

◊ Patients suspected of having a solitary site of metastatic disease should have tissue conrmation of that site if feasible.

◊ Patients suspected of having metastatic disease should have conrmation from one of the metastatic sites if feasible.

◊ Patients who may have multiple sites of metastatic disease—based on a strong clinical suspicion—should have biopsy of the primary

lung lesion or mediastinal lymph nodes if it is technically dicult or very risky to biopsy a metastatic site.

PRINCIPLES OF DIAGNOSTIC EVALUATION

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-1

See Principles of Pathologic Review (NSCL-A).

Enhanced frailty or geriatric assessments may predict complications better

following treatment modalities, particularly surgery. A preferred frailty assessment

system has not been established.

Temel JS, et al. N Engl J Med 2010;363:733-742.

Based on the CT of the chest: Peripheral = outer third of lung; Central = inner two

thirds of lung.

T3, N0 related to size or satellite nodules.

For patients considered to have stage IIB and stage III tumors, where more than

one treatment modality (surgery, radiation therapy, or chemotherapy) is usually

considered, a multidisciplinary evaluation should be performed.

PATHOLOGIC

DIAGNOSIS

OF NSCLC

INITIAL EVALUATION CLINICAL STAGE

NSCLC

• Pathology review

• H&P (include performance

status + weight loss)

• CT chest and upper

abdomen with contrast,

including adrenals

• CBC, platelets

• Chemistry prole

• Smoking cessation advice,

counseling, and

pharmacotherapy

Use the 5 A’s Framework:

Ask, Advise, Assess,

Assist, Arrange

http://www.ahrq.gov/clinic/

tobacco/5steps.htm

• Integrate palliative care

(See NCCN Guidelines for

Palliative Care)

• For tools to aid in the

optimal assessment and

management of older adults,

see the NCCN Guidelines for

Older Adult Oncology

Stage IA, peripheral

(T1abc, N0)

Stage IVB (M1c)

disseminated metastases

Stage IB, peripheral

(T2a, N0);

Stage I, central

(T1abc–T2a, N0);

Stage II (T1abc–T2ab, N1; T2b, N0);

Stage IIB (T3, N0)

; Stage IIIA (T3, N1)

Stage IIB

(T3 invasion, N0);

Stage IIIA

(T4 extension, N0–1; T3, N1; T4, N0–1)

Stage IIIA

(T1–2, N2); Stage IIIB (T3, N2)

Separate pulmonary nodule(s) (Stage IIB, IIIA, IV)

Multiple lung cancers

Stage IIIB

(T1–2, N3); Stage IIIC (T3, N3)

Stage IIIB

(T4, N2); Stage IIIC (T4, N3)

Stage IVA (M1a)

(pleural or pericardial eusion)

Stage IVA (M1b)

See Pretreatment

Evaluation (NSCL-2)

See Pretreatment

Evaluation (NSCL-3)

See Pretreatment

Evaluation (NSCL-5)

See Pretreatment

Evaluation (NSCL-8)

See Pretreatment

Evaluation (NSCL-8)

See Treatment

(NSCL-10)

See Pretreatment

Evaluation (NSCL-12)

See Pretreatment

Evaluation (NSCL-13)

See Pretreatment

Evaluation (NSCL-13)

See Pretreatment

Evaluation (NSCL-14)

See Systemic

Therapy (NSCL-18)

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-2

Testing is not listed in order of priority and is dependent on clinical circumstances,

institutional processes, and judicious use of resources.

Methods for evaluation include mediastinoscopy, mediastinotomy, EBUS,

EUS, and CT-guided biopsy. An EBUS-TBNA negative for malignancy in a

clinically (PET and/or CT) positive mediastinum should undergo subsequent

mediastinoscopy prior to surgical resection.

There is low likelihood of positive mediastinal lymph nodes when these nodes are

CT and PET negative in solid tumors <1 cm and purely non-solid tumors <3 cm.

Thus, pre-resection pathologic mediastinal evaluation is optional in these settings.

PET/CT performed skull base to knees or whole body.

Positive PET/CT scan

findings for distant disease need pathologic or other radiologic confirmation. If

PET/CT scan is positive in the mediastinum, lymph node status needs pathologic

confirmation.

See Principles of Surgical Therapy (NSCL-B).

See Principles of Radiation Therapy (NSCL-C).

Image-guided thermal ablation therapy (eg, cryotherapy, microwave,

radiofrequency) may be an option for select patients not receiving SABR

or definitive RT. See Principles of Image-Guided Thermal Ablation Therapy

(NSCL-D).

If empiric therapy is contemplated without tissue confirmation, multidisciplinary

evaluation that at least includes interventional radiology, thoracic surgery, and

interventional pulmonology is required to determine the safest and most efficient

approach for biopsy, or to provide consensus that a biopsy is too risky or difficult

and that the patient can proceed with therapy without tissue confirmation.

(IJsseldijk MA, et al. J Thorac Oncol 2019;14:583-595.)

CLINICAL ASSESSMENT PRETREATMENT EVALUATION

INITIAL TREATMENT

Stage IA

(peripheral T1abc, N0)

• Pulmonary function tests

(PFTs) (if not previously

done)

• Bronchoscopy

(intraoperative preferred)

• Consider pathologic

mediastinal lymph node

evaluation

h,i

• FDG PET/CT scan

(if not

previously done)

Negative

mediastinal

nodes

Positive

mediastinal

nodes

Operable

Medically

inoperable

Surgical exploration

and resection

mediastinal lymph

node dissection or

systematic lymph

node sampling

Denitive RT, preferably

stereotactic ablative

radiotherapy (SABR)

l,m,n

See Stage IIIA/IIIB (NSCL-8)

or Stage IIIB/IIIC (NSCL-12)

See Adjuvant

Treatment

(NSCL-4)

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-3

CLINICAL ASSESSMENT PRETREATMENT EVALUATION

INITIAL TREATMENT

Stage IB (peripheral

T2a, N0)

Stage I (central

T1abc–T2a, N0)

Stage II (T1abc–2ab,

N1; T2b, N0)

Stage IIB (T3, N0)

Stage IIIA (T3, N1)

• PFTs (if not previously

done)

• Bronchoscopy

• Pathologic mediastinal

lymph node evaluation

• FDG PET/CT scan

(if

not previously done)

• Brain MRI with contrast

(Stage II, IIIA)

(Stage IB [optional])

Negative

mediastinal

nodes

Positive

mediastinal

nodes

Operable

Medically

inoperable

Surgical exploration

and resection

k,p,q

mediastinal lymph node

dissection or systematic

lymph node sampling

See Adjuvant

Treatment (NSCL-4)

Denitive RT,

preferably SABR

l,n

Denitive

chemoradiation

l,t

Consider adjuvant

chemotherapy

for

high-risk stages

IB–IIB

Durvalumab

t,u

(category 1 stage III;

category 2A stage II)

See Stage IIIA/IIIB (NSCL-8)

or Stage IIIB/IIIC (NSCL-12)

T3, N0 related to size or satellite nodules.

Testing is not listed in order of priority and is dependent on clinical circumstances,

institutional processes, and judicious use of resources.

Methods for evaluation include mediastinoscopy, mediastinotomy, EBUS,

EUS, and CT-guided biopsy. An EBUS-TBNA negative for malignancy in a

clinically (PET and/or CT) positive mediastinum should undergo subsequent

mediastinoscopy prior to surgical resection.

PET/CT performed skull base to knees or whole body.

Positive PET/CT scan

findings for distant disease need pathologic or other radiologic confirmation. If

PET/CT scan is positive in the mediastinum, lymph node status needs pathologic

confirmation.

See Principles of Surgical Therapy (NSCL-B).

See Principles of Radiation Therapy (NSCL-C).

If empiric therapy is contemplated without tissue confirmation, multidisciplinary

evaluation that at least includes interventional radiology, thoracic surgery, and

interventional pulmonology is required to determine the safest and most efficient

approach for biopsy, or to provide consensus that a biopsy is too risky or difficult

and that the patient can proceed with therapy without tissue confirmation.

(IJsseldijk MA, et al. J Thorac Oncol 2019;14:583-595.)

If MRI is not possible, CT of head with contrast.

After surgical evaluation, patients likely to receive adjuvant chemotherapy may be

treated with induction chemotherapy as an alternative.

Test for EGFR mutation on surgical tissue or biopsy in stages IB–IIIA.

See Systemic Therapy Regimens for Neoadjuvant and Adjuvant Therapy

(NSCL-E).

Examples of high-risk factors may include poorly differentiated tumors (including

lung neuroendocrine tumors [excluding well-differentiated neuroendocrine tumors]),

vascular invasion, wedge resection, tumors >4 cm, visceral pleural involvement,

and unknown lymph node status (Nx). These factors independently may not be

an indication and may be considered when determining treatment with adjuvant

chemotherapy.

See Concurrent Chemoradiation Regimens (NSCL-F).

Durvalumab is not recommended for patients following definitive surgical

resection.

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-4

See Principles of Radiation Therapy (NSCL-C).

See Systemic Therapy Regimens for Neoadjuvant and Adjuvant Therapy

(NSCL-E).

Examples of high-risk factors may include poorly differentiated tumors (including

lung neuroendocrine tumors [excluding well-differentiated neuroendocrine tumors]),

vascular invasion, wedge resection, tumors >4 cm, visceral pleural involvement,

and unknown lymph node status (Nx). These factors independently may not be

an indication and may be considered when determining treatment with adjuvant

chemotherapy.

See Concurrent Chemoradiation Regimens (NSCL-F).

R0 = no residual tumor, R1 = microscopic residual tumor, R2 = macroscopic

residual tumor.

For patients with EGFR mutation-positive NSCLC who received previous adjuvant

chemotherapy or are ineligible to receive platinum-based chemotherapy.

Increasing size is an important variable when evaluating the need for adjuvant

chemotherapy.

FINDINGS AT SURGERY ADJUVANT TREATMENT

Stage IA (T1abc, N0)

Margins negative (R0)

Margins positive (R1, R2)

Observe

Reresection (preferred)

(category 2B)

Surveillance

(NSCL-16)

Stage IB (T2a, N0)

Stage IIA (T2b, N0)

Stage IIB (T1abc–T2a, N1)

Stage IIB (T3, N0; T2b, N1)

Stage IIIA (T1–2, N2; T3, N1)

Stage IIIB (T3, N2)

Margins negative (R0)

Margins positive (R1, R2)

Margins negative (R0)

Margins positive

Margins negative (R0)

Margins positive

Observe

Chemotherapy

for high-risk patients

and osimertinib

Reresection (preferred) ± chemotherapy

r,x

± chemotherapy

(chemotherapy for stage IIA)

Chemotherapy

(category 1) and osimertinib

Reresection + chemotherapy

Chemoradiation

(sequential

or concurrent

)

Reresection + chemotherapy

Concurrent chemoradiation

l,t

Chemotherapy

(category 1) and osimertinib

Sequential chemotherapy

+ RT

(N2 only)

Chemoradiation

(sequential

or concurrent

)

Concurrent chemoradiation

l,t

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-5

CLINICAL

ASSESSMENT

PRETREATMENT EVALUATION CLINICAL EVALUATION

Stage IIB (T3 invasion, N0)

Stage IIIA (T4 extension,

N0–1; T3, N1; T4, N0–1)

• PFTs (if not previously done)

• Bronchoscopy

• Pathologic mediastinal lymph node

evaluation

• Brain MRI with contrast

• MRI with contrast of spine +

thoracic inlet for superior sulcus

lesions abutting the spine or

subclavian vessels

• FDG PET/CT scan

(if not previously

done)

Superior sulcus tumor

Chest wall

Proximal airway

or mediastinum

Unresectable disease

Metastatic disease

Methods for evaluation include mediastinoscopy, mediastinotomy, EBUS, EUS, and CT-guided biopsy. An EBUS-TBNA negative for malignancy in a clinically (PET

and/or CT) positive mediastinum should undergo subsequent mediastinoscopy prior to surgical resection.

PET/CT performed skull base to knees or whole body.

Positive PET/CT scan findings for distant disease need pathologic or other radiologic confirmation. If PET/CT

scan is positive in the mediastinum, lymph node status needs pathologic confirmation.

If MRI is not possible, CT of head with contrast.

See Treatment (NSCL-6)

See Treatment (NSCL-7)

See Treatment for Metastasis

limited sites (NSCL-14) or

distant disease (NSCL-17)

Stage IIIA (T4, N0–1) See Treatment (NSCL-7)

Positive mediastinal

nodes

See Stage IIIA/IIIB (NSCL-8)

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-6

See Principles of Surgical Therapy (NSCL-B).

See Principles of Radiation Therapy (NSCL-C).

Test for EGFR mutation on surgical tissue or biopsy in stages IB–IIIA.

See Systemic Therapy Regimens for Neoadjuvant and Adjuvant Therapy (NSCL-E).

See Concurrent Chemoradiation Regimens (NSCL-F).

Durvalumab is not recommended for patients following definitive surgical resection.

For patients with EGFR mutation-positive NSCLC who received previous adjuvant chemotherapy or are ineligible to receive platinum-based chemotherapy.

CLINICAL PRESENTATION INITIAL TREATMENT ADJUVANT TREATMENT

Superior

sulcus tumor

(T3 invasion,

N0–1)

Superior

sulcus tumor

(T4 extension,

N0–1)

Preoperative

concurrent

chemoradiation

l,t

Possibly

resectable

Unresectable

Preoperative

concurrent

chemoradiation

l,t

Denitive concurrent

chemoradiation

l,t

Surgical

reevaluation

including chest

CT with or without

contrast ± PET/CT

Resectable

Unresectable

Surgery

k,q

chemotherapy

and osimertinib

Surveillance

(NSCL-16)

Surveillance

(NSCL-16)

Complete denitive

chemoradiation

l,t

Surveillance

(NSCL-16)

Surveillance

(NSCL-16)

Durvalumab

t,u

(category 1)

Surgery

k,q

chemotherapy

and osimertinib

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-7

See Principles of Surgical Therapy (NSCL-B).

See Principles of Radiation Therapy (NSCL-C).

Test for EGFR mutation on surgical tissue or biopsy in stages IB–IIIA.

See Systemic Therapy Regimens for Neoadjuvant and Adjuvant Therapy (NSCL-E).

See Concurrent Chemoradiation Regimens (NSCL-F).

Durvalumab is not recommended for patients following definitive surgical resection.

R0 = no residual tumor, R1 = microscopic residual tumor, R2 = macroscopic residual tumor.

For patients with EGFR mutation-positive NSCLC who received previous adjuvant chemotherapy or are ineligible to receive platinum-based chemotherapy.

Consider RT boost if chemoradiation is given as initial treatment.

CLINICAL

PRESENTATION

INITIAL TREATMENT ADJUVANT TREATMENT

Chest wall,

proximal airway,

or mediastinum

(T3 invasion, N0–1

Resectable T4

extension, N0–1)

Surgery

k,q

(preferred)

Concurrent

chemoradiation

l,t

Chemotherapy

Margins

negative (R0)

Margins

positive

Surgery

Margins

negative (R0)

Margins positive

(R1, R2)

Chemotherapy

and osimertinib

Reresection + chemotherapy

Chemoradiation

(sequential

or concurrent

)

Reresection + chemotherapy

Concurrent chemoradiation

l,t

Observe

Reresection

Surveillance

(NSCL-16)

Surveillance

(NSCL-16)

Surveillance

(NSCL-16)

Surveillance

(NSCL-16)

Surveillance

(NSCL-16)

Stage IIIA (T4, N0–1)

Unresectable

Denitive concurrent

chemoradiation

l,t

(category 1)

Surveillance

(NSCL-16)

Stage IIIA (T4, N0–1)

Durvalumab

t,u

(category 1)

Surgical

reevaluation

including

chest CT ±

PET/CT

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-8

Methods for evaluation include mediastinoscopy, mediastinotomy, EBUS, EUS, and CT-guided biopsy. An EBUS-TBNA negative for malignancy in a clinically (PET

and/or CT) positive mediastinum should undergo subsequent mediastinoscopy prior to surgical resection.

PET/CT performed skull base to knees or whole body. Positive PET/CT scan findings for distant disease need pathologic or other radiologic confirmation. If PET/CT

scan is positive in the mediastinum, lymph node status needs pathologic confirmation.

If MRI is not possible, CT of head with contrast.

CLINICAL

ASSESSMENT

PRETREATMENT EVALUATION MEDIASTINAL BIOPSY FINDINGS

AND RESECTABILITY

Separate pulmonary

nodule(s)

(Stage IIB, IIIA, IV)

• PFTs (if not previously done)

• Bronchoscopy

• Pathologic mediastinal lymph node

evaluation

• FDG PET/CT scan

(if not previously

done)

• Brain MRI with contrast

• PFTs (if not previously done)

• Bronchoscopy

• Pathologic mediastinal lymph node

evaluation

• Brain MRI with contrast

• FDG PET/CT scan

(if not previously

done)

N2, N3 nodes negative

N2 nodes positive, M0

N3 nodes positive, M0

Metastatic disease

See Treatment

T1–3, N0–1 (NSCL-9)

See Treatment (NSCL-9)

See Stage IIIB (NSCL-12)

See Treatment for Metastasis

limited sites (NSCL-14) or

distant disease (NSCL-17)

Separate pulmonary

nodule(s), same lobe

(T3, N0–1) or ipsilateral

non-primary lobe (T4, N0–1)

Stage IVA (N0, M1a):

Contralateral lung

(solitary nodule)

Extrathoracic

metastatic disease

See Treatment (NSCL-10)

See Treatment for Metastasis

limited sites (NSCL-14) or

distant disease (NSCL-17)

Stage IIIA (T1–2, N2)

Stage IIIB (T3, N2)

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-9

See Principles of Surgical Therapy (NSCL-B).

See Principles of Radiation Therapy (NSCL-C).

After surgical evaluation, patients likely to receive adjuvant chemotherapy may be treated with induction chemotherapy as an alternative.

See Systemic Therapy Regimens for Neoadjuvant and Adjuvant Therapy (NSCL-E).

See Concurrent Chemoradiation Regimens (NSCL-F).

Durvalumab is not recommended for patients following definitive surgical resection.

Chest CT with contrast and/or PET/CT to evaluate progression.

MEDIASTINAL BIOPSY

FINDINGS

INITIAL TREATMENT ADJUVANT TREATMENT

T1–3, N0–1

(including T3

with multiple

nodules in

same lobe)

Resectable

k,p

Medically

inoperable

Surgical resection

+ mediastinal lymph

node dissection or

systematic lymph

node sampling

See Treatment according

to clinical stage (NSCL-3)

See Adjuvant Treatment (NSCL-4)

T1–2, T3

(other than

invasive),

N2 nodes

positive, M0

Denitive concurrent

chemoradiation

l,t

(category 1)

Induction

chemotherapy

r,z

± RT

No apparent

progression

Progression

Surgery

± RT

(if not given)

(if not given) ± chemotherapy

Local

Systemic

See Treatment for Metastasis

limited sites (NSCL-14) or

distant disease (NSCL-17)

(invasion),

N2 nodes

positive, M0

Denitive concurrent

chemoradiation

l,t

Surveillance

(NSCL-16)

Surveillance

(NSCL-16)

Durvalumab

t,u

(category 1)

Durvalumab

t,u

(category 1)

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-10

Methods for evaluation include mediastinoscopy, mediastinotomy, EBUS,

EUS, and CT-guided biopsy. An EBUS-TBNA negative for malignancy in a

clinically (PET and/or CT) positive mediastinum should undergo subsequent

mediastinoscopy prior to surgical resection.

PET/CT performed skull base to knees or whole body. Positive PET/CT scan

findings for distant disease need pathologic or other radiologic confirmation. If

PET/CT scan is positive in the mediastinum, lymph node status needs pathologic

confirmation.

See Principles of Surgical Therapy (NSCL-B).

See Principles of Radiation Therapy (NSCL-C).

If MRI is not possible, CT of head with contrast.

After surgical evaluation, patients likely to receive adjuvant chemotherapy may be

treated with induction chemotherapy as an alternative.

See Systemic Therapy Regimens for Neoadjuvant and Adjuvant Therapy (NSCL-E).

See Concurrent Chemoradiation Regimens (NSCL-F).

R0 = no residual tumor, R1 = microscopic residual tumor, R2 = macroscopic

residual tumor.

Lesions with different cell types (eg, squamous cell carcinoma, adenocarcinoma)

are usually different primary tumors. This analysis may be limited by small biopsy

samples. However, lesions of the same cell type are not necessarily metastases.

Single contralateral lung nodules with clinical, radiologic, or pathologic features

suggestive of a synchronous primary lung cancer (eg, long disease-free survival,

ground glass components, different histologic characteristics) that are amenable

to local therapy should be considered as probable separate primary cancers and

eligible for local therapy, see NSCL-11.

For guidance regarding the evaluation, workup, and management of subsolid

pulmonary nodules, please see the diagnostic evaluation of a nodule suspicious

for lung cancer (DIAG-1).

CLINICAL PRESENTATION ADJUVANT TREATMENT

Separate pulmonary

nodule(s), same lobe

(T3, N0–1), or

ipsilateral non-primary

lobe (T4, N0–1)

Stage IVA (N0, M1a):

Contralateral lung

(solitary nodule)

Suspected multiple

lung cancers (based on

the presence of biopsy-

proven synchronous

lesions or history of

lung cancer)

aa,bb

Surgery

k,p

Treat as two primary lung

tumors if both curable

• Chest CT with

contrast

• FDG PET/CT scan

(if not previously

done)

• Brain MRI with

contrast

N0–1

Chemotherapy

Surveillance

(NSCL-16)

Margins negative

(R0)

Margins

positive

Chemotherapy

(category 1)

Sequential chemotherapy

+ RT

Surveillance

(NSCL-16)

Chemoradiation

(sequential

or concurrent

)

Concurrent

chemoradiation

l,t

Surveillance

(NSCL-16)

Surveillance

(NSCL-16)

See Evaluation (NSCL-1)

Disease

outside

of chest

No disease

outside of

chest

See Systemic Therapy for Metastatic Disease (NSCL-18)

Pathologic

mediastinal

lymph node

evaluation

N2–3

N0–1

See Systemic Therapy

for Metastatic Disease

(NSCL-18)

See Initial Treatment

(NSCL-11)

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-11

See Principles of Surgical Therapy (NSCL-B).

See Principles of Radiation Therapy (NSCL-C).

Image-guided thermal ablation therapy (eg, cryotherapy, microwave, radiofrequency) may be an option for select patients not receiving SABR or definitive RT. See

Principles of Image-Guided Thermal Ablation Therapy (NSCL-D).

Lesions at low risk of becoming symptomatic can be observed (eg, small subsolid nodules with slow growth). However, if the lesion(s) becomes symptomatic or

becomes high risk for producing symptoms (eg, subsolid nodules with accelerating growth or increasing solid component or increasing FDG uptake, even while small),

treatment should be considered.

Lung-sparing resection is preferred, but tumor distribution and institutional expertise should guide individual treatment planning. Patients should be evaluated in a

multidisciplinary setting (ie, surgery, radiation oncology, medical oncology, interventional oncology).

CLINICAL

PRESENTATION

INITIAL TREATMENT

Multiple lung

cancers (N0–1)

Asymptomatic

Symptomatic

Multiple

lesions

Solitary lesion

(metachronous

disease)

Low risk of

becoming

symptomatic

High risk of

becoming

symptomatic

Observation

Surveillance

(NSCL-16)

Denitive

local therapy

possible

Denitive

local therapy

not possible

Parenchymal sparing

resection (preferred)

k,dd

Radiation

Image-guided thermal

ablation (IGTA)

Palliative

chemotherapy ± local

palliative therapy

Observe

See Systemic Therapy

for Metastatic Disease

(NSCL-18)

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-12

PET/CT performed skull base to knees or whole body. Positive PET/CT scan findings for distant disease need pathologic or other radiologic confirmation. If PET/CT

scan is positive in the mediastinum, lymph node status needs pathologic confirmation.

See Principles of Radiation Therapy (NSCL-C).

If MRI is not possible, CT of head with contrast.

See Concurrent Chemoradiation Regimens (NSCL-F).

Durvalumab is not recommended for patients following definitive surgical resection.

CLINICAL

ASSESSMENT

PRETREATMENT EVALUATION INITIAL TREATMENT

Stage IIIB

(T1–2, N3)

Stage IIIC

(T3, N3)

• PFTs (if not previously

done)

• FDG PET/CT scan

(if

not previously done)

• Brain MRI with contrast

• Pathologic conrmation

of N3 disease by:

Mediastinoscopy

Supraclavicular lymph

node biopsy

Thoracoscopy

Needle biopsy

Mediastinotomy

EUS biopsy

EBUS biopsy

N3 negative

N3 positive

Metastatic disease

See Initial treatment for stage I–IIIA (NSCL-9)

Denitive concurrent

chemoradiation

l,t

(category 1)

See Treatment for Metastasis

limited sites (NSCL-14) or

distant disease (NSCL-17)

Surveillance

(NSCL-16)

Durvalumab

t,u

(category 1)

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-13

PET/CT performed skull base to knees or whole body. Positive PET/CT scan

findings for distant disease need pathologic or other radiologic confirmation. If

PET/CT scan is positive in the mediastinum, lymph node status needs pathologic

confirmation.

See Principles of Radiation Therapy (NSCL-C).

If MRI is not possible, CT of head with contrast.

See Concurrent Chemoradiation Regimens (NSCL-F).

Durvalumab is not recommended for patients following definitive surgical

resection.

Most pleural (pericardial) effusions with lung cancer are a result of the tumor. In

a few patients, however, multiple microscopic examinations of pleural (pericardial)

fluid are negative for tumor, and fluid is non-bloody and not an exudate. If these

elements and clinical judgment dictate that the effusion is not related to the tumor,

the effusion should be excluded as a staging descriptor.

CLINICAL

ASSESSMENT

PRETREATMENT EVALUATION INITIAL TREATMENT

Stage IIIB

(T4, N2)

Stage IIIC

(T4, N3)

Stage IVA,

M1a: pleural

or pericardial

eusion

• FDG PET/CT scan

(if not

previously done)

• Brain MRI with contrast

• Pathologic conrmation

of N2–3 disease by either:

Mediastinoscopy

Supraclavicular lymph

node biopsy

Thoracoscopy

Needle biopsy

Mediastinotomy

EUS biopsy

EBUS biopsy

• FDG PET/CT scan

(if not

previously done)

• Brain MRI with contrast

• Molecular testing

(as per NSCL-18)

• Thoracentesis or

pericardiocentesis ±

thoracoscopy if thoracentesis

indeterminate

Negative

Positive

Local therapy if necessary (eg,

pleurodesis, ambulatory small catheter

drainage, pericardial window) +

treatment for stage IV disease solitary

site or distant disease (NSCL-18)

See Treatment according to TNM stage

Contralateral

mediastinal

node negative

Contralateral

mediastinal

node positive

(T4, N3)

Metastatic disease

Ipsilateral

mediastinal

node negative

(T4, N0–1)

Ipsilateral

mediastinal

node positive

(T4, N2)

See Treatment for Stage IIIA (NSCL-7)

Denitive

concurrent

chemoradiation

l,t

(category 1)

Denitive concurrent

chemoradiation

l,t

(category 1)

See Treatment for Metastasis

limited sites (NSCL-14) or

distant disease (NSCL-17)

Surveillance

(NSCL-16)

Durvalumab

t,u

(category 1)

Durvalumab

t,u

(category 1)

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-14

PET/CT performed skull base to knees or whole body. Positive PET/CT scan findings for distant disease need pathologic or other radiologic confirmation. If PET/CT

scan is positive in the mediastinum, lymph node status needs pathologic confirmation.

If MRI is not possible, CT of head with contrast.

Including selected patients with stage M1c and limited number and volume of metastatic lesions amenable to definitive local therapy. Limited number is undefined but

clinical trials have included 3 to 5 metastases.

See NCCN Guidelines for Central Nervous System Cancers.

CLINICAL

ASSESSMENT

Stage IVA,

M1b



• Molecular testing

(as per NSCL-18)

If not previously done

• Brain MRI with

contrast

• FDG PET/CT scan

• Pathologic

conrmation of

metastatic lesion, if

possible

Limited

metastases

conrmed

Multiple

metastases

See Systemic Therapy for

Metastatic Disease (NSCL-18)

PRETREATMENT EVALUATION

INITIAL TREATMENT

Stereotactic radiosurgery

(SRS) alone

Surgical resection,

if symptomatic or

warranted for diagnosis,

followed by SRS or whole

brain RT (WBRT)

See Treatment of

Thoracic Disease

(NSCL-15)

Brain

Other site

See Treatment of

Thoracic Disease

(NSCL-15)

PS 0–2

PS 3–4

See Systemic Therapy for

Metastatic Disease (NSCL-18)

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-15

T1–3, N0

• Pathologic

mediastinal nodal

evaluation

and

• Surgical resection

or SABR

l,m

Consider systemic

therapy, if not

already given

(NSCL-18)

Denitive local

therapy for

metastatic site,

not already given

Methods for evaluation include mediastinoscopy, mediastinotomy, EBUS,

EUS, and CT-guided biopsy. An EBUS-TBNA negative for malignancy in a

clinically (PET and/or CT) positive mediastinum should undergo subsequent

mediastinoscopy prior to surgical resection.

See Principles of Surgical Therapy (NSCL-B).

See Principles of Radiation Therapy (NSCL-C).

Image-guided thermal ablation therapy (eg, cryotherapy, microwave,

radiofrequency) may be an option for select patients not receiving SABR

or definitive RT. See Principles of Image-Guided Thermal Ablation Therapy

(NSCL-D).

See Concurrent Chemoradiation Regimens (NSCL-F).

Chest CT with contrast and/or PET/CT to evaluate progression.

Typically, RT (including SABR) or surgical resection.

Image-guided thermal

ablation therapy (eg, cryotherapy, microwave, radiofrequency) may be an option

for select patients not receiving RT or surgery.

TREATMENT OF THORACIC DISEASE

Denitive therapy

for thoracic disease

not feasible

Denitive therapy

for thoracic

disease feasible

See Systemic Therapy

for Metastatic Disease

(NSCL-18)

T1–3, N1

T1–3, N2

T4, N0–2

• Pathologic

mediastinal nodal

evaluation

and

• Chemoradiation

(preferred) or

Surgical resection

or Denitive RT

Denitive

chemoradiation

Consider systemic

therapy (NSCL-18)

and restaging

to conrm non-

progression

Proceed to

denitive therapy

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-16

If MRI is not possible, CT of head with contrast.

Timing of CT scans within Guidelines parameters is a clinical decision.

FDG PET/CT is currently not warranted in the routine surveillance and follow-up of patients with NSCLC. However, many benign conditions (such as atelectasis,

consolidation, and radiation fibrosis) are difficult to differentiate from neoplasm on standard CT imaging, and FDG PET/CT can be used to differentiate true malignancy

in these settings. However, if FDG PET/CT is to be used as a problem-solving tool in patients after radiation therapy, histopathologic confirmation of recurrent disease

is needed because areas previously treated with radiation therapy can remain FDG avid for up to 2 years.

No evidence of clinical/radiographic disease

• Stage I–II (primary treatment included surgery

± chemotherapy)

H&P and chest CT ± contrast every 6 mo

for 2–3 y, then H&P and a low-dose non–

contrast-enhanced chest CT annually

• Stage I–II (primary treatment included RT) or

stage III or stage IV (oligometastatic with all

sites treated with denitive intent)

H&P and chest CT

± contrast every 3–6 mo

for 3 y, then H&P and chest CT ± contrast

every 6 mo for 2 y, then H&P and a low-dose

non–contrast-enhanced chest CT annually

◊ Residual or new radiographic

abnormalities may require more frequent

imaging

• Smoking cessation advice, counseling, and

pharmacotherapy

• PET/CT

or brain MRI is not routinely

indicated

• See Cancer Survivorship Care (NSCL-G)

Locoregional

recurrence

Distant

metastases

See Therapy for Recurrence

and Metastasis (NSCL-17)

SURVEILLANCE AFTER COMPLETION

OF DEFINITIVE THERAPY

See Therapy for Recurrence

and Metastasis (NSCL-17)

Recurrence

• PET/CT

• Brain

MRI with

contrast

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-17

See Principles of Surgical Therapy (NSCL-B).

See Principles of Radiation Therapy (NSCL-C).

Image-guided thermal ablation therapy (eg, cryotherapy, microwave,

radiofrequency) may be an option for select patients not receiving SABR

or definitive RT. See Principles of Image-Guided Thermal Ablation Therapy

(NSCL-D).

If MRI is not possible, CT of head with contrast.

See Concurrent Chemoradiation Regimens (NSCL-F).

See NCCN Guidelines for Central Nervous System Cancers.

Locoregional

recurrence or

symptomatic

local disease

Distant

metastases

THERAPY FOR RECURRENCE AND METASTASIS

Endobronchial

obstruction

Resectable recurrence

Mediastinal lymph

node recurrence

Superior vena cava

(SVC) obstruction

Severe hemoptysis

No prior RT

Prior RT

Any combination of the following:

• Laser/stent/other surgery

• External-beam RT or brachytherapy

• Photodynamic therapy

• Reresection (preferred)

• External-beam RT or SABR

l,m

Concurrent chemoradiation

l,t

Systemic therapy (NSCL-18)

• Concurrent chemoradiation

l,t

(if not previously given) ± SVC stent

• External-beam RT

± SVC stent

• SVC stent

Any combination of the following:

• External-beam RT or brachytherapy

• Laser or photodynamic therapy or

embolization

• Surgery

No evidence

disseminated

disease

Evidence of

disseminated

disease

Observation

Systemic

therapy

(NSCL-18)

(category 2B)

See Systemic

Therapy for

Metastatic

Disease

(NSCL-18)

Localized symptoms Palliative external-beam RT

Diuse brain metastases

Bone metastasis

Limited metastasis

Disseminated metastases

Palliative external-beam RT

l,gg

• If risk of fracture, orthopedic stabilization +

palliative external-beam RT

• Consider bisphosphonate therapy or denosumab

See pathway for Stage IV, M1b (NSCL-14)

See Systemic Therapy for Metastatic Disease (NSCL-18)

• Chest

CT with

contrast

• Brain

MRI with

contrast

• PET/CT

See Systemic

Therapy for

Metastatic

Disease

(NSCL-18)

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-18

HISTOLOGIC

SUBTYPE

Advanced

metastatic

disease

• Establish histologic

subtype

with

adequate tissue for

molecular testing

(consider rebiopsy

if appropriate)

• Smoking cessation

counseling

• Integrate palliative

care

(See NCCN

Guidelines for

Palliative Care)

• Adenocarcinoma

• Large cell

• NSCLC not

otherwise

specied (NOS)

Squamous cell

carcinoma

• Molecular testing, including:

EGFR mutation (category 1), ALK (category 1),

KRAS, ROS1, BRAF, NTRK1/2/3, METex14

skipping, RET

Testing should be conducted as part of broad

molecular proling

• PD-L1 testing

(category 1)

• Consider molecular testing, including:

EGFR mutation, ALK,

KRAS, ROS1, BRAF,

NTRK1/2/3, MET exon 14 skipping, RET

Testing should be conducted as part of

broad molecular proling

• PD-L1 testing

(category 1)

BIOMARKER TESTING

CLINICAL PRESENTATION

See Testing

Results

(NSCL-19)

See Testing

Results

(NSCL-19)

See Principles of Pathologic Review (NSCL-A).

Temel JS, et al. N Engl J Med 2010;363:733-742.

If there is insufficient tissue to allow testing for all of EGFR, KRAS, ALK, ROS1,

BRAF, NTRK1/2/3, MET, and RET, repeat biopsy and/or plasma testing should

be done. If these are not feasible, treatment is guided by available results

and, if unknown, these patients are treated as though they do not have driver

oncogenes.

See Principles of Molecular and Biomarker Analysis (NSCL-H).

The NCCN NSCLC Guidelines Panel strongly advises broader molecular

profiling with the goal of identifying rare driver mutations for which effective

drugs may already be available, or to appropriately counsel patients regarding

the availability of clinical trials. Broad molecular profiling is a key component of

the improvement of care of patients with NSCLC. See Emerging Biomarkers to

Identify Patients for Therapies (NSCL-I).

Lam VK, et al. Clin Lung Cancer 2019;20:30-36.e3; Sands JM, et al. Lung

Cancer 2020;140:35-41.

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

TESTING RESULTS

kk,ll

EGFR mutation positive (eg, exon 19 deletion or L858R) NSCL-20

EGFR exon 20 insertion mutation positive

NSCL-23

KRAS G12C mutation positive

NSCL-24

ALK rearrangement positive

NSCL-25

ROS1 rearrangement positive

NSCL-28

BRAF V600E mutation positive

NSCL-29

NTRK1/2/3 gene fusion positive

NSCL-30

METex14 skipping mutation positive

NSCL-31

RET rearrangement positive

NSCL-32

PD-L1 ≥50%

and negative for actionable molecular markers above NSCL-33

PD-L1 ≥1%–49%

and negative for actionable molecular markers above NSCL-34

PD-L1 <1% and negative for actionable molecular markers above

NSCL-35

If there is insufficient tissue to allow testing for all of EGFR, KRAS, ALK, ROS1, BRAF, NTRK1/2/3, MET, and RET, repeat biopsy and/or plasma testing should be

done. If these are not feasible, treatment is guided by available results and, if unknown, these patients are treated as though they do not have driver oncogenes.

See Principles of Molecular and Biomarker Analysis (NSCL-H).

NSCL-19

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-20

See Principles of Molecular and Biomarker Analysis (NSCL-H).

See Targeted Therapy or Immunotherapy for Advanced or Metastatic Disease (NSCL-J).

For performance status 0–4.

If systemic therapy regimen contains an immune checkpoint inhibitor, physicians should be aware of the long half-life of such drugs and data reporting adverse events

when combining checkpoint inhibitors with osimertinib. Schoenfeld AJ, et al. Ann Oncol 2019;30:839-844; Oshima Y, et al. JAMA Oncol 2018;4:1112-1115; Oxnard GR,

et al. Ann Oncol 2020;31:507-516.

Criteria for treatment with bevacizumab: non-squamous NSCLC, and no recent history of hemoptysis.

An FDA-approved biosimilar is an appropriate substitute for bevacizumab.

FIRST-LINE THERAPY

EGFR

mutation

positive

(eg, exon 19

deletion or

L858R)

EGFR mutation

discovered

prior to rst-line

systemic therapy

EGFR mutation

discovered during

rst-line systemic

therapy

Preferred

Osimertinib

(category 1)

Other Recommended

Erlotinib

(category 1)

or Afatinib

(category 1)

or Getinib

(category 1)

or Dacomitinib

(category 1)

or Erlotinib + ramucirumab

or Erlotinib + bevacizumab

rr,ss

Complete planned systemic

therapy,

including

maintenance therapy,

or interrupt, followed by

osimertinib (preferred)

erlotinib or afatinib or getinib

or dacomitinib or erlotinib +

ramucirumab or erlotinib +

bevacizumab

rr,ss

Progression

See Subsequent

Therapy (NSCL-22)

Progression

See Subsequent

Therapy (NSCL-22)

Progression

See Subsequent

Therapy (NSCL-21)

See Subsequent

Therapy (NSCL-21)

EGFR MUTATION POSITIVE

(eg, EXON 19 DELETION OR L858R)

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

Image-guided thermal ablation therapy (eg, cryotherapy, microwave, radiofrequency) may be an option for select patients not receiving SABR or definitive RT. See

Principles of Image-Guided Thermal Ablation Therapy (NSCL-D).

See Principles of Molecular and Biomarker Analysis (NSCL-H).

See Targeted Therapy or Immunotherapy for Advanced or Metastatic Disease (NSCL-J).

Beware of flare phenomenon in subset of patients who discontinue TKI. If disease flare occurs, restart TKI.

Limited number is undefined but clinical trials have included 3 to 5 metastases.

Consider a biopsy at time of progression to rule out SCLC transformation.

Afatinib + cetuximab may be considered in patients with disease progression on EGFR TKI therapy.

The data in the second-line setting suggest that PD-1/PD-L1 inhibitor monotherapy is less effective, irrespective of PD-L1 expression, in EGFR+/ALK+ NSCLC.

SUBSEQUENT THERAPY

Progression on

osimertinib

Symptomatic

Asymptomatic

Brain

Systemic

Limited

metastases

Multiple

lesions

• Consider denitive local therapy (eg,

SRS) for limited lesions

• Continue osimertinib

• See NCCN Guidelines for CNS Cancers

See Initial systemic therapy options

ww,xx

Adenocarcinoma (NSCL-K 1 of 5) or

Squamous Cell Carcinoma (NSCL-K 2 of 5)

• Consider denitive local therapy (eg,

SABR or surgery) for limited lesions

m,uu

• Continue osimertinib

• Consider denitive local therapy (eg,

SABR or surgery)

• Continue osimertinib

• See subsequent therapy for multiple

lesions, noted below

NSCL-21

Progression, see

therapy for multiple

lesions,

ww,xx

noted below

EGFR MUTATION POSITIVE

(eg, EXON 19 DELETION OR L858R)

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-22

Image-guided thermal ablation therapy (eg, cryotherapy, microwave, radiofrequency)

may be an option for select patients not receiving SABR or definitive RT.

See Principles of Image-Guided Thermal Ablation Therapy (NSCL-D).

See Principles of Molecular and Biomarker Analysis (NSCL-H).

See Targeted Therapy

or Immunotherapy

for Advanced or Metastatic Disease (NSCL-J).

For performance status 0–4.

Criteria for treatment with bevacizumab: non-squamous NSCLC, and no recent history

of hemoptysis.

Beware of flare phenomenon in subset of patients who discontinue TKI. If disease flare

occurs, restart TKI.

Limited number is undefined but clinical trials have included 3 to 5 metastases.

Consider a biopsy at time of progression to rule out SCLC transformation.

Afatinib + cetuximab may be considered in patients with disease progression on EGFR

TKI therapy.

The data in the second-line setting suggest that PD-1/PD-L1 inhibitor monotherapy is

less effective, irrespective of PD-L1 expression, in EGFR+/ALK+ NSCLC.

Plasma-based testing should be considered at progression on EGFR TKIs for the T790M

mutation. If plasma-based testing is negative, tissue-based testing with rebiopsy material

is strongly recommended. Practitioners may want to consider scheduling the biopsy

concurrently with plasma testing referral.

Consider osimertinib (regardless of T790M status) for progressive CNS disease or

leptomeningeal disease. In the Bloom study, osimertinib was used at 160 mg for patients

with leptomeningeal disease.

aaa

In the randomized phase III trial of dacomitinib, patients with brain metastases were not

eligible for enrollment. In the setting of brain metastases, consider other options.

SUBSEQUENT THERAPY

Progression

on erlotinib ±

(ramucirumab

bevacizumab),

afatinib,

getinib, or

dacomitinib

Symptomatic

Asymptomatic

Brain

Systemic

Multiple lesions

vv,zz

• Consider denitive local therapy (eg, SRS) for limited

lesions

• Osimertinib

(if T790M+) (category 1)

Continue erlotinib ± (ramucirumab or bevacizumab

)

or afatinib or getinib or dacomitinib

aaa

• See NCCN Guidelines for CNS Cancers

• Consider denitive local therapy (eg, SABR or surgery)

for limited lesions

m,uu

• Osimertinib

(if T790M+) (category 1)

Continue erlotinib ± (ramucirumab or bevacizumab

)

or afatinib or getinib or dacomitinib

T790M

testing

• Consider denitive local therapy (eg, SABR or surgery)

• Continue erlotinib ± (ramucirumab or bevacizumab

)

or afatinib or getinib or dacomitinib

• See subsequent therapy for multiple lesions below

Osimertinib

(category 1)

(if not previously given)

T790M+

T790M-

See Initial systemic therapy options

ww,xx

Adenocarcinoma (NSCL-K 1 of 5) or

Squamous Cell Carcinoma (NSCL-K 2 of 5)

Progression, see (NSCL-21)

Progression, see

therapy

ww,xx

for

multiple lesions,

noted below

Progression, see

therapy

ww,xx

for

multiple lesions,

noted below

Progression, see

therapy

ww,xx

for

multiple lesions,

noted below

Progression, see (NSCL-21)

Progression,

see (NSCL-21)

Limited

metastases

EGFR MUTATION POSITIVE

(eg, EXON 19 DELETION OR L858R)

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

EGFR exon

20 insertion

mutation

positive

See Principles of Molecular and Biomarker Analysis (NSCL-H).

See Targeted Therapy or Immunotherapy for Advanced or Metastatic Disease (NSCL-J).

For performance status 0–2. Best supportive care for PS 3-4.

bbb

Monitoring During Initial Therapy: Response assessment after 2 cycles, then every 2–4 cycles with CT of known sites of disease with or without contrast or when

clinically indicated. Timing of CT scans within Guidelines parameters is a clinical decision.

ccc

In general, 4 cycles of initial systemic therapy (ie, with carboplatin or cisplatin) are administered prior to maintenance therapy. However, if patient is tolerating therapy

well, consideration can be given to continue to 6 cycles.

ddd

Monitoring During Subsequent Therapy: Response assessment with CT of known sites of disease with or without contrast every 6–12 weeks. Timing of CT scans

within Guidelines parameters is a clinical decision.

Amivantamab-vmjw

See Initial

systemic therapy

options

Adenocarcinoma

(NSCL-K 1 of 5) or

Squamous Cell

Carcinoma

(NSCL-K 2 of 5)

FIRST-LINE THERAPY

bbb

NSCL-23

EGFR EXON 20 INSERTION MUTATION POSITIVE

SUBSEQUENT THERAPY

PS 0–2

PS 3–4

Subsequent systemic

therapy

ddd

(NSCL-K 4 of 5)

Best supportive care

See NCCN Guidelines

for Palliative Care

Progression

Tumor

response

evaluation

Progression

Response

or stable

disease

4–6

cycles

(total)

ccc

Progression

Response

or stable

disease

Maintenance

therapy

(NSCL-K 3 of 5)

Tumor

response

evaluation

Amivantamab-vmjw

Progression

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-24

KRAS G12C

mutation

positive

See Principles of Molecular and Biomarker Analysis (NSCL-H).

See Targeted Therapy or Immunotherapy for Advanced or Metastatic Disease (NSCL-J).

For performance status 0–2. Best supportive care for PS 3-4.

bbb

Monitoring During Initial Therapy: Response assessment after 2 cycles, then every 2–4 cycles with CT of known sites of disease with or without contrast or when

clinically indicated. Timing of CT scans within Guidelines parameters is a clinical decision.

ccc

In general, 4 cycles of initial systemic therapy (ie, with carboplatin or cisplatin) are administered prior to maintenance therapy. However, if patient is tolerating therapy

well, consideration can be given to continue to 6 cycles.

ddd

Monitoring During Subsequent Therapy: Response assessment with CT of known sites of disease with or without contrast every 6–12 weeks. Timing of CT scans

within Guidelines parameters is a clinical decision.

See Initial

systemic therapy

options

Adenocarcinoma

(NSCL-K 1 of 5) or

Squamous Cell

Carcinoma

(NSCL-K 2 of 5)

FIRST-LINE THERAPY

bbb

KRAS G12C MUTATION POSITIVE

SUBSEQUENT THERAPY

PS 0–2

PS 3–4

Subsequent systemic

therapy

ddd

(NSCL-K 4 of 5)

Best supportive care

See NCCN Guidelines

for Palliative Care

Progression

Tumor

response

evaluation

Progression

Response

or stable

disease

4–6

cycles

(total)

ccc

Progression

Response

or stable

disease

Maintenance

therapy

(NSCL-K 3 of 5)

Tumor

response

evaluation

Sotorasib

Progression

Sotorasib

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-25

See Principles of Molecular and Biomarker Analysis (NSCL-H).

See Targeted Therapy or Immunotherapy for Advanced or Metastatic Disease (NSCL-J).

For performance status 0–4.

ALK REARRANGEMENT POSITIVE

FIRST-LINE THERAPY

ALK

rearrangement

positive

ALK rearrangement

discovered prior to

rst-line systemic

therapy

ALK rearrangement

discovered during

rst-line systemic

therapy

Preferred

Alectinib

(category 1)

Brigatinib

(category 1)

Lorlatinib

(category 1)

Other Recommended

Ceritinib

(category 1)

Useful in Certain

Circumstances

Crizotinib

(category 1)

Complete planned

systemic therapy,

including maintenance

therapy, or interrupt,

followed by alectinib

(preferred) or brigatinib

(preferred) or lorlatinib

(preferred) or ceritinib

crizotinib

Progression

See Subsequent

Therapy (NSCL-27)

See Subsequent

Therapy (NSCL-26)

See Subsequent

Therapy (NSCL-27)

See Subsequent

Therapy (NSCL-26)

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-26

Progression

on alectinib

or brigatinib

or ceritinib or

lorlatinib

Symptomatic

Asymptomatic

• Consider denitive local therapy (eg,

SABR or surgery) for limited lesions

m,uu

• Continue alectinib or brigatinib or

ceritinib or lorlatinib

Brain

Systemic

• Consider denitive local therapy

(eg, SRS) for limited lesions

• Continue alectinib or brigatinib or

ceritinib or lorlatinib

• See NCCN Guidelines for CNS Cancers

Multiple lesions

• Consider denitive local therapy

(eg, SABR or surgery)

• Continue alectinib or brigatinib or

ceritinib or lorlatinib

Lorlatinib (if not previously given)

See Initial systemic therapy options

for

Adenocarcinoma (NSCL-K 1 of 5) or

Squamous Cell Carcinoma (NSCL-K 2 of 5)

Image-guided thermal ablation therapy (eg, cryotherapy, microwave, radiofrequency) may be an option for select patients not receiving SABR or definitive RT. See

Principles of Image-Guided Thermal Ablation Therapy (NSCL-D).

See Principles of Molecular and Biomarker Analysis (NSCL-H).

See Targeted Therapy or Immunotherapy for Advanced or Metastatic Disease (NSCL-J).

Beware of flare phenomenon in subset of patients who discontinue TKI. If disease flare occurs, restart TKI.

Limited number is undefined but clinical trials have included 3 to 5 metastases.

The data in the second-line setting suggest that PD-1/PD-L1 inhibitor monotherapy is less effective, irrespective of PD-L1 expression, in EGFR+/ALK+ NSCLC.

SUBSEQUENT THERAPY

ALK REARRANGEMENT POSITIVE

Progression,

Lorlatinib (if not

previously given) or

See Initial systemic

therapy options

Adenocarcinoma

(NSCL-K 1 of 5) or

Squamous Cell

Carcinoma

(NSCL-K 2 of 5)

Limited

metastases

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-27

SUBSEQUENT THERAPY

Progression on

crizotinib

tt,eee

ALK REARRANGEMENT POSITIVE

Progression,

Lorlatinib

ggg

See Initial systemic

therapy options

Adenocarcinoma

(NSCL-K 1 of 5) or

Squamous Cell

Carcinoma

(NSCL-K 2 of 5)

Symptomatic

Asymptomatic

• Consider denitive local therapy (eg, SABR

or surgery) for limited lesions

m,uu

• Continue crizotinib

Alectinib

pp,ccc

or brigatinib

pp,f

or ceritinib

pp,f

Brain

Systemic

• Consider denitive local therapy (eg, SRS)

for limited lesions

• Alectinib

pp,f

or brigatinib

pp,f

or ceritinib

pp,f

• See NCCN Guidelines for CNS Cancers

Multiple lesions

• Consider denitive local therapy (eg, SABR

or surgery)

• Continue crizotinib

• Alectinib

pp,f

or brigatinib

pp,f

or ceritinib

pp,f

• See Initial systemic therapy options

Adenocarcinoma (NSCL-K 1 of 5) or

Squamous Cell Carcinoma (NSCL-K 2 of 5)

Image-guided thermal ablation therapy (eg, cryotherapy, microwave,

radiofrequency) may be an option for select patients not receiving SABR or

definitive RT.

See Principles of Image-Guided Thermal Ablation Therapy (NSCL-D).

See Principles of Molecular and Biomarker Analysis (NSCL-H).

See Targeted Therapy or Immunotherapy for Advanced or Metastatic Disease

(NSCL-J).

For performance status 0–4.

Beware of flare phenomenon in subset of patients who discontinue TKI. If disease

flare occurs, restart TKI.

Limited number is undefined but clinical trials have included 3 to 5 metastases.

The data in the second-line setting suggest that PD-1/PD-L1 inhibitor

monotherapy is less effective, irrespective of PD-L1 expression, in EGFR+/ALK+

NSCLC.

eee

Patients who are intolerant to crizotinib may be switched to ceritinib, alectinib,

or brigatinib.

fff

Ceritinib, alectinib, or brigatinib are treatment options for patients with ALK-

positive metastatic NSCLC that has progressed on crizotinib.

ggg

Lorlatinib is a treatment option after progression on crizotinib and either

alectinib, brigatinib, or ceritinib.

Limited

metastases

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-28

ROS1 REARRANGEMENT POSITIVE

FIRST-LINE THERAPY

SUBSEQUENT THERAPY

See Principles of Molecular and Biomarker Analysis (NSCL-H).

See Targeted Therapy or Immunotherapy for Advanced or Metastatic Disease (NSCL-J).

For performance status 0–4.

Beware of flare phenomenon in subset of patients who discontinue TKI. If disease flare occurs, restart TKI.

hhh

Entrectinib may be better for patients with brain metastases.

iii

Entrectinib is primarily for patients with CNS progression after crizotinib.

ROS1

rearrangement

positive

Preferred

Entrectinib

pp,hhh

Crizotinib

Other Recommended

Ceritinib

Progression

Lorlatinib

Entrectinib

iiif

See Initial systemic therapy options

Adenocarcinoma (NSCL-K 1 of 5) or

Squamous Cell Carcinoma

(NSCL-K 2 of 5)

ROS1 rearrangement

discovered prior to

rst-line systemic

therapy

ROS1 rearrangement

discovered during

rst-line systemic

therapy

Complete planned

systemic therapy, including

maintenance therapy,

or interrupt, followed by

crizotinib (preferred) or

entrectinib

hhh

(preferred)

or ceritinib

Lorlatinib

Entrectinib

iii

See Initial systemic therapy options

Adenocarcinoma (NSCL-K 1 of 5) or

Squamous Cell Carcinoma

(NSCL-K 2 of 5)

Progression

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-29

BRAF V600E MUTATION POSITIVE

FIRST-LINE THERAPY

SUBSEQUENT THERAPY

BRAF V600E

mutation

positive

Preferred

Dabrafenib + trametinib

Useful in Certain Circumstances

Vemurafenib

jjj

See Initial systemic therapy options

Adenocarcinoma (NSCL-K 1 of 5) or

Squamous Cell Carcinoma

(NSCL-K 2 of 5)

Progression

See Initial systemic therapy

options

Adenocarcinoma

(NSCL-K 1 of 5) or

Squamous Cell Carcinoma

(NSCL-K 2 of 5)

Progression Dabrafenib + trametinib

jjj

See Principles of Molecular and Biomarker Analysis (NSCL-H).

See Targeted Therapy or Immunotherapy for Advanced or Metastatic Disease (NSCL-J).

jjj

Single-agent vemurafenib is a treatment option if the combination of dabrafenib + trametinib is not tolerated.

BRAF V600E

mutation discovered

during rst-line

systemic therapy

Complete planned

systemic therapy, including

maintenance therapy,

or interrupt, followed by

dabrafenib + trametinib

jjj

Progression

See Initial systemic therapy

options

Adenocarcinoma

(NSCL-K 1 of 5) or

Squamous Cell Carcinoma

(NSCL-K 2 of 5)

BRAF V600E

mutation discovered

prior to rst-line

systemic therapy

Progression

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-30

NTRK GENE FUSION POSITIVE

FIRST-LINE THERAPY

SUBSEQUENT THERAPY

NTRK1/2/3

gene fusion

positive

Preferred

Larotrectinib

Entrectinib

Useful in Certain Circumstances

See Initial systemic therapy options

Adenocarcinoma (NSCL-K 1 of 5) or

Squamous Cell Carcinoma

(NSCL-K 2 of 5)

Progression

See Initial systemic therapy

options

Adenocarcinoma

(NSCL-K 1 of 5) or

Squamous Cell Carcinoma

(NSCL-K 2 of 5)

Progression

Larotrectinib

Entrectinib

See Principles of Molecular and Biomarker Analysis (NSCL-H).

See Targeted Therapy or Immunotherapy for Advanced or Metastatic Disease (NSCL-J).

For performance status 0–4.

NTRK1/2/3 gene

fusion discovered

during rst-line

systemic therapy

Complete planned

systemic therapy, including

maintenance therapy,

or interrupt, followed by

larotrectinib or entrectinib

Progression

See Initial systemic therapy

options

Adenocarcinoma

(NSCL-K 1 of 5) or

Squamous Cell Carcinoma

(NSCL-K 2 of 5)

NTRK1/2/3 gene

fusion discovered

prior to rst-line

systemic therapy

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-31

METex14 SKIPPING MUTATION

FIRST-LINE THERAPY

SUBSEQUENT THERAPY

METex14

skipping

mutation

Preferred

Capmatinib

Tepotinib

Useful in Certain Circumstances

Crizotinib

See Initial systemic therapy options

Adenocarcinoma (NSCL-K 1 of 5) or

Squamous Cell Carcinoma

(NSCL-K 2 of 5)

Progression

See Initial systemic therapy

options

Adenocarcinoma

(NSCL-K 1 of 5) or

Squamous Cell Carcinoma

(NSCL-K 2 of 5)

Progression

Preferred

Capmatinib

Tepotinib

Useful in Certain Circumstances

Crizotinib

See Principles of Molecular and Biomarker Analysis (NSCL-H).

See Targeted Therapy or Immunotherapy for Advanced or Metastatic Disease (NSCL-J).

Beware of flare phenomenon in subset of patients who discontinue TKI. If disease flare occurs, restart TKI.

METex14 skipping

mutation discovered

during rst-line

systemic therapy

Complete planned systemic

therapy, including maintenance

therapy, or interrupt, followed by

capmatinib (preferred) or tepotinib

(preferred) or crizotinib

See Initial systemic therapy

options

Adenocarcinoma

(NSCL-K 1 of 5) or

Squamous Cell Carcinoma

(NSCL-K 2 of 5)

METex14 skipping

mutation discovered

prior to rst-line

systemic therapy

Progression

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

RET REARRANGEMENT POSITIVE

FIRST-LINE THERAPY

SUBSEQUENT THERAPY

RET

rearrangement

positive

Preferred

Selpercatinib

Pralsetinib

Useful in Certain Circumstances

Cabozantinib

Vandetanib (category 2B)

Other Recommended

See Initial systemic therapy options

Adenocarcinoma (NSCL-K 1 of 5)

or Squamous Cell Carcinoma

(NSCL-K 2 of 5)

See Initial systemic therapy

options

Adenocarcinoma

(NSCL-K 1 of 5) or

Squamous Cell Carcinoma

(NSCL-K 2 of 5)

Progression

Preferred

Selpercatinib

Pralsetinib

Useful in Certain Circumstances

Cabozantinib

Vandetanib (category 2B)

See Principles of Molecular and Biomarker Analysis (NSCL-H).

See Targeted Therapy or Immunotherapy for Advanced or Metastatic Disease (NSCL-J).

Beware of flare phenomenon in subset of patients who discontinue TKI. If disease flare occurs, restart TKI.

RET rearrangement

discovered during

rst-line systemic

therapy

Complete planned

systemic therapy, including

maintenance therapy,

or interrupt, followed by

selpercatinib (preferred),

pralsetinib (preferred),

cabozantinib,

or vandetanib (category 2B)

See Initial systemic therapy

options

Adenocarcinoma

(NSCL-K 1 of 5) or

Squamous Cell Carcinoma

(NSCL-K 2 of 5)

RET rearrangement

discovered prior to

rst-line systemic

therapy

Progression

NSCL-32

Progression

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-33

PD-L1 EXPRESSION POSITIVE (≥50%)

FIRST-LINE THERAPY

PD-L1 expression

positive (≥50%)

and negative

for actionable

molecular

markers and no

contraindications

to PD-1 or PD-L1

inhibitors

kkk

• Preferred

Pembrolizumab (category 1)

(Carboplatin or cisplatin) + pemetrexed +

pembrolizumab (category 1)

Atezolizumab (category 1)

Cemiplimab-rwlc (category 1)

• Other Recommended

Carboplatin + paclitaxel + bevacizumab

atezolizumab (category 1)

Carboplatin + albumin-bound paclitaxel

+ atezolizumab

Nivolumab + ipilimumab + pemetrexed

+ (carboplatin or cisplatin) (category 1)

• Useful in Certain Circumstances

Nivolumab + ipilimumab (category 1)

Adenocarcinoma,

large cell,

NSCLC NOS

Squamous cell

carcinoma

• Preferred

Pembrolizumab (category 1)

Carboplatin + (paclitaxel or albumin-bound

paclitaxel) + pembrolizumab (category 1)

Atezolizumab (category 1)

Cemiplimab-rwlc (category 1)

• Other Recommended

Nivolumab + ipilimumab + paclitaxel

+ carboplatin (category 1)

• Useful in Certain Circumstances

Nivolumab + ipilimumab (category 1)

PS 0–2

Continuation maintenance

• Pembrolizumab (category 1)

lll

• Pembrolizumab + pemetrexed

(category 1)

mmm

• Atezolizumab and bevacizumab

(category 1)

nnn

• Atezolizumab

ooo

• Nivolumab + ipilimumab

(category 1)

ppp

• Cemiplimab-rwlc (category 1)

Progression

See Systemic Therapy

qqq

(NSCL-K 1 of 5) or Subsequent

Therapy

(NSCL-K 4 of 5)

qqq

Continuation maintenance

• Pembrolizumab

(category 1)

ooo,rrr

• Atezolizumab

ooo

• Nivolumab + ipilimumab

(category 1)

ppp

• Cemiplimab-rwlc (category 1)

Response

or stable

disease

Progression

See Systemic Therapy

qqq

(NSCL-K 2 of 5) or

Subsequent Therapy

(NSCL-K 4 of 5)

qqq

See Principles of Molecular and Biomarker Analysis (NSCL-H).

See Targeted Therapy or Immunotherapy for Advanced or Metastatic Disease (NSCL-J).

An FDA-approved biosimilar is an appropriate substitute for bevacizumab.

kkk

Contraindications for treatment with PD-1/PD-L1 inhibitors may include active or previously

documented autoimmune disease and/or current use of immunosuppressive agents or

presence of an oncogene, which would predict lack of benefit. If there are contraindications,

refer to NSCL-K 1 of 5 (adenocarcinoma) or NSCL-K 2 of 5 (squamous cell carcinoma).

lll

If pembrolizumab monotherapy given.

mmm

If pembrolizumab/carboplatin/pemetrexed or pembrolizumab/cisplatin/pemetrexed given.

nnn

If atezolizumab/carboplatin/paclitaxel/bevacizumab given.

ooo

If atezolizumab/carboplatin/albumin-bound paclitaxel or atezolizumab given (category 1

following atezolizumab alone).

ooo

If nivolumab + ipilimumab ± chemotherapy given.

qqq

If patient has not received platinum-doublet chemotherapy, refer to "systemic therapy."

If patient received platinum chemotherapy and anti-PD-1/PD-L1, refer to “subsequent

therapy.”

rrr

If pembrolizumab/carboplatin/(paclitaxel or albumin-bound paclitaxel) given.

Response

or stable

disease

See PD-L1 expression

positive (≥1%–49%) NSCL-34

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-34

PD-L1 EXPRESSION POSITIVE (≥1%–49%)

FIRST-LINE THERAPY

PD-L1 expression

positive (≥1%–49%)

and negative

for actionable

molecular

markers and no

contraindications

to PD-1 or PD-L1

inhibitors

kkk

• Preferred

(Carboplatin or cisplatin) + pemetrexed

+ pembrolizumab (category 1)

• Other Recommended

Carboplatin + paclitaxel +

bevacizumab

+ atezolizumab

(category 1)

Carboplatin + albumin-bound paclitaxel

+ atezolizumab

Nivolumab + ipilimumab + pemetrexed

+ (carboplatin or cisplatin) (category 1)

• Useful in Certain Circumstances

Nivolumab + ipilimumab (category 1)

Pembrolizumab (category 2B)

sss

Adenocarcinoma,

large cell, NSCLC

NOS

Squamous cell

carcinoma

• Preferred

Carboplatin + (paclitaxel or albumin-

bound paclitaxel) + pembrolizumab

(category 1)

• Other Recommended

Nivolumab + ipilimumab + paclitaxel

+ carboplatin (category 1)

• Useful in Certain Circumstances

Nivolumab + ipilimumab (category 1)

Pembrolizumab (category 2B)

sss

PS 0–2

Continuation maintenance

• Pembrolizumab (category 1)

lll

• Pembrolizumab + pemetrexed

(category 1)

mmm

• Atezolizumab and

bevacizumab (category 1)

nnn

• Atezolizumab

ooo

• Nivolumab + ipilimumab

(category 1)

ppp

Continuation maintenance

• Pembrolizumab

lll,rrr

• Nivolumab + ipilimumab

(category 1)

ppp

Response

or stable

disease

See Principles of Molecular and Biomarker Analysis (NSCL-H).

See Targeted Therapy or Immunotherapy for Advanced or Metastatic Disease (NSCL-J).

An FDA-approved biosimilar is an appropriate substitute for bevacizumab.

kkk

Contraindications for treatment with PD-1/PD-L1 inhibitors may include active or

previously documented autoimmune disease and/or current use of immunosuppressive

agents or presence of an oncogene, which would predict lack of benefit. If there are

contraindications, refer to NSCL-K 1 of 5 (adenocarcinoma) or NSCL-K 2 of 5 (squamous

cell carcinoma).

lll

If pembrolizumab monotherapy given.

mmm

If pembrolizumab/carboplatin/pemetrexed or pembrolizumab/cisplatin/pemetrexed given.

nnn

If atezolizumab/carboplatin/paclitaxel/bevacizumab given.

ooo

If atezolizumab/carboplatin/albumin-bound paclitaxel given.

ppp

If nivolumab + ipilimumab ± chemotherapy given.

qqq

If patient has not received platinum-doublet chemotherapy, refer to "systemic therapy."

If patient received platinum chemotherapy and anti-PD-1/PD-L1, refer to “subsequent

therapy.”

rrr

If pembrolizumab/carboplatin/(paclitaxel or albumin-bound paclitaxel) given.

sss

Pembrolizumab monotherapy can be considered in PD-L1 1%–49%, in patients with

poor PS or other contraindications to combination chemotherapy.

Response

or stable

disease

See PD-L1 expression

positive (≥50%) NSCL-33

Progression

See Systemic Therapy

qqq

(NSCL-K 2 of 5) or

Subsequent Therapy

(NSCL-K 4 of 5)

qqq

Progression

See Systemic Therapy

qqq

(NSCL-K 1 of 5) or

Subsequent Therapy

(NSCL-K 4 of 5)

qqq

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-35

bbb

Monitoring During Initial Therapy: Response assessment after 2 cycles, then every 2–4 cycles with CT of known sites of disease with or without contrast or when

clinically indicated. Timing of CT scans within Guidelines parameters is a clinical decision.

ccc

In general, 4 cycles of initial systemic therapy (ie, with carboplatin or cisplatin) are administered prior to maintenance therapy. However, if patient is tolerating therapy

well, consideration can be given to continue to 6 cycles.

ddd

Monitoring During Subsequent Therapy: Response assessment with CT of known sites of disease with or without contrast every 6–12 weeks. Timing of CT scans

within Guidelines parameters is a clinical decision.

INITIAL SYSTEMIC THERAPY

bbb

SUBSEQUENT THERAPY

ddd

PS 0–2

Systemic therapy

• Adenocarcinoma,

Large Cell,

NSCLC NOS

(NSCL-K 1 of 5)

• Squamous Cell

Carcinoma

(NSCL-K 2 of 5)

Tumor

response

evaluation

Progression

Response

or stable

disease

PS 0–2

PS 3–4

4–6

cycles

(total)

ccc

Progression

Response

or stable

disease

Subsequent systemic

therapy (NSCL-K 4 of 5)

Maintenance

therapy

(NSCL-K 3 of 5)

Progression,

Subsequent

systemic

therapy

(NSCL-K 4 of 5)

PS 3–4

Best supportive care

See NCCN Guidelines

for Palliative Care

Tumor

response

evaluation

Subsequent systemic

therapy (NSCL-K 4 of 5)

Best supportive care

See NCCN Guidelines

for Palliative Care

PD-L1 <1% AND NEGATIVE FOR ACTIONABLE MOLECULAR MARKERS

Progression,

Subsequent systemic

therapy (NSCL-K 4 of 5)

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-A

1 OF 4

PRINCIPLES OF PATHOLOGIC REVIEW

• Pathologic Evaluation

The purpose of the pathologic evaluation of NSCLC will vary depending on whether the sample 1) is a biopsy or cytology specimen

intended for initial diagnosis in a case of suspected NSCLC; 2) is a resection specimen; or 3) is obtained for molecular evaluation in the

setting of an established NSCLC diagnosis.

◊ In small biopsies or cytology specimens intended for initial diagnosis, the primary purpose is a) to make an accurate diagnosis using the

2015 WHO classication; and b) to preserve the tissue for molecular studies, especially if the patient has advanced-stage disease.

◊ In small biopsies of poorly dierentiated carcinomas, the terms "non-small cell carcinoma (NSCC)

" or "non-small cell carcinoma not

otherwise specied (NSCC-NOS)" should be used as little as possible and only when a more specic diagnosis is not possible by

morphology and/or special staining.

◊ The following terms are acceptable: "NSCC favor adenocarcinoma" and "NSCC favor squamous cell carcinoma." "NSCC-NOS" should be

reserved only for cases in which immunohistochemical testing is uninformative or ambiguous (see section on Immunohistochemistry).

◊ Preservation of material for molecular testing is critical. Eorts should be undertaken to minimize block reorientation and the number of

(IHC) stains for cases that cannot be classied on histologic examination alone (see section on Immunohistochemistry).

In resection specimens, the primary purpose is a) to classify the histologic type; and b) to determine all staging parameters, as

recommended by the American Joint Committee on Cancer (AJCC), including tumor size, extent of invasion, adequacy of surgical margins,

and presence or absence of lymph node metastases.

◊ The number of involved lymph node stations should be documented since it has prognostic signicance (AJCC 8th ed). Direct extension

of the primary tumor into an adjacent lymph node is considered as nodal involvement.

◊ All lobectomy specimens should be extensively dissected to search for involved lymph nodes.

In small biopsies or cytology specimens—obtained for molecular testing in the context of an established diagnosis after progression on

targeted therapies, the primary purpose is a) to conrm the original pathologic type with minimal use of tissue for IHC only in suspected

small cell carcinoma transformation or a dierent histology; and b) to preserve material for molecular analysis.

• Formalin-xed paran-embedded (FFPE) material is suitable for most molecular analyses, except bone biopsies that were previously treated

with acid decalcifying solutions. Non-acid decalcication approaches may be successful for subsequent molecular testing. While many

molecular pathology laboratories currently also accept cytopathology specimens such as cell blocks, direct smears, or touch preparations,

laboratories that do not currently do so are strongly encouraged to identify approaches to testing on non-FFPE cytopathology specimens.

Non-small cell carcinomas (NSCC, without the L for lung) that show no clear adenocarcinoma or squamous cell carcinoma morphology or immunohistochemical

markers are regarded as NSCC not otherwise specified (NOS). In this setting, it is recommended that pathologists use the term NSCC rather than NSCLC, because

the lack of pneumocyte marker expression in small biopsies or cytology leaves open the possibility of a metastatic carcinoma and the determination of a lung primary

must be established clinically after excluding other primary sites.

Continued

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCLC Classication

• The types of NSCLC are: adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, large cell carcinoma, and sarcomatoid

carcinoma.

Squamous cell carcinoma: A malignant epithelial tumor that either shows keratinization and/or intercellular bridges, or a morphologically

undierentiated NSCC that expresses immunohistochemical markers of squamous cell dierentiation.

Adenocarcinoma:

◊ For small (<3 cm), resected lesions, determining extent of invasion is critical.

– Adenocarcinoma in situ (AIS; formerly BAC): A small (≤3 cm) localized nodule with lepidic growth, mostly non-mucinous, although

mucinous types can occur. Multiple synchronous AIS tumors can also occur.

– Minimally invasive adenocarcinoma (MIA): A small (≤3 cm) solitary adenocarcinoma with a predominantly lepidic pattern and ≤5 mm

invasion in greatest dimension. MIA is usually non-mucinous, but rarely may be mucinous. MIA is, by denition, solitary and discrete.

– Invasive adenocarcinoma: A malignant epithelial tumor with glandular dierentiation, mucin production, or pneumocyte marker

expression. The tumors show an acinar, papillary, micropapillary, lepidic, or solid growth pattern, with either mucin or pneumocyte

marker expression. The invasive adenocarcinoma component should be present in at least one focus measuring >5 mm in greatest

dimension.

– Invasive adenocarcinoma variants: invasive mucinous adenocarcinoma, colloid adenocarcinoma, fetal adenocarcinoma, and enteric

adenocarcinoma.

– Refer to College of American Pathologists Protocols for additional information.

Adenosquamous carcinoma: A carcinoma showing components of both squamous cell carcinoma and adenocarcinoma, with each

component constituting at least 10% of the tumor. Denitive diagnosis requires a resection specimen, although it may be suggested based

on ndings in small biopsies, cytology, or excisional biopsies. Presence of any adenocarcinoma component in a biopsy specimen that is

otherwise squamous should trigger molecular testing.

Large cell carcinoma: Undierentiated NSCC that lacks the cytologic, architectural, and histochemical features of small cell carcinoma,

adenocarcinoma, or squamous cell carcinoma. The diagnosis requires a thoroughly sampled resected tumor and cannot be made on non-

resection or cytology specimens.

Sarcomatoid carcinoma is a general term that includes pleomorphic carcinoma, carcinosarcoma, and pulmonary blastoma. For this reason,

it is best to use the specic term for these entities whenever possible rather than the general term.

◊ Pleomorphic carcinoma is a poorly dierentiated NSCC that contains at least 10% spindle and/or giant cells or a carcinoma consisting

only of spindle and giant cells. Spindle cell carcinoma consists of an almost pure population of epithelial spindle cells, while Giant cell

carcinoma consists almost entirely of tumor giant cells.

◊ Carcinosarcoma is a malignant tumor that consists of a mixture of NSCC and sarcoma-containing heterologous elements (eg,

rhabdomyosarcoma, chondrosarcoma, osteosarcoma).

◊ Pulmonary blastoma is a biphasic tumor that consists of fetal adenocarcinoma (typically low grade) and primitive mesenchymal stroma.

NSCL-A

2 OF 4

PRINCIPLES OF PATHOLOGIC REVIEW

Continued

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-A

3 OF 4

Immunohistochemistry

• Judicious use of IHC is strongly recommended to preserve tissue for molecular testing, most notably in small specimens. When

adenocarcinoma or squamous cell carcinomas are poorly dierentiated, the dening morphologic criteria that would allow for specic

diagnosis may be inconspicuous or absent. In this case, IHC or mucin staining may be necessary to determine a specic diagnosis.

• In small specimens, a limited number of immunostains with one lung adenocarcinoma marker (TTF1, napsin A) and one squamous

carcinoma marker (p40, p63) should suce for most diagnostic problems. Virtually all tumors that lack squamous cell morphology and show

co-expression of p63 and TTF1 are preferably classied as adenocarcinoma. A simple panel of TTF1 and p40 may be sucient to classify

most NSCC-NOS cases.

• Testing for NUT expression by IHC should be considered in all poorly dierentiated carcinomas that lack glandular dierentiation or specic

etiology, particularly in non-smokers or in patients presenting at a young age, for consideration of a pulmonary NUT carcinoma.

• IHC should be used to dierentiate primary lung adenocarcinoma from squamous cell carcinoma, large cell carcinoma, metastatic

carcinoma, and primary pleural mesothelioma (particularly for pleural specimens).

• Primary pulmonary adenocarcinoma:

In patients for whom the primary origin of the carcinoma is uncertain, an appropriate panel of immunohistochemical stains is

recommended to assess for metastatic carcinoma to the lung.

TTF1 is a homeodomain-containing nuclear transcription protein of the NKX2 gene family that is expressed in epithelial cells of the

embryonal and mature lung and thyroid. TTF1 immunoreactivity is seen in primary pulmonary adenocarcinoma in the majority (70%–90%)

of non-mucinous adenocarcinoma subtypes. Metastatic adenocarcinoma to the lung is nearly always negative for TTF1 except in metastatic

thyroid malignancies, in which case thyroglobulin and PAX8 are also positive. Rare cases of TTF1 positivity in tumors of other organs

(gynecologic tract, pancreatobiliary) have been noted, and may be dependent on the specic TTF1 clone utilized, stressing the importance

of correlation with clinical and radiologic features.

Napsin A—an aspartic proteinase expressed in normal type II pneumocytes and in proximal and distal renal tubules—appears to be

expressed in >80% of lung adenocarcinomas and may be a useful adjunct to TTF1.

The panel of TTF1 (or alternatively napsin A) and p40 (or alternatively p63) may be useful in rening the diagnosis to either adenocarcinoma

or squamous cell carcinoma in small biopsy specimens previously classied as NSCC NOS.

PRINCIPLES OF PATHOLOGIC REVIEW

Continued

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-A

4 OF 4

Immunohistochemistry

• IHC should be used to conrm neuroendocrine dierentiation when there is morphologic evidence of neuroendocrine morphology (eg,

speckled chromatin pattern, nuclear molding, peripheral palisading):

NCAM (CD56), chromogranin, and synaptophysin are used to identify neuroendocrine tumors in cases in which morphologic suspicion of

neuroendocrine dierentiation exists.

A panel of markers is useful, but one positive marker is enough if the staining is unambiguous in more than 10% of the tumor cells.

• Malignant mesothelioma versus pulmonary adenocarcinoma

The distinction between pulmonary adenocarcinoma and malignant mesothelioma (epithelioid type) can be made by correlation of the

histology with the clinical impression, imaging studies, and a panel of immunomarkers.

Immunostains sensitive and specic for mesothelioma include WT-1, calretinin, CK5/6, and D2-40 (usually negative in adenocarcinoma).

Immunostains sensitive and specic for adenocarcinoma include pCEA, Claudin 4, TTF1, and napsin A (negative in mesothelioma). Other

potentially useful markers that can be considered include B72.3, Ber-EP4, MOC31, and CD15, but these generally do not have the sensitivity

and specicity of the above markers.

A pancytokeratin such as AE1/AE3 is also useful, as a negative result suggests the possibility of other tumors.

Other markers can be helpful in the dierential diagnosis between mesothelioma and metastatic carcinoma, and will also help determine

the tumor origin. Examples include markers for lung adenocarcinoma (TTF1 and napsin A), breast carcinoma (ERα, PR, GCDFP15,

mammaglobin, and GATA-3), renal cell carcinoma (PAX8), papillary serous carcinoma (PAX8, PAX2, and ER), adenocarcinomas of

the gastrointestinal tract (CDX2), and prostate cancer (NKX3.1). Additionally, p40 (or p63) is helpful for distinguishing epithelioid

mesotheliomas with pseudosquamous morphology from squamous cell carcinomas.

PRINCIPLES OF PATHOLOGIC REVIEW

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-B

1 OF 4

PRINCIPLES OF SURGICAL THERAPY

Peripheral is defined as the outer one third of the lung parenchyma.

Margins and Nodal Assessment (see NSCL-B 2 of 4)

The Role of Surgery in Patients with Stage IIIA (N2) NSCLC

(see NSCL-B 2 of 4 through NSCL-B 4 of 4)

Evaluation

• Determination of resectability, surgical staging, and pulmonary resection should be performed by thoracic surgeons who perform lung

cancer surgery as a prominent part of their practice.

• CT and PET/CT used for staging should be within 60 days before proceeding with surgical evaluation.

• For medically operable disease, resection is the preferred local treatment modality (other modalities include SABR, thermal ablation such

as radiofrequency ablation, and cryotherapy). Thoracic surgical oncology consultation should be part of the evaluation of any patient being

considered for curative local therapy. In cases where SABR is considered for high-risk or borderline operable patients, a multidisciplinary

evaluation including a radiation oncologist is recommended.

• The overall plan of treatment as well as needed imaging studies should be determined before any non-emergency treatment is initiated.

• Thoracic surgeons should actively participate in multidisciplinary discussions and meetings regarding lung cancer patients (eg,

multidisciplinary clinic and/or tumor board).

• Patients who are active smokers should be provided counseling and smoking cessation support (NCCN Guidelines for Smoking Cessation).

While active smokers have a mildly increased incidence of postoperative pulmonary complications, these should not be considered

a prohibitive risk for surgery. Surgeons should not deny surgery to patients solely due to smoking status, as surgery provides the

predominant therapy for patients with early-stage lung cancer.

Resection

• Anatomic pulmonary resection is preferred for the majority of patients with NSCLC.

• Sublobar resection - Segmentectomy and wedge resection should achieve parenchymal resection margins ≥2 cm or ≥ the size of the nodule.

• Sublobar resection should also sample appropriate N1 and N2 lymph node stations unless not technically feasible without substantially

increasing the surgical risk.

• Segmentectomy (preferred) or wedge resection is appropriate in selected patients for the following reasons:

Poor pulmonary reserve or other major comorbidity that contraindicates lobectomy

Peripheral nodule

≤2 cm with at least one of the following:

◊ Pure AIS histology

◊ Nodule has ≥50% ground-glass appearance on CT

◊ Radiologic surveillance conrms a long doubling time (≥400 days)

• VATS or minimally invasive surgery (including robotic-assisted approaches) should be strongly considered for patients with no anatomic or

surgical contraindications, as long as there is no compromise of standard oncologic and dissection principles of thoracic surgery.

• In high-volume centers with signicant VATS experience, VATS lobectomy in selected patients results in improved early outcomes (ie,

decreased pain, reduced hospital length of stay, more rapid return to function, fewer complications) without compromise of cancer

outcomes.

• Lung-sparing anatomic resection (sleeve lobectomy) is preferred over pneumonectomy, if anatomically appropriate and margin-negative

resection is achieved.

• T3 (invasion) and T4 local extension tumors require en-bloc resection of the involved structure with negative margins. If a surgeon or center

is uncertain about potential complete resection, consider obtaining an additional surgical opinion from a high-volume specialized center.

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-B

2 OF 4

Margins and Nodal Assessment

• Surgical pathologic correlation is critical to assess apparent close or positive margins, as these may not represent true margins or may not

truly represent areas of risk for local recurrence (eg, medial surface of mainstem or bronchus intermedius when separate subcarinal lymph

node dissection has been performed; pleural margin adjacent to aorta when no attachment to aorta is present).

• N1 and N2 node resection and mapping should be a routine component of lung cancer resections—a minimum of three N2 stations sampled

or complete lymph node dissection.

• Formal ipsilateral mediastinal lymph node dissection is indicated for patients undergoing resection for stage IIIA (N2) disease.

• Complete resection requires free resection margins, systematic node dissection or sampling, and the highest mediastinal node negative

for tumor. The resection is dened as incomplete whenever there is involvement of resection margins, unremoved positive lymph nodes,

or positive pleural or pericardial eusions. A complete resection is referred to as R0, microscopically positive resection as R1, and

macroscopic residual tumor as R2.

• Patients with pathologic stage II or greater should be referred to medical oncology for evaluation.

• Consider referral to a radiation oncologist for resected stage IIIA.

The Role of Surgery in Patients with Stage IIIA (N2) NSCLC

The role of surgery in patients with pathologically documented N2 disease remains controversial.

Two randomized trials evaluated the role of

surgery in this population, but neither showed an overall survival benet with the use of surgery.

2,3

However, this population is heterogeneous

and the panel believes that these trials did not suciently evaluate the nuances present with the heterogeneity of N2 disease and the likely

oncologic benet of surgery in specic clinical situations.

• The presence or absence of N2 disease should be vigorously determined by both radiologic and invasive staging prior to the initiation of

therapy since the presence of mediastinal nodal disease has a profound impact on prognosis and treatment decisions. (NSCL-1, NSCL-2, and

NSCL-6)

• Patients with occult-positive N2 nodes discovered at the time of pulmonary resection should continue with the planned resection along

with formal mediastinal lymph node dissection. If N2 disease is noted in patients undergoing VATS, the surgeon may consider stopping the

procedure so that induction therapy can be administered before surgery; however, continuing the procedure is also an option.

• The determination of the role of surgery in a patient with N2-positive lymph nodes should be made prior to the initiation of any therapy by a

multidisciplinary team, including a thoracic surgeon who has a major part of his/her practice dedicated to thoracic oncology.

• The presence of N2-positive lymph nodes substantially increases the likelihood of positive N3 lymph nodes. Pathologic evaluation of the

mediastinum must include evaluation of the subcarinal station and contralateral lymph nodes. EBUS +/- EUS are additional techniques for

minimally invasive pathologic mediastinal staging that are complementary to mediastinoscopy. Even when these modalities are employed

it is important to have an adequate evaluation of the number of stations involved and biopsy and documentation of negative contralateral

lymph node involvement prior to a nal treatment decision.

The Role of Surgery in Patients with Stage IIIA (N2) NSCLC is continued on NSCL-B 3 of 4 through NSCL-B 4 of 4

PRINCIPLES OF SURGICAL THERAPY

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-B

3 OF 4

• Repeat mediastinoscopy, while possible, is technically dicult and has a lower accuracy compared to primary mediastinoscopy. One

possible strategy is to perform EBUS (± EUS) in the initial pretreatment evaluation and reserve mediastinoscopy for nodal restaging after

neoadjuvant therapy.

• Patients with a single lymph node smaller than 3 cm can be considered for a multimodality approach that includes surgical resection.

1,6,7

• Restaging after induction therapy is dicult to interpret, but CT +/- PET should be performed to exclude disease progression or interval

development of metastatic disease.

• Patients with negative mediastinum after neoadjuvant therapy have a better prognosis.

7,8

• Neoadjuvant chemoradiotherapy is used in 50% of the NCCN Member Institutions, while neoadjuvant chemotherapy is used in the other

50%. Overall survival appears similar provided RT is given postoperatively, if not given preoperatively.

5,9

Neoadjuvant chemoradiotherapy

is associated with higher rates of pathologic complete response and negative mediastinal lymph nodes.

However, that is achieved at the

expense of higher rates of acute toxicity and increased cost.

• When neoadjuvant chemoradiotherapy is used with doses lower than those used for standard denitive therapy, all eorts should be made

to minimize any possible breaks in radiotherapy for surgical evaluation. Treatment breaks of more than 1 week are considered unacceptable.

• When timely surgical evaluation is not available, the strategy of neoadjuvant chemoradiotherapy should not be used. Another option in

individual cases, and with the agreement of the thoracic surgeon, is to complete denitive chemoradiotherapy prior to re-evaluation and

consideration for surgery.

11,12

If a surgeon or center is uncertain about the feasibility or safety of resection after denitive doses of radiation,

consider obtaining an additional surgical opinion from a high-volume specialized center. These operations may also benet from additional

considerations of soft tissue ap coverage in the radiation eld at the time of resection.

• Data from a large multi-institutional trial indicate that pneumonectomy after neoadjuvant chemoradiotherapy has unacceptable morbidity

and mortality.

However, it is not clear if this is also true with neoadjuvant chemotherapy alone. Further, many groups have challenged

that cooperative group nding with single-institution experiences demonstrating safety of pneumonectomy after induction therapy.

13-16

addition, there is no evidence that adding RT to induction regimens for patients with operable stage IIIA (N2) disease improves outcomes

compared to induction chemotherapy.

A questionnaire was submitted to the NCCN Member Institutions in 2010 regarding their approach to patients with N2 disease. Their

responses indicate the patterns of practice when approaching this dicult clinical problem.

a) Would consider surgery in patients with one N2 lymph node station involved by a lymph node smaller than 3 cm: (90.5%)

b) Would consider surgery with more than one N2 lymph node station involved, as long as no lymph node was bigger than 3 cm: (47.6%)

c) Uses EBUS (+/- EUS) in the initial evaluation of the mediastinum: (80%)

d) Uses pathologic evaluation of the mediastinum, after neoadjuvant therapy, to make a nal decision before surgery: (40.5%)

e) Would consider neoadjuvant therapy followed by surgery when a patient is likely, based on initial evaluation, to require a

pneumonectomy: (54.8%)

The Role of Surgery in Patients with Stage IIIA (N2) NSCLC

PRINCIPLES OF SURGICAL THERAPY

References

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-B

4 OF 4

The Role of Surgery in Patients with Stage IIIA (N2) NSCLC - References

Martins RG, D'Amico TA, Loo BW Jr, et al. The management of patients with stage IIIA non-small cell lung cancer with N2 mediastinal node involvement. J Natl Compr

Canc Netw 2012;10:599-613.

Albain K, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III

randomized controlled trial. Lancet 2009;374:379-386.

van Meerbeeck JP, Kramer GW, Van Schil PE, et al. Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-

small-cell lung cancer. J Natl Cancer Inst 2007;99:442-450.

Farjah F, Flum DR, Varghese TK Jr, et al. Surgeon specialty and long-term survival after pulmonary resection for lung cancer. Ann Thorac Surg 2009;87:995-1006.

Thomas M, Rübe C, Hoffknecht P, et al. Effect of preoperative chemoradiation in addition to preoperative chemotherapy: a randomised trial in stage III non-small-cell

lung cancer. Lancet Oncol 2008;9:636-648.

Andre F, Grunenwald D, Pignon J, et al. Survival of patients with resected N2 non-small-cell lung Cancer: Evidence for a subclassification and implications. J Clin Oncol

2000;18:2981-2989.

Decaluwé H, De Leyn P, Vansteenkiste J, et al. Surgical multimodality treatment for baseline resectable stage IIIA-N2 non-small cell lung cancer. Degree of mediastinal

lymph node involvement and impact on survival. Eur J Cardiothorac Surg 2009;36:433-439.

Bueno R, Richards WG, Swanson SJ, et al. Nodal stage after induction therapy for stage IIIA lung cancer determines patient survival. Ann Thorac Surg 2000;70:1826-

1831.

Higgins K, Chino JP, Marks LB, et al. Preoperative chemotherapy versus preoperative chemoradiotherapy for stage III (N2) non-small-cell lung cancer. Int J Radiat

Oncol Biol Phys 2009;75:1462-1467.

de Cabanyes Candela S, Detterbeck FC. A systematic review of restaging after induction therapy for stage IIIa lung cancer: prediction of pathologic stage. J Thorac

Oncol 2010;5:389-398.

Bauman JE, Mulligan MS, Martins RG, et al. Salvage lung resection after definitive radiation (>59 Gy) for non-small cell lung cancer: surgical and oncologic outcomes.

Ann Thorac Surg 2008;86:1632-1638.

Sonett JR, Suntharalingam M, Edelman MJ, et al. Pulmonary resection after curative intent radiotherapy (>59 Gy) and concurrent chemotherapy in non-small-cell lung

cancer. Ann Thorac Surg 2004;78:1200-1205.

Evans NR 3rd, Li S, Wright CD, et al. The impact of induction therapy on morbidity and operative mortality after resection of primary lung cancer. J Thorac Cardiovasc

Surg 2010;139:991-996.

Gaissert HA, Keum DY, Wright CD, et al. POINT: Operative risk of pneumonectomy—Influence of preoperative induction therapy. J Thorac Cardiovasc Surg

2009;138:289-294.

Mansour Z, Kochetkova EA, Ducrocq X, et al. Induction chemotherapy does not increase the operative risk of pneumonectomy! Eur J Cardiothorac Surg 2007;31:181-

185.

Weder W, Collaud S, Eberhardt WE, et al. Pneumonectomy is a valuable treatment option after neoadjuvant therapy for stage III non-small-cell lung cancer. J Thorac

Cardiovasc Surg 2010;139:1424-1430.

Shah AA, Berry MF, Tzao C, et al. Induction chemoradiotherapy is not superior to induction chemotherapy alone in stage IIIA lung cancer: a systematic review and

meta-analysis. Ann Thorac Surg 2012;93:1807-1812.

PRINCIPLES OF SURGICAL THERAPY

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-C

1 OF 10

PRINCIPLES OF RADIATION THERAPY

I. General Principles (see Table 1. Commonly Used Abbreviations in Radiation Therapy)

• Determination of the appropriateness of radiation therapy (RT) should be made by radiation oncologists who perform lung cancer RT as a

prominent part of their practice.

• RT has a potential role in all stages of NSCLC, as either denitive or palliative therapy. Radiation oncology input as part of a multidisciplinary

evaluation or discussion should be provided for all patients with stage III NSCLC, with early-stage disease who are medically inoperable,

who refuse surgery, or who are high-risk surgical candidates, and with stage IV disease that may benet from local therapy.

• The critical goals of modern RT are to maximize tumor control and to minimize treatment toxicity. A minimum technologic standard is CT-

planned 3D-CRT.

• More advanced technologies are appropriate when needed to deliver curative RT safely. These technologies include (but are not limited to)

4D-CT and/or PET/CT simulation, IMRT/VMAT, IGRT, motion management, and proton therapy (https://www.astro.org/Daily-Practice/

Reimbursement/Model-Policies/Model-Policies/). Nonrandomized comparisons of using advanced technologies demonstrate reduced toxicity

and improved survival versus older techniques.

2-4

In a prospective trial of denitive chemo/RT for patients with stage III NSCLC (RTOG

0617), IMRT was associated with a nearly 60% decrease (from 7.9% to 3.5%) in high-grade radiation pneumonitis as well as similar survival

and tumor control outcomes despite a higher proportion of stage IIIB and larger treatment volumes compared to 3D-CRT;

as such, IMRT is

preferred over 3D-CRT in this setting.

• Centers using advanced technologies should implement and document modality-specic quality assurance measures. The ideal is external

credentialing of both treatment planning and delivery such as required for participation in RTOG clinical trials employing advanced

technologies. Useful references include the ACR Practice Parameters and Technical Standards (https://www.acr.org/~/media/ACR/

Documents/PGTS/toc.pdf).

• The interaction of strong VEGF inhibitors with prior or subsequent dose-intensive RT (SABR or denitive dose accelerated fractionation)

involving the proximal bronchial tree, hilar vessels, or esophagus can lead to serious toxicity. Careful coordination of medical and radiation

oncology on the therapeutic strategy is important, including the choice and sequencing of systemic agents with strong VEGF inhibitors and

the dose and fractionation of radiation, especially for patients with metastatic disease.

II. Radiation Therapy Simulation, Planning, and Delivery

• Simulation should be performed using CT scans obtained in the RT treatment position with appropriate immobilization devices. IV contrast

with or without oral contrast is recommended for better target/organ delineation whenever possible in patients with central tumors or nodal

disease. Because IV contrast can aect tissue heterogeneity correction calculations, density masking or use of a pre-contrast scan may be

needed when intense enhancement is present.

• PET/CT signicantly improves targeting accuracy,

especially for patients with signicant atelectasis and when IV CT contrast is

contraindicated. A randomized trial of PET/CT versus CT-only RT planning demonstrated improved preemption of futile radical RT, decreased

recurrences, and a trend toward improved overall survival with PET/CT RT planning.

Given the potential for rapid progression of NSCLC,

8,9

PET/CT should be obtained preferably within 4 weeks before treatment. It is ideal to obtain PET/CT in the treatment position.

• Tumor and organ motion, especially owing to breathing, should be assessed or accounted for at simulation. Options include uoroscopy,

inhale/exhale or slow scan CT, or, ideally, 4D-CT.

Continued

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

PRINCIPLES OF RADIATION THERAPY

II. Radiation Therapy Simulation, Planning, and Delivery (continued)

• Photon beam energy should be individualized based on the anatomic location of the tumors and beam paths. In general, photon energies

between 4 to 10 MV are recommended for beams passing through low-density lung tissue before entering the tumor. When there is no air

gap before the beam enters the tumor (such as for some large mediastinal tumors or tumors attached to the chest wall), higher energies may

improve the dose distribution, especially when using a smaller number of xed beam angles.

• Tissue heterogeneity correction and accurate dose calculation algorithms are recommended that account for buildup and lateral electron

scatter eects in heterogeneous density tissues. Heterogeneity correction with simple pencil beam algorithms is not recommended.

• Respiratory motion should be managed when motion is excessive. This includes (but is not limited to) forced shallow breathing with

abdominal compression, accelerator beam gating with the respiratory cycle, dynamic tumor tracking, active breathing control (ABC), or

coaching/biofeedback techniques. If motion is minimal or the ITV is small, motion-encompassing targeting is appropriate. A useful resource

for implementation of respiratory motion management is the report of AAPM Task Group 76.

• IGRT—including (but not limited to) orthogonal pair planar imaging and/or volumetric imaging (such as CBCT or CT on rails)—is

recommended when using SABR, 3D-CRT/IMRT, and proton therapy with steep dose gradients around the target, when OARs are in close

proximity to high-dose regions, and when using complex motion management techniques.

III. Target Volumes, Prescription Doses, and Normal Tissue Dose Constraints (See Tables 2–5 on NSCL-C 7 of 10 and NSCL-C 8 of 10)

• ICRU Reports 62 and 83 detail the current denitions of target volumes for 3D-RT and IMRT. GTV comprises the known extent of disease

(primary and nodal) on imaging and pathologic assessment, CTV includes regions of presumed microscopic extent or dissemination, and

PTV comprises the ITV (which includes margin for target motion) plus a setup margin for positioning and mechanical variability.

https://www.nrgoncology.org/ciro-lung

• PTV margin can be decreased by immobilization, motion management, and IGRT techniques.

• Consistent delineation of normal structures is critical for evaluating plans for safety. The RTOG consensus lung-contouring atlas is a useful

resource. https://www.nrgoncology.org/ciro-lung

• Commonly used prescription doses and normal tissue dose constraints are summarized in Tables 2 through 5. These are based on

published experience, ongoing trials, historical data, modeling, and empirical judgment.

12,13

Useful references include the recent reviews of

normal organ dose responses from the QUANTEC project.

14-18

Because risk of normal organ toxicity increases with dose, doses to normal

organs should be kept as low as reasonably achievable rather than simply meeting nominal constraints. This is generally facilitated by more

advanced techniques to achieve better dose conformity.

NSCL-C

2 OF 10

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-C

3 OF 10

Continued

PRINCIPLES OF RADIATION THERAPY

IV. General Treatment Information

Early-Stage NSCLC (Stage I, selected node-negative Stage IIA)

• SABR (also known as SBRT)

is recommended for patients who are medically inoperable or who refuse to have surgery after thoracic

surgery evaluation. SABR has achieved good primary tumor control rates and overall survival, and higher than conventionally fractionated

radiotherapy, although not proven equivalent to lobectomy.

20-29

• SABR is also an appropriate option for patients with high surgical risk (able to tolerate sublobar resection but not lobectomy [eg, age ≥75

years, poor lung function]).

• More modestly hypofractionated or dose-intensied conventionally fractionated 3D-CRT regimens are less preferred alternatives and may be

considered if referral for SABR is not feasible.

30-32

• In patients treated with surgery, postoperative radiotherapy (PORT) is not recommended unless there are positive margins or upstaging to N2

(see Locally Advanced NSCLC in this section).

SABR for Node-Negative Early-Stage NSCLC

• The high-dose intensity and conformity of SABR require minimizing the PTV.

• Dosing regimen

For SABR, intensive regimens of BED ≥100 Gy are associated with signicantly better local control and survival than less intensive

regimens.

33,34

In the United States, only regimens of ≤5 fractions meet the arbitrary billing code denition of SBRT, but slightly more

protracted regimens are appropriate as well.

33,35

For centrally located tumors (dened variably as within 2 cm of the proximal bronchial tree

and/or abutting mediastinal pleura) and even ultra-central tumors (dened as abutting the proximal bronchial tree), 4 to 10 fraction risk-

adapted SABR regimens appear to be eective and safe,

36-39

while 54 to 60 Gy in 3 fractions is unsafe and should be avoided.

However,

particular attention should be paid to tumors abutting the bronchial tree and esophagus to avoid severe toxicity. RTOG 0813 evaluated the

toxicity of 5-fraction regimens and found no high-grade toxicities at 50 Gy in 5 fractions.

• SABR is most commonly used for tumors up to 5 cm in size, though selected larger isolated tumors can be treated safely if normal tissue

constraints are respected.

41,42

• Prescription doses incompletely describe the actual delivered doses, which also strongly depend on how the dose is prescribed (to the

isocenter vs. an isodose volume covering a proportion of the PTV), the degree of dose heterogeneity, whether tissue density heterogeneity

corrections are used, and the type of dose calculation algorithm.

10,43,44

All of these must be considered when interpreting or emulating

regimens from prior studies.

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-C

4 OF 10

Continued

PRINCIPLES OF RADIATION THERAPY

Locally Advanced NSCLC (Stage II–III)

• Concurrent chemotherapy/RT is recommended for patients with inoperable stage II (node-positive) and stage III NSCLC.

45-48

• RT interruptions and dose reductions for manageable acute toxicities should be avoided by employing supportive care.

• Sequential chemotherapy/RT or RT alone is appropriate for frail patients unable to tolerate concurrent therapy.

49,50

Accelerated RT regimens may be benecial, particularly if concurrent chemotherapy would not be tolerated (ie, in a sequential or RT-only

approach).

51,52

• Preoperative concurrent chemotherapy/RT is an option for patients with resectable stage IIIA (minimal N2 and treatable with lobectomy)

NSCLC and is recommended for resectable superior sulcus tumors.

54,55

RT should be planned up front such that it continues to a denitive

dose without interruption if the patient does not proceed to surgery as initially planned.

• Preoperative chemotherapy and postoperative RT is an alternative for patients with resectable stage IIIA disease.

56,57

The optimal timing of

RT in trimodality therapy (preoperative with chemotherapy or postoperative) is not established and is controversial.

58,59

• The determination of resectability in trimodality therapy should be made prior to initiation of all treatment. Upfront multidisciplinary

consultation is particularly important when considering surgical treatment of patients with stage III NSCLC.

• In patients with clinical stage I/II upstaged surgically to N2+, PORT appears to improve survival signicantly as an adjunct to postoperative

chemotherapy in non-randomized analyses.

60,61

Although the optimal sequence is not established, PORT is generally administered after

postoperative chemotherapy and concurrently with chemotherapy for positive resection margins.

62-65

• PORT is not recommended for patients with pathologic stage N0–1 disease, because it has been associated with increased mortality, at least

when using older RT techniques.

Conventionally Fractionated RT for Locally Advanced NSCLC

• IFI omitting ENI allows tumor dose escalation and is associated with a low risk of isolated nodal relapse, particularly in a patient staged with

PET/CT.

67-71

Three randomized trials found improved survival for IFI versus ENI, possibly because it enabled dose escalation.

72-74

IFI is

reasonable in order to optimize denitive dosing to the tumor and/or decrease normal tissue toxicity.

73-74

• Dosing Regimens

The most commonly prescribed doses for denitive RT are 60 to 70 Gy in 2 Gy fractions. Doses of at least 60 Gy should be given.

Dose

escalation is associated with better survival in non-randomized comparisons in RT alone,

sequential chemo/RT,

or concurrent chemo/

. While optimal RT dose intensication remains a valid question, a high dose of 74 Gy is not currently recommended for routine use.

79-

A meta-analysis demonstrated improved survival with accelerated fractionation RT regimens,

and individualized accelerated RT dose

intensication is now being analyzed in a randomized trial (RTOG 1106).

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-C

5 OF 10

Continued

PRINCIPLES OF RADIATION THERAPY

Conventionally Fractionated RT for Locally Advanced NSCLC (continued)

• Dosing Regimens

Doses of 45 to 54 Gy in 1.8 to 2 Gy fractions are standard preoperative doses.

Denitive RT doses delivered as preoperative chemoRT

can safely be administered and achieve promising nodal clearance and survival rates,

87-90

but require experience in thoracic surgical

techniques to minimize the risk of surgical complications after high-dose RT.

In PORT, the CTV includes the bronchial stump and high-risk draining lymph node stations.

Standard doses after complete resection are

50 to 54 Gy in 1.8 to 2 Gy fractions, but a boost may be administered to high-risk regions including areas of nodal extracapsular extension

or microscopic positive margins.

60,61,92

Lung dose constraints should be more conservative, because tolerance appears to be reduced

after surgery. The ongoing European LungART trial provides useful guidelines for PORT technique.

Advanced/Metastatic NSCLC (Stage IV)

• RT is recommended for local palliation or prevention of symptoms (such as pain, bleeding, or obstruction).

• Denitive local therapy to isolated or limited metastatic sites (oligometastases) (including but not limited to brain, lung, and adrenal gland)

achieves prolonged survival in a small proportion of well-selected patients with good performance status who have also received radical

therapy to the intrathoracic disease.

Denitive RT to oligometastases (limited number is not universally dened but clinical trials have

included 3–5 metastases), particularly SABR, is an appropriate option in such cases if it can be delivered safely to the involved sites.

95,96

In two randomized phase II trials, signicantly improved progression-free survival and overall survival in one trial

97,98

were found for local

consolidative therapy (RT or surgery) to oligometastatic lesions versus maintenance systemic therapy or observation for patients not

progressing on systemic therapy.

97-99

• In the setting of progression at a limited number of sites on a given line of systemic therapy (oligoprogression), local ablative therapy to the

oligoprogressive sites may extend the duration of benet of the current line of systemic therapy.

• When treating oligometastatic/oligoprogressive lesions, if SABR is not feasible, other dose-intensive accelerated/hypofractionated CRT

regimens may be used.

• See the NCCN Guidelines for Central Nervous System Cancers regarding RT for brain metastases.

Palliative RT for Advanced/Metastatic NSCLC

• The dose and fractionation of palliative RT should be individualized based on goals of care, symptoms, performance status, and logistical

considerations. Shorter courses of RT are preferred for patients with poor performance status and/or shorter life expectancy because

they provide similar pain relief as longer courses, although there is a higher potential need for retreatment.

100-103

For palliation of thoracic

symptoms, higher dose/longer-course thoracic RT (eg, ≥30 Gy in 10 fractions) is associated with modestly improved survival and symptoms,

particularly in patients with good performance status.

104,105

When higher doses (>30 Gy) are warranted, technologies to reduce normal

tissue irradiation (at least 3D-CRT and including IMRT or proton therapy as appropriate) may be used.

• Single-fraction stereotactic RT of 12–16 Gy produced better control of pain response and local control of non-spine bone metastases

compared to standard 30 Gy in 10 fractions in a randomized phase II trial, and may be promising for patients with longer expected

survival.

106

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-C

6 OF 10

Table 1. Commonly Used Abbreviations in Radiation Therapy

*Refer to ICRU Report 83 for detailed denitions.

RT Radiation Therapy or Radiotherapy

2D-RT 2-Dimensional RT

3D-CRT 3-Dimensional Conformal RT

4D-CT 4-Dimensional Computed

Tomography

AAPM American Association of Physicists

in Medicine

ABC Active Breathing Control

ACR American College of Radiology

ASTRO American Society for Radiation

Oncology

BED Biologically Eective Dose

CBCT Cone-Beam CT

CTV* Clinical Target Volume

ENI Elective Nodal Irradiation

GTV* Gross Tumor Volume

ICRU International Commission on Radiation

Units and Measurements

IFI Involved Field Irradiation

IGRT Image-Guided RT

IMRT Intensity-Modulated RT

ITV* Internal Target Volume

OAR Organ at Risk

OBI On-Board Imaging

PORT Postoperative RT

PTV* Planning Target Volume

QUANTEC Quantitative Analysis of Normal Tissue

Eects in the Clinic

RTOG Radiation Therapy Oncology Group

now part of NRG Oncology

SABR Stereotactic Ablative RT, also known as

Stereotactic Body RT (SBRT)

VMAT Volumetric Modulated Arc Therapy

Continued

PRINCIPLES OF RADIATION THERAPY

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-C

7 OF 10

Table 2. Commonly Used Doses for SABR Table 3. Maximum Dose Constraints for SABR*

*Based on constraints used in recent RTOG SABR trials (RTOG 0618, 0813, & 0915).

For central tumor location. NS = not specied.

Total Dose # Fractions Example Indications

25–34 Gy 1 Peripheral, small (<2 cm)

tumors, esp. >1 cm from

chest wall

45–60 Gy 3 Peripheral tumors and

>1 cm from chest wall

48–50 Gy 4 Central or peripheral tumors

<4–5 cm, especially <1 cm

from chest wall

50–55 Gy 5 Central or peripheral tumors,

especially <1 cm from chest

wall

60–70 Gy 8–10 Central tumors

OAR/Regimen 1 Fraction 3 Fractions 4 Fractions 5 Fractions

Spinal cord 14 Gy 18 Gy

(6 Gy/fx)

26 Gy

(6.5 Gy/fx)

30 Gy

(6 Gy/fx)

Esophagus 15.4 Gy 27 Gy

(9 Gy/fx)

30 Gy

(7.5 Gy/fx)

105% of PTV

prescription^

Brachial

plexus

17.5 Gy 24 Gy

(8 Gy/fx)

27.2 Gy

(6.8 Gy/fx)

32 Gy

(6.4 Gy/fx)

Heart/

pericardium

22 Gy 30 Gy

(10 Gy/fx)

34 Gy

(8.5 Gy/fx)

105% of PTV

prescription^

Great vessels 37 Gy NS 49 Gy

(12.25 Gy/fx)

105% of PTV

prescription^

Trachea &

proximal

bronchi

20.2 Gy 30 Gy

(10 Gy/fx)

34.8 Gy

(8.7 Gy/fx)

105% of PTV

prescription^

Rib 30 Gy 30 Gy

(10 Gy/fx)

40 Gy

(10 Gy/fx)

Skin 26 Gy 24 Gy

(8 Gy/fx)

36 Gy

(9 Gy/fx)

32 Gy

(6.4 Gy/fx)

Stomach 12.4 Gy NS 27.2 Gy

(6.8 Gy/fx)

Please note - Tables 2–4 provide doses and constraints used

commonly or in past clinical trials as useful references rather

than specic recommendations.

Continued

PRINCIPLES OF RADIATION THERAPY

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-C

8 OF 10

Treatment Type Total Dose Fraction

Size

Treatment

Duration

Denitive RT with or without

chemotherapy

60–70 Gy 2 Gy 6–7 weeks

Preoperative RT 45–54 Gy 1.8–2 Gy 5 weeks

Postoperative RT

• Negative margins

• Extracapsular nodal

extension or microscopic

positive margins

• Gross residual tumor

50–54 Gy

54–60 Gy

60–70 Gy

1.8–2 Gy

2 Gy

5–6 weeks

6 weeks

6–7 weeks

Palliative RT

• Obstructive disease (SVC

syndrome or obstructive

pneumonia)

• Bone metastases with soft

tissue mass

• Bone metastases without

soft tissue mass

• Brain metastases

• Symptomatic chest disease

in patients with poor PS

• Any metastasis in patients

with poor PS

30–45 Gy

20–30 Gy

8–30 Gy

CNS GLs*

17 Gy

8–20 Gy

3 Gy

4–3 Gy

8–3 Gy

CNS GLs*

8.5 Gy

8–4 Gy

2–3 weeks

1–2 weeks

1 day–2 weeks

CNS GLs*

1–2 weeks

1 day–1 week

Table 4. Commonly Used Doses for Conventionally Fractionated and

Palliative RT

Table 5. Normal Tissue Dose-Volume Constraints for

Conventionally Fractionated RT with Concurrent Chemotherapy*

,‡

OAR Constraints in 30–35 fractions

Spinal cord Max ≤50 Gy

Lung V20 ≤35%–40%

†

; MLD ≤20 Gy

Heart V50 ≤25%; Mean ≤20 Gy

Esophagus Mean ≤34 Gy; Max ≤105% of prescription dose;

V60 ≤17%; contralateral sparing is desirable

Brachial plexus Median dose ≤69 Gy

*NCCN Guidelines for Central Nervous System Cancers

Vxx = % of the whole OAR receiving ≥xx Gy.

Please note: Tables 2–5 provide doses and constraints used commonly or in past

clinical trials as useful references rather than specic recommendations.

*These constraints represent doses that generally should not be exceeded, based on a

consensus survey of NCCN Member Institutions. Because the risk of toxicity increases

progressively with dose to normal tissues, a key principle of radiation treatment planning is

to keep normal tissue doses "as low as reasonably achievable" while adequately covering

the target. The doses to any given organ at risk should typically be lower than these

constraints, approaching them only when there is close proximity to the target volume.

†

Use V20 <35%, especially for the following: elderly ≥70 years, taxane chemotherapy, and

poor PFTs (such as FEV1 or DLCO <50% normal). Use more conservative limits with a

diagnosis or radiologic evidence of idiopathic pulmonary fibrosis (IDP)/usual interstitial

pneumonia (UIP) (the tolerance of these patients is lower though not well characterized).

‡ Speirs CK, DeWees TA, Rehman S, et al. Heart dose is an independent dosimetric

predictor of overall survival in locally advanced non-small cell lung cancer. J Thorac Oncol

2017;12:293-301; Wang K, Eblan MJ, Deal AM, et al. Cardiac toxicity after radiotherapy

for stage III non-small-cell lung cancer: pooled analysis of dose-escalation trials delivering

70 to 90 Gy. J Clin Oncol 2017;35:1387-1394; Al-Halabi H, Paetzold P, Sharp GC, et al.

A contralateral esophagus-sparing technique to limit severe esophagitis associated with

concurrent high-dose radiation and chemotherapy in patients with thoracic malignancies.

Int J Radiat Oncol Biol Phys 2015;92:803-810; Amini A, Yang J, Williamson R, et al. Dose

constraints to prevent radiation-induced brachial plexopathy in patients treated for lung

cancer. Int J Radiat Oncol Biol Phys 2012;82:e391-398; Graham MV, Purdy JA, Emami B, et

al. Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small

cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys 1999;45:323-329; Palma DA, Senan

S, Tsujino K, et al. Predicting radiation pneumonitis after chemoradiation therapy for lung

cancer: an international individual patient data meta-analysis. Int J Radiat Oncol Biol Phys

2013;85:444-450.

References

PRINCIPLES OF RADIATION THERAPY

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-C

9 OF 10

Chen AB, et al. Survival outcomes after radiation therapy for stage III non-small-cell lung cancer after adoption of computed

tomography-based simulation. J Clin Oncol 2011;29:2305-2311.

Liao ZX, et al. Influence of technologic advances on outcomes in patients with unresectable, locally advanced non-small-cell lung

cancer receiving concomitant chemoradiotherapy. Int J Radiat Oncol Biol Phys 2010;76:775-781.

Sejpal S, et al. Early findings on toxicity of proton beam therapy with concurrent chemotherapy for nonsmall cell lung cancer.

Cancer 2011;117:3004-3013.

Chang JY, et al. Proton beam radiotherapy and concurrent chemotherapy for unresectable stage III non-small cell lung cancer:

final results of a phase 2 study. JAMA Oncol 2017;3:e172032.

Chun SG, et al. Impact of intensity-modulated radiation therapy technique for locally advanced non-small cell lung cancer: a

secondary analysis of the NRG Oncology RTOG 0617 randomized clinical trial. J Clin Oncol 2017;35:56-62.

MacManus M, et al. Use of PET and PET/CT for radiation therapy planning: IAEA expert report 2006-2007. Radiother Oncol

2009;91:85-94.

Ung YC, et al. An Ontario Clinical Oncology Group (OCOG) randomized trial (PET START) of FDG PET/CT in patients with

stage 3 non-small cell lung cancer (NSCLC): impact of PET on radiation treatment volumes [Abstract]. J Thorac Oncol

2011;6:S428.

Everitt S, et al. High rates of tumor growth and disease progression detected on serial pretreatment positrooxyglucose-positron

emission tomography/computed tomography scans in radical radiotherapy candidates with nonsmall cell lung cancer. Cancer

2010;116:5030-5037.

Mohammed N, et al. Rapid disease progression with delay in treatment of non-small-cell lung cancer. Int J Radiat Oncol Biol

Phys 2011;79:466-472.

Liu MB, et al. Clinical impact of dose overestimation by effective path length calculation in stereotactic ablative radiation therapy

of lung tumors. Pract Radiat Oncol 2013;3:294-300.

Keall PJ, et al. The management of respiratory motion in radiation oncology report of AAPM Task Group 76. Med Phys

2006;33:3874-3900.

Kong FM, et al. Physical models and simpler dosimetric descriptors of radiation late toxicity. Semin Radiat Oncol 2007;17:108-

120.

Timmerman RD. An overview of hypofractionation and introduction to this issue of seminars in radiation oncology. Semin Radiat

Oncol 2008;18:215-222.

Marks LB, et al. Use of normal tissue complication probability models in the clinic. Int J Radiat Oncol Biol Phys 2010;76:S10-19.

Marks LB, et al. Radiation dose-volume effects in the lung. Int J Radiat Oncol Biol Phys 2010; 76:S70-76.

Werner-Wasik M, et al. Radiation dose-volume effects in the esophagus. Int J Radiat Oncol Biol Phys 2010;76:S86-93.

Gagliardi G, et al. Radiation dose-volume effects in the heart. Int J Radiat Oncol Biol Phys 2010;76:S77-85.

Kirkpatrick JP, et al. Radiation dose-volume effects in the spinal cord. Int J Radiat Oncol Biol Phys 2010;76:S42-49.

Videtec GMM, et al. Stereotactic body radiation therapy for early-stage non-small cell lung cancer: executive summary of an

ASTRO evidence-based guideline. Pract Radiat Oncol 2017;7:295-301.

Timmerman R, et al. Stereotactic Body Radiation Therapy for Inoperable Early Stage Lung Cancer. JAMA 2010;303:1070-1076.

Baumann P, et al. Outcome in a prospective phase II trial of medically inoperable stage I non-small-cell lung cancer patients

treated with stereotactic body radiotherapy. J Clin Oncol 2009;27:3290-3296.

Onishi H, et al. Stereotactic body radiotherapy (SBRT) for operable stage I non-small-cell lung cancer: can SBRT be

comparable to surgery? Int J Radiat Oncol Biol Phys 2011;81:1352-1358.

Grutters JPC, et al. Comparison of the effectiveness of radiotherapy with photons, protons and carbon-ions for non-small cell

lung cancer: a meta-analysis. Radiother Oncol 2010;95:32-40.

Palma D, et al. Impact of introducing stereotactic lung radiotherapy for elderly patients with stage I non-small-cell lung cancer: a

population-based time-trend analysis. J Clin Oncol 2010;28:5153-5159.

Shirvani SM, et al. Comparative effectiveness of 5 treatment strategies for early-stage non-small cell lung cancer in the elderly.

Int J Radiat Oncol Biol Phys 2012;84:1060-1070.

Sun B, et al. 7-year follow-up after stereotactic ablative radiotherapy for patients with stage I non-small cell lung cancer: Results

of a phase 2 clinical trial. Cancer 2017;123:3031-3039.

Grills IS, et al. Outcomes after stereotactic lung radiotherapy or wedge resection for stage I non-small-cell lung Cancer. J Clin

Oncol 2010;28:928-935.

Crabtree TD, et al. Stereotactic body radiation therapy versus surgical resection for stage I non-small cell lung cancer. J Thorac

Cardiovasc Surg 2010;140:377-386.

Chang JY, Senan S, Paul MA, et al. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung

cancer: a pooled analysis of two randomised trials. Lancet Oncol 2015;16:630-637.

Bogart JA, et al. Phase I study of accelerated conformal radiotherapy for stage I non-small-cell lung cancer in patients with

pulmonary dysfunction: CALGB 39904. J Clin Oncol 2010;28:202-206.

Zhao L, et al. High radiation dose may reduce the negative effect of large gross tumor volume in patients with medically

inoperable early-stage non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2007;68:103-110.

Cheung P, et al. Phase II study of accelerated hypofractionated three-dimensional conformal radiotherapy for stage T1-3 N0 M0

non-small cell lung cancer: NCIC CTG BR.25. J Natl Cancer Inst 2014;106:1-8.

Onishi H, et al. Hypofractionated stereotactic radiotherapy (HypoFXSRT) for stage I non-small cell lung cancer: updated results

of 257 patients in a Japanese multi-institutional study. J Thorac Oncol 2007;2:S94-100.

Moreno AC, Fellman B, Hobbs BP, et al. Biologically effective dose in stereotactic body radiotherapy and survival for patients

with early-stage NSCLC. J Thorac Oncol 2020;15:101-109.

Lagerwaard FJ, et al. Outcomes of risk-adapted fractionated stereotactic radiotherapy for stage I non-small-cell lung cancer. Int

J Radiat Oncol Biol Phys 2008;70:685-692.

Chang JY, et al. Stereotactic body radiation therapy for centrally located early stage or isolated parenchymal recurrences of

non-small-cell lung cancer: how to fly in a “no fly zone”. Int J Radiat Oncol Biol Phys 2014;88:1120-1128.

Timmerman R, et al. Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for

medically inoperable early-stage lung cancer. J Clin Oncol 2006; 24:4833-4839.

Chaudhuri AA, et al. Stereotactic ablative radiotherapy for treatment of central and ultra-central lung tumors. Lung Cancer

2015;89:50-56.

Haseltine JM, et al. Fatal complications after stereotactic body radiation therapy for central lung tumors abutting the proximal

bronchial tree. Pract Radiat Oncol 2016;6:e27-33.

Woody NM, et al. Stereotactic body radiation therapy for non-small cell lung cancer tumors greater than 5 cm: safety and

efficacy. Int J Radiat Oncol Biol Phys 2015:92:325-331.

Bezjak A, Paulus R, Gaspar LE, et al. Safety and efficacy of a five-fraction stereotactic body radiotherapy schedule for centrally

located non-small-cell lung cancer: NRG Oncology/RTOG 0813 Trial. J Clin Oncol 2019;37:1316-1325.

Fakiris AJ, et al. Stereotactic body radiation therapy for early-stage non-small-cell lung carcinoma: four-year results of a

prospective phase II study. Int J Radiat Oncol Biol Phys 2009;75:677-682.

Xiao Y, et al. Dosimetric evaluation of heterogeneity corrections for RTOG 0236: stereotactic body radiotherapy of inoperable

stage I-II non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2009;73:1235-1242.

Zhao L, et al. Planning target volume D95 and mean dose should be considered for optimal local control for stereotactic ablative

radiation therapy. Int J Radiat Oncol Biol Phys 2016;95:1226-35.

Aupérin A, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung

cancer. J Clin Oncol 2010;28:2181-2190.

O'Rourke N, et al. Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev 2010:CD002140.

Curran WJ Jr, et al. Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial

RTOG 9410. J Natl Cancer Inst 2011;103:1452-1460.

Sause W, et al. Final results of phase III trial in regionally advanced unresectable non-small cell lung cancer: Radiation Therapy

Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. Chest 2000;117:358-364.

Dillman RO, et al. Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of cancer and leukemia group

B (CALGB) 8433 trial. J Natl Cancer Inst 1996;88:1210-1215.

Baumann M, et al. Final results of the randomized phase III CHARTWEL-trial (ARO 97-1) comparing hyperfractionated-

accelerated versus conventionally fractionated radiotherapy in non-small cell lung cancer (NSCLC). Radiother Oncol

2011;100:76-85.

Mauguen A, et al. Hyperfractionated or accelerated radiotherapy in lung cancer: an individual patient data meta-analysis. J Clin

Oncol 2012;30:2788-2797.

Albain KS, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a

phase III randomised controlled trial. Lancet 2009;374:379-386

Kunitoh H, et al. Phase II trial of preoperative chemoradiotherapy followed by surgical resection in patients with superior sulcus

non-small-cell lung cancers: report of Japan Clinical Oncology Group trial 9806. J Clin Oncol 2008;26:644-649.

Rusch VW, et al. Induction chemoradiation and surgical resection for superior sulcus non-small-cell lung carcinomas: long-term

results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Clin Oncol 2007;25:313-318.

Thomas M, et al. Effect of preoperative chemoradiation in addition to preoperative chemotherapy: a randomized trial in stage III

non-small-cell lung cancer. Lancet Oncol 2008;9:607-608.

Higgins K, et al. Preoperative chemotherapy versus preoperative chemoradiotherapy for stage III (N2) non-small-cell lung

cancer. Int J Radiat Biol Phys 2009;75:1462-1467.

Sher DJ, et al. Comparative effectiveness of neoadjuvant chemoradiotherapy versus chemotherapy alone followed by surgery

for patients with stage IIIA non-small cell lung cancer. Lancet Oncol 2015;88:267-274.

Shah AA, et al. Induction chemoradiation is not superior to induction chemotherapy alone in stage IIIA lung cancer. Ann Thorac

Surg 2012;93:1807-1812.

Continued

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-C

10 OF 10

Douillard J-Y, et al. Impact of postoperative radiation therapy on survival in patients with complete resection and stage I, II, or

IIIA non-small-cell lung cancer treated with adjuvant chemotherapy: the adjuvant Navelbine International Trialist Association

(ANITA) Randomized Trial. Int J Radiat Oncol Biol Phys 2008;72:695-701.

Lally BE, et al. Postoperative radiotherapy for stage II or III non-small-cell lung cancer using the surveillance, epidemiology, and

end results database. J Clin Oncol 2006;24:2998-3006.

Feigenberg SJ, et al. A phase II study of concurrent carboplatin and paclitaxel and thoracic radiotherapy for completely resected

stage II and IIIA non-small cell lung cancer. J Thorac Oncol 2007;2:287-292.

Bradley JD, et al. Phase II trial of postoperative adjuvant paclitaxel/carboplatin and thoracic radiotherapy in resected stage II

and IIIA non-small-cell lung cancer: promising long-term results of the Radiation Therapy Oncology Group--RTOG 9705. J Clin

Oncol 2005;23:3480-3487.

Keller SM, et al. A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-

small-cell lung cancer. Eastern Cooperative Oncology Group. N Engl J Med 2000; 343:1217-1222.

Hancock JG, et al. Impact of adjuvant treatment for microscopic residual disease after non-small cell lung cancer surgery. Ann

Thorac Surg 2015;99:406-416.

Burdett S, Stewart L, Group PM-a. Postoperative radiotherapy in non-small-cell lung cancer: update of an individual patient data

meta-analysis. Lung Cancer 2005;47:81-83.

Francis S, et al. Sequencing of postoperative radiotherapy and chemotherapy for locally advanced or incompletely resected

non-small-cell lung cancer. J Clin Oncol 2018;36:333-341.

Belderbos JS, et al. Report from the International Atomic Energy Agency (IAEA) consultants’ meeting on elective nodal

irradiation in lung cancer: non-small cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys 2008;72:335-342.

Bradley J, et al. A phase II comparative study of gross tumor volume definition with or without

PET/CT fusion in dosimetric planning for non-small-cell lung cancer (NSCLC): primary analysis of radiation therapy oncology

group (RTOG) 0515. Int J Radiat Oncol Biol Phys 2012;82:435-441.

Sanuki-Fujimoto N, et al. Relation between elective nodal failure and irradiated volume in non-small-cell lung cancer (NSCLC)

treated with radiotherapy using conventional fields and doses. Radiother Oncol 2009; 91:433-437.

Sulman EP, et al. Exclusion of elective nodal irradiation is associated with minimal elective nodal failure in non-small cell lung

cancer. Radiat Oncol 2009;4:5-11.

Rosenzweig KE, Sura S, Jackson A, Yorke E. Involved-field radiation therapy for inoperable non small-cell lung cancer. J Clin

Oncol 2007;25:5557-5561.

Yuan S, et al. A randomized study of involved-field irradiation versus elective nodal irradiation in combination with concurrent

chemotherapy for inoperable stage III nonsmall cell lung cancer. Am J Clin Oncol 2007;30:239-244.

Chen M, et al. Involved-field radiotherapy versus elective nodal irradiation in combination with concurrent chemotherapy for

locally advanced non-small cell lung cancer: a propective randomized study. Biomed Res Int 2013;3711819.

Nestle U, Schimek-Jasch T, Kremp S, et al. Imaging-based target volume reduction in chemoradiotherapy for locally advanced

non-small-cell lung cancer (PET-Plan): a multicentre, open-label, randomised, controlled trial. Lancet Oncol 2020;21:581-592.

Perez CA, et al. Long-term observations of the patterns of failure in patients with unresectable non-oat cell carcinoma of the

lung treated with definitive radiotherapy. Report by the Radiation Therapy Oncology Group. Cancer 1987;59:1874-1881.

Kong FM, et al. High-dose radiation improved local tumor control and overall survival in patients with inoperable/unresectable

non-small-cell lung cancer: long-term results of a radiation dose escalation study. Int J Radiat Oncol Biol Phys 2005;63:324-333.

Rengan R, et al. Improved local control with higher doses of radiation in large-volume stage III non-small-cell lung cancer. Int J

Radiat Oncol Biol Phys 2004;60:741-747.

Machtay M, et al. Higher biologically effective dose of radiotherapy is associated with improved outcomes for locally advanced

non-small cell lung carcinoma treated with chemoradiation: an analysis of the radiation therapy oncology group. Int J Radiat

Oncol Biol Phys 2012;82:425-434.

Schild SE, et al. Results of a phase I trial of concurrent chemotherapy and escalating doses of radiation for unresectable non-

small-cell lung cancer. Int J Radiat Oncol Biol Phys 2006;65:1106-1111.

Socinski MA, et al. Randomized phase II trial of induction chemotherapy followed by concurrent chemotherapy and dose-

escalated thoracic conformal radiotherapy (74 Gy) in stage III non-small-cell lung cancer: CALGB 30105. J Clin Oncol

2008;26:2457-2463.

Stinchcombe TE, et al. Long-term follow-up of a phase I/II trial of dose escalating three-dimensional conformal thoracic radiation

therapy with induction and concurrent carboplatin and paclitaxel in unresectable stage IIIA/B non-small cell lung cancer. J

Thorac Oncol 2008;3:1279-1285.

Bradley JD, et al. Primary analysis of the phase II component of a phase I/II dose intensification study using three-dimensional

conformal radiation therapy and concurrent chemotherapy for patients with inoperable non-small-cell lung cancer: RTOG 0117. J

Clin Oncol 2010;28:2475-2480.

Bradley JD, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus

paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised,

two-by-two factorial phase 3 study. Lancet Oncol 2015;16:187-199.

Schild SE, et al. Toxicity related to radiotherapy dose and targeting strategy: a pooled analysis of cooperative group trials of

combined modality therapy for locally advanced non-small cell lung cancer. J Thorac Oncol 2019;14:298-303.

Maugen A, et al. Hyperfractionated or accelerated radiotherapy in lung cancer: an individual patient data meta-analysis. J Clin

Oncol 2012;30:2788-2797.

Sher DJ, et al. Relationship between radiation therapy dose and outcome in patients treated with neoadjuvant chemoradiation

therapy and surgery for stage IIIA non-small cell lung cancer: a population-based, comparative effectiveness analysis. in J

Radiat Oncol Biol Phys 2015;92:307-316.

Cerfolio RJ, Bryant AS, Jones VL, Cerfolio RM. Pulmonary resection after concurrent chemotherapy and high dose (60Gy)

radiation for non-small cell lung cancer is safe and may provide increased survival. Eur J Cardiothorac Surg 2009;35:718-723;

discussion 723.

Kwong KF, et al. High-dose radiotherapy in trimodality treatment of Pancoast tumors results in high pathologic complete

response rates and excellent long-term survival. J Thorac Cardiovasc Surg 2005;129:1250-1257.

Sonett JR, et al. Pulmonary resection after curative intent radiotherapy (>59 Gy) and concurrent chemotherapy in non-small-cell

lung cancer. Ann Thorac Surg 2004;78:1200-1205.

Suntharalingam M, et al. Radiation therapy oncology group protocol 02-29: a phase II trial of neoadjuvant therapy with

concurrent chemotherapy and full-dose radiation therapy followed by surgical resection and consolidative therapy for locally

advanced non-small cell carcinoma of the lung. Int J Radiat Oncol Biol Phys 2012;84:456-463.

Kelsey CR, Light KL, Marks LB. Patterns of failure after resection of non-small-cell lung cancer: implications for postoperative

radiation therapy volumes. Int J Radiat Oncol Biol Phys 2006;65:1097-1105.

Corso CD, et al. Re-evaluation of the role of postoperative radiotherapy and the impact of radiation dose for non-small-cell lung

cancer using the National Cancer Database. J Thorac Oncol 2015;10:148-155.

Spoelstra FOB, et al. Variations in target volume definition for postoperative radiotherapy in stage III non-small-cell lung cancer:

analysis of an international contouring study. Int J Radiat Oncol Biol Phys 2010; 76:1106-1113.

Ashworth AB, et al. An individual patient data metaanalysis of outcomes and prognostic factors after treatment of

oligometastatic non-small-cell lung cancer. Clin Lung Cancer 2014;15:346-355.

Milano MT, Katz AW, Okunieff P. Patterns of recurrence after curative-intent radiation for oligometastases confined to one organ.

Am J Clin Oncol 2010;33:157-163.

Salama JK, et al. An initial report of a radiation dose-escalation trial in patients with one to five sites of metastatic disease. Clin

Cancer Res 2008;14:5255-5259.

Gomez DR, et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-

small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study.

Lancet Oncol 2016;17:1672-1682.

Gomez DR, et al. Local consolidative therapy vs. maintenance therapy or observation for patients with oligometastatic non-

small-cell lung cancer: long-term results of a multi-institutional, phase II, randomized study. J Clin Oncol 2019;37:1558-1565.

Iyengar P, et al. Consolidative radiotherapy for limited metastatic non-small-cell lung cancer: A phase 2 randomized clinical trial.

JAMA Oncol 2018;4:e173501.

100

Chow E, et al. Palliative radiotherapy trials for bone metastases: a systematic review. J Clin Oncol 2007;25:1423-1436.

101

Lutz S, et al. Palliative radiotherapy for bone metastases: an ASTRO evidence-based guideline. Int J Radiat Oncol Biol Phys

2011;79:965-976.

102

Cross CK, et al. Prospective study of palliative hypofractionated radiotherapy (8.5 Gy x 2) for patients with symptomatic non-

small-cell lung cancer. Int J Radiat Oncol Biol Phys 2004;58:1098-1105.

103

Medical Research Council Lung Cancer Working Party. A Medical Research Council (MRC) randomised trial of palliative

radiotherapy with two fractions or a single fraction in patients with inoperable non-small-cell lung cancer (NSCLC) and poor

performance status. Medical Research Council Lung Cancer Working Party. Br J Cancer 1992;65:934-941.

104

Rodrigues G, et al. Palliative thoracic radiotherapy in lung cancer: An American Society for Radiation Oncology evidence-

based clinical practice guideline. Pract Radiat Oncol 2011;1:60-71.

105

Koshy M, et al. Comparative effectiveness of aggressive thoracic radiation therapy and concurrent chemoradiation therapy in

metastatic lung cancer. Pract Radiat Oncol 2015;5:374-382.

106

Nguyen QN, Chun SG, Chow E, et al. Single-fraction stereotactic vs conventional multifraction radiotherapy for pain relief in

patients with predominantly nonspine bone metastases: a randomized phase 2 trial. JAMA Oncol 2019;5:872-878.

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

General Principles

• Interventional radiologists should actively participate in multidisciplinary discussions and meetings regarding patients with NSCLC (eg,

multidisciplinary clinic and/or tumor board).

• Decisions about whether ablation is feasible should be performed by interventional radiologists who perform IGTA as a prominent part of

their practice.

• IGTA includes radiofrequency ablation, microwave ablation, and cryoablation. IGTA is a form of “local therapy” or “local ablative therapy.”

• IGTA is a lung parenchymal sparing technique with at most a temporary decrement in FEV1 and DLCO, which is statistically

indistinguishable from baseline after recovery.

2-6

Evaluation

• IGTA may be considered for those patients who are deemed “high risk”—those with tumors that are for the most part surgically resectable

but rendered medically inoperable due to comorbidities. In cases where IGTA is considered for high-risk or borderline operable patients, a

multidisciplinary evaluation is recommended.

• IGTA has been successfully accomplished in patients considered “high risk,” objectively dened with a single major and/or two or more

minor criteria. Major criteria included an FEV1 or DCLO ≤50%, and minor criteria included a less depressed FEV1 or DLCO between 51%–

60%, advanced age ≥75 years, pulmonary hypertension, LVEF ≤40%, resting or exercise PaO2 <55 mmHg, and pCO2 >45 mmHg.

• If an interventional radiologist or center is uncertain about the feasibility or safety of IGTA, consider obtaining an additional interventional

radiology opinion from a high-volume specialized center.

Ablation

• Each energy modality has advantages and disadvantages. Determination of energy modality to be used for ablation should take into

consideration the size and location of the target tumor, risk of complication, as well as local expertise and/or operator familiarity.

Ablation for NSCLC

• IGTA is an option for the management of NSCLC lesions <3 cm. Ablation for NSCLC lesions >3 cm may be associated with higher rates of

local recurrence and complications.

8,9

• There is evidence on the use of IGTA for selected patients with Stage 1A NSCLC, those who present with multiple lung cancers, or those who

present with locoregional recurrence of symptomatic local thoracic disease.

PRINCIPLES OF IMAGE-GUIDED THERMAL ABLATION THERAPY

NSCL-D

Lam A, Yoshida EJ, Bui K, et al. Patient and facility demographics related outcomes in early-

stage non-small cell lung cancer treated with radiofrequency ablation: a National Cancer

Database analysis. J Vasc Interv Radiol 2018;29:1535-1541.

Dupuy DE, DiPetrillo T, Gandhi S, et al. Radiofrequency ablation followed by conventional

radiotherapy for medically inoperable stage I non-small cell lung cancer. Chest 2006;129:738-

745.

Lencioni R, Crocetti L, Cioni R, et al. Response to radiofrequency ablation of pulmonary

tumours: a prospective, intention-to-treat, multicentre clinical trial (the RAPTURE study).

Lancet Oncol 2008;9:621-628.

Dupuy DE, Fernando HC, Hillman S, et al. Radiofrequency ablation of stage IA non-small cell

lung cancer in medically inoperable patients: Results from the American College of Surgeons

Oncology Group Z4033 (Alliance) trial. Cancer 2015;121:3491-3498.

de Baere T, Tselikas L, Woodrum D, et al. Evaluating cryoablation of metastatic lung tumors

in patients--safety and efficacy: The ECLIPSE Trial--interim analysis at 1 year. J Thorac Oncol

2015;10:1468-1474.

Tada A, Hiraki T, Iguchi T, et al. Influence of radiofrequency ablation of lung cancer on

pulmonary function. Cardiovasc Intervent Radiol 2012;35:860-867.

Abtin F, De Baere T, Dupuy DE, et al. Updates on current role and practice of lung ablation. J

Thorac Imaging 2019;34(4):266-277.

Lee JM, Jin GY, Goldberg SN, et al. Percutaneous radiofrequency ablation for inoperable

non-small cell lung cancer and metastases: preliminary report. Radiology 2004;230:125-134.

Akeboshi M, Yamakado K, Nakatsuka A, et al. Percutaneous radiofrequency ablation of lung

neoplasms: initial therapeutic response. J Vasc Interv Radiol 2004;15:463-470.

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-E

Kreuter M, Vansteenkiste J, Fishcer JR, et al. Randomized phase 2 trial on refinement of

early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin

and vinorelbine: the TREAT study. Ann Oncol 2013;24:986-992.

Pérol M, Chouaid C, Pérol D, et al. Randomized, phase III study of gemcitabine or

erlotinib maintenance therapy versus observation, with predefined second-line treatment,

after cisplatin-gemcitabine induction chemotherapy in advanced non-small-cell lung

cancer. J Clin Oncol 2012;30:3516-3524.

Fossella F, Pereira JR, von Pawel J, et al. Randomized, multinational, phase III study of

docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-

small-cell lung cancer: the TAX 326 study group. J Clin Oncol 2003;21:3016-3024.

Winton T, Livingston R, Johnson D, et al. Vinorelbine plus cisplatin vs. observation in

resected non-small-lung cancer. N Engl J Med 2005;352:2589-2597.

Arriagada R, Bergman B, Dunant A, et al. The International Adjuvant Lung Cancer Trial

Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely

resected non-small cell lung cancer. N Engl J Med 2004;350:351-360.

Douillard JY, Rosell R, De Lena M, et al. Adjuvant vinorelbine plus cisplatin versus

observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer

(Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled

trial. Lancet Oncol 2006;7:719-727.

Strauss GM, Herndon III JE, Maddaus MA, et al. Adjuvant paclitaxel plus carboplatin

compared with observation in stage IB non-small cell lung cancer: CALGB 9633 with the

Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central

Cancer Treatment Group Study Groups. J Clin Oncol 2008;26:5043-5051.

Usami N, Yokoi K, Hasegawa Y, et al. Phase II study of carboplatin and gemcitabine as

adjuvant chemotherapy in patients with completely resected non-small cell lung cancer:

a report from the Central Japan Lung Study Group, CJLSG 0503 trial. Int J Clin Oncol

2010;15:583-587.

Zhang L, Ou W, Liu Q, et al. Pemetrexed plus carboplatin as adjuvant chemotherapy in

patients with curative resected non-squamous non-small cell lung cancer. Thorac Cancer

2014;5:50-56.

Wu Y-L, Tsuboi M, He J, et al. Osimertinib in resected EGFR-mutated non-small-cell lung

cancer. N Engl J Med 2020;383:1711-1723.

SYSTEMIC THERAPY REGIMENS FOR NEOADJUVANT AND ADJUVANT THERAPY

Preferred (nonsquamous)

• Cisplatin 75 mg/m

day 1, pemetrexed 500 mg/m

day 1 every 21 days for 4 cycles

Preferred (squamous)

• Cisplatin 75 mg/m

day 1; gemcitabine 1250 mg/m

days 1 and 8, every 21 days for 4 cycles

• Cisplatin 75 mg/m

day 1; docetaxel 75 mg/m

day 1 every 21 days for 4 cycles

Other Recommended

• Cisplatin 50 mg/m

days 1 and 8; vinorelbine 25 mg/m

days 1, 8, 15, and 22, every 28 days for 4 cycles

• Cisplatin 100 mg/m

day 1; vinorelbine 30 mg/m

days 1, 8, 15, and 22, every 28 days for 4 cycles

5,6

• Cisplatin 75–80 mg/m

day 1; vinorelbine 25–30 mg/m

days 1 and 8, every 21 days for 4 cycles

• Cisplatin 100 mg/m

day 1; etoposide 100 mg/m

days 1–3, every 28 days for 4 cycles

Useful in Certain Circumstances

Chemotherapy Regimens for Patients with Comorbidities or Patients Not Able to Tolerate Cisplatin

• Carboplatin AUC 6 day 1, paclitaxel 200 mg/m

day 1, every 21 days for 4 cycles

• Carboplatin AUC 5 day 1, gemcitabine 1000 mg/m

days 1 and 8, every 21 days for 4 cycles

• Carboplatin AUC 5 day 1, pemetrexed 500 mg/m

day 1 for nonsquamous every 21 days for 4 cycles

All regimens can be used for sequential chemotherapy/RT.

Previous Adjuvant Chemotherapy or Ineligible for Platinum-Based Chemotherapy

• Osimertinib 80 mg daily

Osimertinib for patients with completely resected stage IIB-IIIA or high risk stage IB-IIA EGFR mutation-positive NSCLC who received

previous adjuvant chemotherapy or are ineligible to receive platinum-based chemotherapy.

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-F

CONCURRENT CHEMORADIATION REGIMENS

Concurrent Chemoradiation Regimens

€

Preferred (nonsquamous)

• Carboplatin AUC 5 on day 1, pemetrexed 500 mg/m

on day 1 every 21 days for 4 cycles; concurrent thoracic RT

,†,‡

• Cisplatin 75 mg/m

on day 1, pemetrexed 500 mg/m

on day 1 every 21 days for 3 cycles; concurrent thoracic RT

2,3,

,†,‡

± additional 4 cycles of pemetrexed 500 mg/m

†,§

• Paclitaxel 45–50 mg/m

weekly; carboplatin AUC 2, concurrent thoracic RT

,†,‡

± additional 2 cycles every 21 days of paclitaxel 200 mg/m

and

carboplatin AUC 6

†,§

• Cisplatin 50 mg/m

on days 1, 8, 29, and 36; etoposide 50 mg/m

days 1–5 and 29–33; concurrent thoracic RT

5,6,

,†,‡

Preferred (squamous)

• Paclitaxel 45–50 mg/m

weekly; carboplatin AUC 2, concurrent thoracic RT

,†,‡

± additional 2 cycles every 21 days of paclitaxel 200 mg/m

and

carboplatin AUC 6

†,§

• Cisplatin 50 mg/m

on days 1, 8, 29, and 36; etoposide 50 mg/m

days 1–5 and 29–33; concurrent thoracic RT

5,6,

,†,‡

Consolidation Immunotherapy for Patients with Unresectable Stage II/III NSCLC, PS 0–1, and No Disease Progression After 2 or More Cycles of

Denitive Concurrent Chemoradiation

Durvalumab 10 mg/kg IV every 2 weeks or 1500 mg every 4 weeks for up to 12 months (patients with a body weight of ≥30 kg)

7,8

(category 1 for stage III; category 2A for stage II)

€

For patients with superior sulcus tumors, the recommendation is for 2 cycles concurrent with radiation therapy and 2 more cycles after surgery. Rusch VW, Giroux DJ, Kraut MJ, et

al. Induction chemoradiation and surgical resection for superior sulcus non-small-cell lung carcinomas: long-term results of Southwest Oncology Group Trial 9416 (Intergroup Trial

0160). J Clin Oncol 2007;25:313-318.

Regimens can be used as preoperative/adjuvant chemotherapy/RT.

†

Regimens can be used as definitive concurrent chemotherapy/RT.

‡

For eligible patients, durvalumab may be used after noted concurrent chemo/RT regimens.

If using durvalumab, an additional 2 cycles of chemotherapy is not recommended, if patients have not received full-dose chemotherapy concurrently with RT.

Govindan R, Bogart J, Stinchcombe T, et al. Randomized phase II study of pemetrexed, carboplatin, and thoracic radiation with or without cetuximab in patients with locally

advanced unresectable non-small-cell lung cancer: Cancer and Leukemia Group B trial 30407. J Clin Oncol 2011;29:3120-3125.

Choy H, Gerber DE, Bradley JD, et al. Concurrent pemetrexed and radiation therapy in the treatment of patients with inoperable stage III non-small cell lung cancer: a systematic

review of completed and ongoing studies. Lung Cancer 2015;87:232-240.

Senan S, Brade A, Wang LH, et al. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation

chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol 2016;34:953-962.

Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without

cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol 2015;16:187-199.

Albain KS, Crowley JJ, Turrisi AT III, et al. Concurrent cisplatin, etoposide, and chest radiotherapy in pathologic stage IIIB non-small-cell lung cancer: A Southwest Oncology Group

Phase II Study, SWOG 9019. J Clin Oncol 2002;20:3454-3460.

Curran WJ Jr, Paulus R, Langer CJ, et al. Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer

Inst 2011;103:1452-1460.

Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med 2018;379:2342-2550.

Baverel PG, Dubois VFS, Jin CY, et al. Population pharmacokinetics of durvalumab in cancer patients and association with longitudinal biomarkers of disease status. Clin

Pharmacol Ther 2018;103:631-642.

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-G

ACS Guidelines on Nutrition and Physical Activity for Cancer Prevention:

http://www.cancer.org/healthy/eathealthygetactive/acsguidelinesonnutritionphysicalactivityforcancerprevention/index?sitearea=PED.

Memorial Sloan Kettering Cancer Center Screening Guidelines: https://www.mskcc.org/cancer-care/risk-assessment-screening/screening-guidelines.

American Cancer Society Guidelines for Early Detection of Cancer:

http://www.cancer.org/healthy/findcancerearly/cancerscreeningguidelines/american-cancer-society-guidelines-for-the-early-detection-of-cancer?sitearea=PED.

CANCER SURVIVORSHIP CARE

NSCLC Long-term Follow-up Care

• Cancer Surveillance (See NSCL-16)

• Immunizations

Annual inuenza vaccination

Herpes zoster vaccine

Pneumococcal vaccination with revaccination as appropriate

• See NCCN Guidelines for Survivorship

Counseling Regarding Health Promotion and Wellness

• Maintain a healthy weight

• Adopt a physically active lifestyle (Regular physical activity: 30

minutes of moderate-intensity physical activity on most days of

the week)

• Consume a healthy diet with emphasis on plant sources

• Limit consumption of alcohol if one consumes alcoholic beverages

Additional Health Monitoring

• Routine blood pressure, cholesterol, and glucose monitoring

• Bone health: Bone density testing as appropriate

• Dental health: Routine dental examinations

• Routine sun protection

Resources

• National Cancer Institute Facing Forward: Life After Cancer Treatment

https://www.cancer.gov/publications/patient-education/facing-

forward

Cancer Screening Recommendations

2,3

These recommendations are for average-risk individuals and high-risk

patients should be individualized.

• Colorectal Cancer:

See NCCN Guidelines for Colorectal Cancer Screening

• Prostate Cancer:

See NCCN Guidelines for Prostate Cancer Early Detection

• Breast Cancer:

See NCCN Guidelines for Breast Cancer Screening and Diagnosis

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-H

1 OF 5

PRINCIPLES OF MOLECULAR AND BIOMARKER ANALYSIS

Molecular Diagnostic Studies in Non-Small Cell Lung Cancer

• Numerous gene alterations have been identied that impact therapy selection. Testing of lung cancer specimens for these alterations is important for

identication of potentially ecacious targeted therapies, as well as avoidance of therapies unlikely to provide clinical benet.

• Some selection approaches for targeted therapy include predictive immunohistochemical analyses, which are distinct from immunohistochemical

studies utilized to identify tumor type and lineage.

• Major elements of molecular testing that are critical for utilization and interpretation of molecular results include:

Use of a laboratory that is properly accredited, with a minimum of CLIA accreditation

Understanding the methodologies that are utilized and the major limitations of those methodologies

Understanding the spectrum of alterations tested (and those not tested) by a specic assay

Knowledge of whether a tumor sample is subjected to pathologic review and tumor enrichment (ie, microdissection, macrodissection) prior to testing

The types of samples accepted by the testing laboratory

• Specimen Acquisition and Management:

Although tumor testing has been primarily focused on use of FFPE tissues, increasingly, laboratories accept other specimen types, notably

cytopathology preparations not processed by FFPE methods. Although testing on cell blocks is not included in the FDA approval for multiple

companion diagnostic assays, testing on these specimen types is highly recommended when it is the only or best material.

A major limitation in obtaining molecular testing results for NSCLC occurs when minimally invasive techniques are used to obtain samples; the

yield may be insucient for molecular, biomarker, and histologic testing. Therefore, bronchoscopists and interventional radiologists should procure

sucient tissue to enable all appropriate testing.

When tissue is minimal, laboratories should deploy techniques to maximize tissue for molecular and ancillary testing, including dedicated histology

protocols for small biopsies, including “up-front” slide sectioning for diagnostic and predictive testing.

• Testing Methodologies

Appropriate possible testing methodologies are indicated below for each analyte separately; however, several methodologies are generally

considerations for use:

◊ Next-generation sequencing (NGS) is used in clinical laboratories. Not all types of alterations are detected by individual NGS assays and it is

important to be familiar with the types of alterations identiable in individual assays or combination(s) of assays.

◊ It is recommended at this time that when feasible, testing be performed via a broad, panel-based approach, most typically performed by NGS.

For patients who, in broad panel testing don’t have identiable driver oncogenes (especially in never smokers), consider RNA-based NGS if not

already performed, to maximize detection of fusion events.

◊ Real-time polymerase chain reaction (PCR) can be used in a highly targeted fashion (specic mutations targeted). When this technology is

deployed, only those specic alterations that are targeted by the assay are assessed.

◊ Sanger sequencing requires the greatest degree of tumor enrichment. Unmodied Sanger sequencing is not appropriate for detection of mutations

in tumor samples with less than 25% to 30% tumor after enrichment and is not appropriate for assays in which identication of subclonal events

(eg, resistance mutations) is important. If Sanger sequencing is utilized, tumor enrichment methodologies are nearly always recommended.

◊ Other methodologies may be utilized, including multiplex approaches not listed above (ie, SNaPshot, MassARRAY).

◊ Fluorescence in situ hybridization (FISH) analysis is utilized for many assays examining copy number, amplication, and structural alterations

such as gene rearrangements.

◊ IHC is specically utilized for some specic analytes, and can be a useful surrogate or screening assay for others.

Continued

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

• Molecular Targets for Analysis

In general, the mutations/alterations described below are seen in a non-overlapping fashion, although between 1%–3% of NSCLC may harbor

concurrent alterations.

EGFR (Epidermal Growth Factor Receptor) Gene Mutations: EGFR is a receptor tyrosine kinase normally found on the surface of epithelial cells

and is often overexpressed in a variety of human malignancies.

◊ The most commonly described mutations in EGFR (exon 19 deletions, p.L858R point mutation in exon 21) are associated with responsiveness

to oral EGFR tyrosine kinase inhibitor (TKI) therapy; most recent data indicate that tumors that do not harbor a sensitizing EGFR mutation

should not be treated with EGFR TKI in any line of therapy.

◊ Molecular testing for EGFR mutation to be performed on diagnostic biopsy or surgical resection sample to ensure the EGFR mutation results

are available for adjuvant treatment decisions for patients with

stage IIB-IIIA or high risk stage IB-IIA NSCLC.

◊ Many of the less commonly observed alterations in EGFR, which cumulatively account for ~10% of EGFR-mutation positive NSCLC (ie,

exon 19 insertions, p.L861Q, p.G719X, p.S768I) are also associated with responsiveness to EGFR TKI therapy, although the number of

studied patients is lower.

◊ EGFR exon 20 (EGFRex20) mutations are a heterogeneous group, some of which are responsive to targeted therapy and that require detailed

knowledge of the specic alteration.

– EGFR p.T790M is most commonly observed as a mutation that arises in response to and as a mechanism of resistance to rst- and second-

generation EGFR TKI. In patients with progression on rst- or second-generation TKI with p.T790M as the primary mechanism of resistance,

third-generation TKIs are typically ecacious. If p.T790M is observed in the absence of prior EGFR TKI therapy, genetic counseling and

possible germline genetic testing is warranted.

– Most other EGFRex20 alterations are a diverse group of in-frame duplication or insertion mutations.

▪ These are generally associated with lack of response to EGFR TKI therapy, with select exceptions:

p.A763_Y764insFQEA is associated with sensitivity to TKI therapy

p. A763_Y764insLQEA may be associated with sensitivity to TKI therapy

▪ For this reason, the specic sequence of EGFRex20 insertion mutations is important, and some assays will identify the presence of an

EGFRex20 insertion without specifying the sequence. In this scenario, additional testing to further clarify the EGFRex20 insertion is

indicated.

◊ As use of NGS testing increases, additional EGFR variants are increasingly identied; however, the clinical implications of individual alterations

are unlikely to be well established.

◊ Some clinicopathologic features—such as smoking status, ethnicity, and histology—are associated with the presence of an EGFR mutation;

however, these features should not be utilized in selecting patients for testing.

◊ Testing Methodologies: Real-time PCR, Sanger sequencing (ideally paired with tumor enrichment), and NGS are the most commonly deployed

methodologies for examining EGFR mutation status.

NSCL-H

2 OF 5

Continued

PRINCIPLES OF MOLECULAR AND BIOMARKER ANALYSIS

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

• Molecular Targets for Analysis (continued)

ALK (Anaplastic Lymphoma Kinase) Gene Rearrangements: ALK is a receptor tyrosine kinase that can be rearranged in NSCLC, resulting in

dysregulation and inappropriate signaling through the ALK kinase domain.

◊ The most common fusion partner seen with ALK is echinoderm microtubule-associated protein-like 4 (EML4), although a variety of other fusion

partners have been identied.

◊ The presence of an ALK rearrangement is associated with responsiveness to oral ALK TKIs.

◊ Some clinicopathologic features—such as smoking status and histology—have been associated with the presence of an ALK rearrangement;

however, these features should not be utilized in selecting patients for testing.

◊ Testing Methodologies: FISH break-apart probe methodology was the rst methodology deployed widely. IHC can be deployed as an eective

screening strategy. FDA-approved IHC (ALK [D5F3] CDx Assay) can be utilized as a stand-alone test, not requiring conrmation by FISH.

Numerous NGS methodologies can detect ALK fusions. Targeted real-time PCR assays are used in some settings, although it is unlikely to detect

fusions with novel partners.

ROS1 (ROS proto-oncogene 1) Gene Rearrangements: ROS1 is a receptor tyrosine kinase that can be rearranged in NSCLC, resulting in

dysregulation and inappropriate signaling through the ROS1 kinase domain.

◊ Numerous fusion partners are seen with ROS1, and common fusion partners include: CD74, SLC34A2, CCDC6, and FIG.

◊ The presence of a ROS1 rearrangement is associated with responsiveness to oral ROS1 TKIs.

◊ Some clinicopathologic features—such as smoking status and histology—have been associated with the presence of a ROS1 rearrangement;

however, these features should not be utilized in selecting patients for testing.

◊ Testing Methodologies: FISH break-apart probe methodology can be deployed; however, it may under-detect the FIG-ROS1 variant. IHC

approaches can be deployed; however, IHC for ROS1 fusions has low specicity, and follow-up conrmatory testing is a necessary component of

utilizing ROS1 IHC as a screening modality. Numerous NGS methodologies can detect ROS1 fusions, although DNA-based NGS may under-detect

ROS1 fusions. Targeted real-time PCR assays are utilized in some settings, although they are unlikely to detect fusions with novel partners.

BRAF (B-Raf proto-oncogene) point mutations: BRAF is a serine/threonine kinase that is part of the canonical MAP/ERK signaling pathway.

Activating mutations in BRAF result in unregulated signaling through the MAP/ERK pathway.

◊ Mutations in BRAF can be seen in NSCLC. The presence of a specic mutation resulting in a change in amino acid position 600 (p.V600E) has been

associated with responsiveness to combined therapy with oral inhibitors of BRAF and MEK.

◊ Note that other mutations in BRAF are observed in NSCLC, and the impact of those mutations on therapy selection is not well understood at this

time.

◊ Testing Methodologies: Real-time PCR, Sanger sequencing (ideally paired with tumor enrichment), and NGS are the most commonly deployed

methodologies for examining BRAF mutation status. While an anti-BRAF p.V600E-specic monoclonal antibody is commercially available, and

some studies have examined utilizing this approach, it should only be deployed after extensive validation.

KRAS (KRAS proto-oncogene) point mutations: KRAS is a G-protein with intrinsic GTPase activity, and activating mutations result in unregulated

signaling through the MAP/ERK pathway.

◊ Mutations in KRAS are most commonly seen at codon 12, although other mutations can be seen in NSCLC.

◊ The presence of a KRAS mutation is prognostic of poor survival when compared to patients with tumors without KRAS mutation.

◊ Mutations in KRAS have been associated with reduced responsiveness to EGFR TKI therapy.

◊ Owing to the low probability of overlapping targetable alterations, the presence of a known activating mutation in KRAS identies patients who are

unlikely to benet from further molecular testing.

NSCL-H

3 OF 5

Continued

PRINCIPLES OF MOLECULAR AND BIOMARKER ANALYSIS

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

• Molecular Targets for Analysis (continued)

MET (mesenchymal-epithelial transition) exon 14 (METex14) skipping variants: MET is a receptor tyrosine kinase. A mutation that results in loss of

exon 14 can occur in NSCLC. Loss of

METex14 leads to dysregulation and inappropriate signaling.

◊ The presence of METex14 skipping mutation is associated with responsiveness to oral MET TKIs.

◊ A broad range of molecular alterations lead to METex14 skipping.

◊ Testing Methodologies: NGS-based testing is the primary method for detection of METex14 skipping events, with RNA-based NGS demonstrating

improvement in detection. IHC is not a method for detection of METex14 skipping.

RET (rearranged during transfection) Gene Rearrangements: RET is a receptor tyrosine kinase that can be rearranged in NSCLC, resulting in

dysregulation and inappropriate signaling through the RET kinase domain.

◊ Common fusion partners are KIF5B, NCOA4, and CCDC6; however, numerous other fusion partners have been identied.

◊ The presence of a RET rearrangement is associated with responsiveness to oral RET TKIs regardless of fusion partner.

◊ Testing Methodologies: FISH break-apart probe methodology can be deployed; however, it may under-detect some fusions. Targeted real-time

reverse-transcriptase PCR assays are utilized in some settings, although they are unlikely to detect fusions with novel partners. NGS-based

methodology has a high specicity, and RNA-based NGS is preferable to DNA-based NGS for fusion detection.

NTRK1/2/3 (neurotrophic tyrosine receptor kinase) gene fusions

◊ NTRK1/2/3 are tyrosine receptor kinases that are rarely rearranged in NSCLC as well as in other tumor types, resulting in dysregulation and

inappropriate signaling.

◊ Numerous fusion partners have been identied.

◊ To date, no specic clinicopathologic features, other than absence of other driver alterations, have been identied in association with these

fusions.

◊ Point mutations in NTRK1/2/3 are generally non-activating and have not been studied in association with targeted therapy.

◊ Testing Methodologies: Various methodologies can be used to detect NTRK1/2/3 gene fusions, including: FISH, IHC, PCR, and NGS; false

negatives may occur. IHC methods are complicated by baseline expression in some tissues. FISH testing may require at least 3 probe sets for full

analysis. NGS testing can detect a broad range of alterations. DNA-based NGS may under-detect NTRK1 and NTRK3 fusions.

• In the event that a complete assessment for all biomarkers cannot be reasonably accomplished prior to initiation of therapy, consider repeat panel

testing or selected biomarker testing at progression on rst-line therapy if a lesion can be accessed for sampling and testing.

• Testing in the Setting of Progression on Targeted Therapy:

For many of the above listed analytes, there is growing recognition of the molecular mechanisms of resistance to therapy. Re-testing of a sample

from a tumor that is actively progressing while exposed to targeted therapy can shed light on appropriate next therapeutic steps:

◊ For patients with an underlying EGFR sensitizing mutation who have been treated with EGFR TKI, minimum appropriate testing includes high-

sensitivity evaluation for p.T790M; when there is no evidence of p.T790M, testing for alternate mechanisms of resistance (MET amplication,

ERBB2 amplication) may be used to direct patients for additional therapies. The presence of p.T790M can direct patients to third-generation

EGFR TKI therapy.

– Assays for the detection of EGFR p.T790M should be designed to have an analytic sensitivity of a minimum of 5% allelic fraction. The original

sensitizing mutation can be utilized as an internal control in many assays to determine whether a p.T790M is within the range of detection if

present as a sub-clonal event.

◊ For patients with underlying ALK rearrangement who have been treated with ALK TKI, it is unclear whether identication of specic tyrosine

kinase domain mutation can identify appropriate next steps in therapy, although some preliminary data suggest that specic kinase domain

mutations can impact next line of therapy.

NSCL-H

4 OF 5

PRINCIPLES OF MOLECULAR AND BIOMARKER ANALYSIS

Continued

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-H

5 OF 5

PRINCIPLES OF MOLECULAR AND BIOMARKER ANALYSIS

• PD-L1 (Programmed Death Ligand 1): PD-L1 is a co-regulatory molecule that can be expressed on tumor cells and inhibit T-cell–mediated

cell death. T-cells express PD-1, a negative regulator, which binds to ligands including PD-L1 (CD274) or PD-L2 (CD273). In the presence of

PD-L1, T-cell activity is suppressed.

Checkpoint inhibitor antibodies block the PD-1 and PD-L1 interaction, thereby improving the antitumor eects of endogenous T cells.

IHC for PD-L1 can be utilized to identify disease most likely to respond to rst-line anti PD-1/PD-L1.

◊ Various antibody clones have been developed for IHC analysis of PD-L1 expression, and while several show relative equivalence, some

do not.

◊ Interpretation of PD-L1 IHC in NSCLC is typically focused on the proportion of tumor cells expressing membranous staining at any level

and therefore is a linear variable; scoring systems may be dierent in other tumor types.

◊ The FDA-approved companion diagnostic for PD-L1 guides utilization of pembrolizumab in patients with NSCLC and is based on the

tumor proportion score (TPS). TPS is the percentage of viable tumor cells showing partial or complete membrane staining at any

intensity.

◊ The denition of positive and negative testing is dependent on the individual antibody and platform deployed, which may be unique to

each checkpoint inhibitor therapy. The potential for multiple dierent assays for PD-L1 has raised concern among both pathologists and

oncologists.

◊ Although PD-L1 expression can be elevated in patients with an oncogenic driver, targeted therapy for the oncogenic driver should take

precedence over treatment with an immune checkpoint inhibitor.

• Plasma Cell-Free/Circulating Tumor DNA Testing:

Cell-free/circulating tumor DNA testing should not be used in lieu of a histologic tissue diagnosis.

Some laboratories oer testing for molecular alterations examining nucleic acids in peripheral circulation, most commonly in processed

plasma (sometimes referred to as "liquid biopsy").

Studies have demonstrated cell-free tumor DNA testing to generally have very high specicity, but signicantly compromised sensitivity,

with up to 30% false-negative rate.

Standards for analytical performance characteristics of cell-free tumor DNA have not been established, and in contrast to tissue-based

testing, no guidelines exist regarding the recommended performance characteristics of this type of testing.

Cell-free tumor DNA testing can identify alterations that are unrelated to a lesion of interest, for example, clonal hematopoiesis of

indeterminate potential (CHIP).

The use of cell-free/circulating tumor DNA testing can be considered in specic clinical circumstances, most notably:

◊ If a patient is medically unt for invasive tissue sampling

◊ In the initial diagnostic setting, if following pathologic conrmation of a NSCLC diagnosis there is insucient material for molecular

analysis, cell-free/circulating tumor DNA should be used only if follow-up tissue-based analysis is planned for all patients in which an

oncogenic driver is not identied (see NSCL-18 for oncogenic drivers with available targeted therapy options).

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-I

Ou SH, Kwak EL, Siwak-Tapp C, et al. Activity of crizotinib (PF02341066), a dual mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK)

inhibitor, in a non-small cell lung cancer patient with de novo MET amplification. J Thorac Oncol 2011;6:942-946.

Camidge RD, Ou S-HI, Shapiro G, et al. Efficacy and safety of crizotinib in patients with advanced c-MET-amplified non-small cell lung cancer. J Clin Oncol

2014;32(Suppl 5):Abstract 8001.

Wolf J, Seto T, Han JY, et al; GEOMETRY mono-1 Investigators. Capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer. N Engl J Med

2020;383:944-957.

Li BT, Shen R, Buonocore D, et al. Ado-trastuzumab emtansine in patients with HER2 mutant lung cancers: Results from a phase II basket trial. J Clin Oncol

2018;36:2532-2537.

Smit EF, Nakagawa K, Nagasaka Met al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer: interim

results of DESTINY-Lung01[abstract]. J Clin Oncol 2020;38:Abstract 9504.

EMERGING BIOMARKERS TO IDENTIFY NOVEL THERAPIES FOR PATIENTS WITH METASTATIC NSCLC

Genetic Alteration (ie, Driver event) Available Targeted Agents with Activity

Against Driver Event in Lung Cancer

High-level MET amplication

Crizotinib

1-2

Capmatinib

ERBB2 (HER2) mutations

Ado-trastuzumab emtansine

Fam-trastuzumab deruxtecan-nxki

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

TARGETED THERAPY OR IMMUNOTHERAPY FOR ADVANCED OR METASTATIC DISEASE

NSCL-J

1 OF 2

References

Monitoring During Initial Therapy

• Response assessment after 2 cycles, then every 2–4 cycles with CT of known sites of disease with or without contrast or when clinically indicated.

Monitoring During Subsequent Therapy

• Response assessment with CT of known sites of disease with or without contrast every 6–12 weeks. Timing of CT scans within Guidelines parameters is a

clinical decision.

*An FDA-approved biosimilar is an appropriate substitute for bevacizumab.

**Continuation maintenance refers to the use of at least one of the agents given in first line, beyond 4–6 cycles, in the absence of disease progression.

EGFR Mutation Positive

(eg, exon 19 deletion or L858R)

• First-line therapy

Afatinib

Erlotinib

Dacomitinib

Getinib

4,5

Osimertinib

Erlotinib + ramucirumab

Erlotinib + bevacizumab* (nonsquamous)

• Subsequent therapy

Osimertinib

EGFR exon 20 insertion mutation positive

• Subsequent therapy

Amivantamab-vmjw

KRAS G12C mutation positive

• Subsequent therapy

Sotorasib

ALK Rearrangement Positive

• First-line therapy

Alectinib

12,13

Brigatinib

Ceritinib

Crizotinib

12,16

Lorlatinib

• Subsequent therapy

Alectinib

18,19

Brigatinib

Ceritinib

Lorlatinib

ROS1 Rearrangement Positive

• First-line therapy

Ceritinib

Crizotinib

Entrectinib

• Subsequent therapy

Lorlatinib

Entrectinib

BRAF V600E Mutation Positive

• First-line therapy

Dabrafenib/trametinib

• Subsequent therapy

Dabrafenib/trametinib

28,29

NTRK1/2/3 Gene Fusion Positive

• First-line/Subsequent therapy

Larotrectinib

Entrectinib

MET Exon 14 Skipping Mutation

• First-line therapy/Subsequent therapy

Capmatinib

Crizotinib

Tepotinib

RET Rearrangement Positive

• First-line therapy/Subsequent therapy

Selpercatinib

Pralsetinib

Cabozantinib

37,38

Vandetanib

PD-L1 ≥1%

• First-line therapy**

Pembrolizumab

40-42

(Carboplatin or cisplatin)/pemetrexed/

pembrolizumab (nonsquamous)

Carboplatin/paclitaxel/bevacizumab*/

atezolizumab (nonsquamous)

Carboplatin/(paclitaxel or albumin-bound

paclitaxel)/pembrolizumab (squamous)

Carboplatin/albumin-bound paclitaxel/

atezolizumab (nonsquamous)

Nivolumab/ipilimumab

Nivolumab/ipilimumab/pemetrexed/

(carboplatin or cisplatin) (nonsquamous)

Nivolumab/ipilimumab/paclitaxel/carboplatin

(squamous)

PD-L1 ≥50% (in addition to above)

• First-line therapy**

Atezolizumab

Cemiplimab-rwlc

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-J

2 OF 2

Yang JC, Wu YL, Schuler M, et al. Afatinib versus cisplatin based chemotherapy

for EGFR mutation positive lung adenocarcinoma (LUX Lung 3 and LUX Lung

6): analysis of overall survival data from two randomised, phase 3 trials. Lancet

Oncol 2015;16:141-151.

Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy

as first line treatment for European patients with advanced EGFR mutation

positive non small cell lung cancer (EURTAC): a multicentre, open label,

randomised phase 3 trial. Lancet Oncol 2012;13:239-246.

Wu Y-L, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib as first-line

treatment for patients with EGFR-mutation-positive non-small-cell lung cancer

(ARCHER 1050): a randomized, open-label, phase 3 trial. Lancet Oncol

2017;18:1454-1466.

Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin paclitaxel in

pulmonary adenocarcinoma. N Engl J Med 2009;361:947-957.

Douillard JY, Ostoros G, Cobo M, et al. First line gefitinib in Caucasian EGFR

mutation positive NSCLC patients: a phase IV, open label, single arm study. Br

J Cancer 2014;110:55-62.

Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated

advanced non-small-cell lung cancer. N Engl J Med 2018;378:113-125.

Nakagawa K, Garon EB, Seto T, et al. Ramucirumab plus erlotinib in patients

with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY):

a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol

2019;20:1655-1669.

Saito H, Fukuhara T, Furuya N, et al. Erlotinib plus bevacizumab versus erlotinib

alone in patients with EGFR-positive advanced non-squamous non-small-

cell lung cancer (NEJ026): interim analysis of an open-label, randomised,

multicentre, phase 3 trial. Lancet Oncol 2019;20:625-635.

Mok TS, Wu YL, Ahn MJ, et al. Osimertinib or platinum pemetrexed in EGFR

T790M positive lung cancer. N Engl J Med 2017;376:629-640.

Sabari JK, Shu CA, Park K, et al. OA04.04 Amivantamab in post-platinum

EGFR exon 20 insertion mutant non-small cell lung cancer [abstract]. J Thorac

Oncol 2021;16:S108-S109

Skoulidis F, Li BT, Dy GK, et al. Sotorasib for lung cancers with KRAS p.G12C

mutation. N Engl J Med. 2021 Jun 4. Epub ahead of print.

Peters S, Camidge DR, Shaw AT, et al. Alectinib versus crizotinib in untreated

ALK-positive non-small-cell lung cancer. N Engl J Med 2017;377:829-838.

Hida T, Nokihara H, Kondo M, et al. Alectinib versus crizotinib in patients with

ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised

phase 3 trial. Lancet 2017;390(10089):29-39.

Camidge DR, Kim HR, Ahn JC-H, et al. Brigatinib versus crizotinib in ALK-

positive non-small-cell lung cancer. N Eng J Med 2018;379:2027-2039.

Soria JC, Tan DS, Chiari R, et al. First line ceritinib versus platinum based

chemotherapy in advanced ALK rearranged non small cell lung cancer

(ASCEND 4): a randomised, open label, phase 3 study. Lancet 2017;389:917-

929.

Solomon BJ, Mok T, Kim DW, et al. First line crizotinib versus chemotherapy in

ALK positive lung cancer. N Engl J Med 2014;371:2167-2177.

Shaw, AT, Bauer TM, de Marinis F, et al. First-line lorlatinib or crizotinib in

advanced ALK-positive lungcCancer. N Engl J Med 2020;383;2018-2029.

Ou SI, Ahn JS, De Petris L, et al. Alectinib in crizotinib refractory ALK

rearranged non small cell lung cancer: a phase II global study. J Clin Oncol

2016;34:661-668.

Shaw AT, Gandhi L, Gadgeel S, et al. Alectinib in ALK positive, crizotinib

resistant, non small cell lung cancer: a single group, multicentre, phase 2 trial.

Lancet Oncol 2016;17:234-242.

Kim DW, Tiseo M, Ahn MJ, et al. Brigatinib in patients with crizotinib refractory

anaplastic lymphoma kinase positive non small cell lung cancer: a randomized,

multicenter phase II trial. J Clin Oncol 2017;35:2490-2498.

Shaw AT, Kim TM, Crinò L, et al. Ceritinib versus chemotherapy in patients

with ALK-rearranged non-small-cell lung cancer previously given chemotherapy

and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial.

Lancet Oncol 2017;18:874-86.

Solomon BJ, Besse B, Bauer TM, et al. Lorlatinib in patients with ALK-positive

non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol

2018;19:1654-1667.

Lim SM, Kim HR, Lee JS, et al. Open-label, multicenter, phase II study

of ceritinib in patients with non-small-cell lung cancer harboring ROS1

rearrangement. J Clin Oncol 2017;35:2613-2618.

Shaw AT, Ou SH, Bang YJ, et al. Crizotinib in ROS1-rearranged non-small-cell

lung cancer. N Engl J Med 2014;371:1963-1971.

Drilon A, Siena S, Dziadziuszko R, et al. Entrectinib in ROS1 fusion-positive

non-small-cell lung cancer: integrated analysis of three phase 1-2 trials. Lancet

Oncol 2020;21:261-270.

Shaw AT, Solomon BJ, Besse B, et al. ALK resistance mutations and efficacy

of lorlatinib in advanced anaplastic lymphoma kinase-positive non-small-cell

lung cancer. J Clin Oncol 2019;37:1370-1379.

Planchard D, Smit EF, Groen HJM, et al. Dabrafenib plus trametinib in patients

with previously untreated BRAF(V600E)-mutant metastatic non-small-cell lung

cancer: an open-label, phase 2 trial. Lancet Oncol 2017;18:1307-1316.

Planchard D, Besse B, Groen HJM, et al. Dabrafenib plus trametinib in patients

with previously treated BRAF(V600E) mutant metastatic non small cell lung

cancer: an open label, multicentre phase 2 trial. Lancet Oncol 2016;17:984-993.

Planchard D, Besse B, Kim TM, et al. Updated survival of patients (pts) with

previously treated BRAF V600E–mutant advanced non-small cell lung cancer

(NSCLC) who received dabrafenib (D) or D + trametinib (T) in the phase II

BRF113928 study [abstract]. J Clin Oncol 2017;35: Abstract 9075.

Drilon A, Laetsch TW, Kummar W et al. Efficacy of larotrectinib in TRK fusion-

positive cancers in adults and children. N Engl J Med 2018;378:731-739.

Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced

or metastatic NTRK fusion-positive solid tumours: integrated analysis of three

phase 1-2 trials. Lancet Oncol 2020;21:271-282.

Wolf J, Seto T, Han JY, et al; GEOMETRY mono-1 Investigators. Capmatinib

in MET exon 14-mutated or MET-amplified non-small-cell lung cancer. N Engl J

Med 2020;383:944-957.

Drilon A, Clark JW, Weiss J, et al. Antitumor activity of crizotinib in lung cancers

harboring a MET exon 14 alteration. Nat Med 2020;26:47-51.

Paik PK, Felip E, Veillon R, et al. Tepotinib in Non-Small-Cell Lung Cancer with

MET Exon 14 Skipping Mutations. N Engl J Med 2020;383:931-943.

Drilon A, Oxnard GR, Tan DSW, et al. Efficacy of selpercatinib in RET fusion-

positive non-small-cell lung cancer. N Engl J Med 2020;383:813-824.

Gainor JF, Curigliano G, Kim D-W, et al. Registrational dataset from the

phase I/II ARROW trial of pralsetinib (BLU-667) in patients (pts) with advanced

RET fusion+ non-small cell lung cancer (NSCLC)[abstract]. J Clin Oncol

2020;38:Abstract 9515.

Drilon A, Wang L, Hasanovic A, et al. Response to cabozantinib in patients with

RET fusion-positive lung adenocarcinomas. Cancer Discov 2013;3:630-635.

Drilon A, Rekhtman N, Arcila M, et al. Cabozantinib in patients with advanced

RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase

2, single-arm trial. Lancet Oncol 2016;17:1653-1660.

Lee SH, Lee JK, Ahn MJ, et al. Vandetanib in pretreated patients with

advanced non-small cell lung cancer-harboring RET rearrangement: a phase II

clinical trial. Ann Oncol 2017;28:292-297.

Reck M, Rodriguez Abreu D, Robinson AG, et al. Pembrolizumab versus

chemotherapy for PD L1 positive non small cell lung cancer. N Engl J Med

2016;375:1823-1833.

Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with

or without pembrolizumab for advanced, non squamous non small cell lung

cancer: a randomised, phase 2 cohort of the open label KEYNOTE 021 study.

Lancet Oncol 2016;17:1497-1508.

Mok TSK, Wu YL, Kudaba I, et al. Pembrolizumab versus chemotherapy

for previously untreated, PD-L1-expressing, locally advanced or metastatic

non-small-cell lung cancer (Keynote-042): a randomized open-label, controlled,

phase 3 trial. Lancet 2019;393:1819-1830.

Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus

chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med

2018;378:2078-2092.

Socinski M, Jotte R, Cappuzzo F, et al. Atezolizumab for first-line treatment of

metastatic nonsquamous NSCLC. N Engl J Med 2018;378:2288-2301.

Paz-Ares L. Luft A, Vincente D, et al. Pembrolizumab plus chemotherapy for

squamous non-small-cell lung cancer. N Engl J Med 2018;379:2040-2051.

West H, McCleod M, Hussein M, et al. Atezolizumab in combination with

carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy

alone as first-line treatment for metastatic non-squamous non-small-cell lung

cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial.

Lancet Oncol. 2019;20:924-937

Hellmann MD, Paz-Ares L, Bernabe Caro, R, et al. Nivolumab plus ipilimumab

in advanced non-small-cell lung cancer. N Engl J Med 2019;381:2020-2031.

Paz-Ares L, Ciuleanu TE, Cobo M, et al. First-line nivolumab plus ipilimumab

combined with two cycles of chemotherapy in patients with non-small-cell lung

cancer (CheckMate 9LA): an international, randomised, open-label, phase 3

trial. Lancet Oncol 2021;22;198-211.

Herbst RS, Giaccone G, de Marinis F, et al. Atezolizumab for first-line treatment

of PD-L1-selected patients with NSCLC. N Engl J Med 2020;383:1328-1339.

Sezer A, Kilickap S, GϋmϋŞ M, et al. Cemiplimab monotherapy for first-line

treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%:

a multicentre, open-label, global, phase 3, randomised, controlled trial. Lancet

2021;397:592-604.

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-K

1 OF 5

Continued

ADENOCARCINOMA, LARGE CELL, NSCLC NOS (PS 0–1)

No contraindications to

PD-1 or PD-L1 inhibitors

Preferred

• Pembrolizumab/carboplatin/pemetrexed (category 1)

1,2,d

• Pembrolizumab/cisplatin/pemetrexed (category 1)

2,d

Other Recommended

• Atezolizumab/carboplatin/paclitaxel/bevacizumab

(category 1)

d,f,g,h

• Atezolizumab/carboplatin/albumin-bound paclitaxel

4,d

• Nivolumab/ipilimumab

5,d

• Nivolumab/ipilimumab/pemetrexed/(carboplatin or cisplatin)

6,d

(category 1)

Contraindications to

PD-1 or PD-L1 inhibitors

Useful in Certain Circumstances

• Bevacizumab

/carboplatin/paclitaxel (category 1)

7,f,g,h

• Bevacizumab

/carboplatin/pemetrexed

7,8,f,g,h

• Bevacizumab

/cisplatin/pemetrexed

9,f,g,h

• Carboplatin/albumin-bound paclitaxel (category 1)

• Carboplatin/docetaxel (category 1)

• Carboplatin/etoposide (category 1)

12,13

• Carboplatin/gemcitabine (category 1)

• Carboplatin/paclitaxel (category 1)

• Carboplatin/pemetrexed (category 1)

• Cisplatin/docetaxel (category 1)

• Cisplatin/etoposide (category 1)

• Cisplatin/gemcitabine (category 1)

15,18

• Cisplatin/paclitaxel (category 1)

• Cisplatin/pemetrexed (category 1)

• Gemcitabine/docetaxel (category 1)

• Gemcitabine/vinorelbine (category 1)

ADENOCARCINOMA, LARGE CELL, NSCLC NOS (PS 2)

Preferred

• Carboplatin/pemetrexed

Other Recommended

• Carboplatin/albumin-bound paclitaxel

23,24

• Carboplatin/docetaxel

• Carboplatin/etoposide

12,13

• Carboplatin/gemcitabine

• Carboplatin/paclitaxel

Useful in Certain Circumstances

• Albumin-bound paclitaxel

• Docetaxel

25,26

• Gemcitabine

27-29

• Gemcitabine/docetaxel

• Gemcitabine/vinorelbine

• Paclitaxel

30-32

• Pemetrexed

Albumin-bound paclitaxel may be substituted for either paclitaxel or docetaxel in patients who

have experienced hypersensitivity reactions after receiving paclitaxel or docetaxel despite

premedication, or for patients where the standard premedications (ie, dexamethasone, H2

blockers, H1 blockers) are contraindicated.

Carboplatin-based regimens are often used for patients with comorbidities or those who cannot

tolerate cisplatin.

Contraindications for treatment with PD-1/PD-L1 inhibitors may include active or previously

documented autoimmune disease and/or current use of immunosuppressive agents, or

presence of an oncogene (eg, EGFR [exon 19 deletions, p.L858R point mutation in exon 21],

ALK rearrangements, RET rearrangements), which would predict lack of benefit.

If progression on PD-1/PD-L1 inhibitor, using a PD-1/PD-L1 inhibitor is not recommended.

An FDA-approved biosimilar is an appropriate substitute for bevacizumab.

Bevacizumab should be given until progression.

Any regimen with a high risk of thrombocytopenia and the potential risk of bleeding should be

used with caution in combination with bevacizumab.

Criteria for treatment with bevacizumab: non-squamous NSCLC, and no recent history of

hemoptysis. Bevacizumab should not be given as a single agent, unless as maintenance if

initially used with chemotherapy.

SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE –

INITIAL SYSTEMIC THERAPY OPTIONS

a,b

References

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE –

INITIAL SYSTEMIC THERAPY OPTIONS

a,b

SQUAMOUS CELL CARCINOMA (PS 0–1)

No contraindications to PD-1 or PD-L1 inhibitors

Preferred

• Pembrolizumab/carboplatin/paclitaxel

34,d

(category 1)

• Pembrolizumab/carboplatin/albumin-bound paclitaxel

34,d

(category 1)

Other recommended

• Nivolumab/ipilimumab

5,d

• Nivolumab/ipilimumab/paclitaxel/carboplatin

6,d

(category 1)

Contraindications to PD-1 or PD-L1 inhibitors

Useful in Certain Circumstances

• Carboplatin/albumin-bound paclitaxel (category 1)

• Carboplatin/docetaxel (category 1)

• Carboplatin/gemcitabine (category 1)

• Carboplatin/paclitaxel (category 1)

• Cisplatin/docetaxel (category 1)

• Cisplatin/etoposide (category 1)

• Cisplatin/gemcitabine (category 1)

15,18

• Cisplatin/paclitaxel (category 1)

• Gemcitabine/docetaxel (category 1)

• Gemcitabine/vinorelbine (category 1)

SQUAMOUS CELL CARCINOMA (PS 2)

Preferred

• Carboplatin/albumin-bound paclitaxel

23,24

• Carboplatin/gemcitabine

• Carboplatin/paclitaxel

Other Recommended

• Carboplatin/docetaxel

• Carboplatin/etoposide

12,13

Useful in Certain Circumstances

• Albumin-bound paclitaxel

• Docetaxel

25,26

• Gemcitabine

27-29

• Gemcitabine/docetaxel

• Gemcitabine/vinorelbine

• Paclitaxel

30-32

NSCL-K

2 OF 5

Albumin-bound paclitaxel may be substituted for either paclitaxel or docetaxel in patients who have experienced hypersensitivity reactions after receiving paclitaxel or

docetaxel despite premedication, or for patients where the standard premedications (ie, dexamethasone, H2 blockers, H1 blockers) are contraindicated.

Carboplatin-based regimens are often used for patients with comorbidities or those who cannot tolerate cisplatin.

Contraindications for treatment with PD-1/PD-L1 inhibitors may include active or previously documented autoimmune disease and/or current use of

immunosuppressive agents or presence of an oncogene (eg, EGFR [exon 19 deletions, p.L858R point mutation in exon 21], ALK rearrangements, RET

rearrangements), which would predict lack of benefit.

If progression on PD-1/PD-L1 inhibitor, using a PD-1/PD-L1 inhibitor is not recommended.

References

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-K

3 OF 5

SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE –

MAINTENANCE THERAPY OPTIONS

Maintenance Therapy

• Continuation maintenance refers to the use of at least one of the agents given in rst line, beyond 4–6 cycles, in the absence of disease

progression. Switch maintenance refers to the initiation of a dierent agent, not included as part of the rst-line regimen, in the absence of

disease progression, after 4–6 cycles of initial therapy.

• Patients should receive maintenance therapy for 2 years if they received front-line immunotherapy.

• Patients should receive maintenance therapy until progression if they received second-line immunotherapy.

If bevacizumab was used with a first-line pemetrexed/platinum chemotherapy regimen.

If pembrolizumab/carboplatin/pemetrexed or pembrolizumab/cisplatin/pemetrexed given.

If atezolizumab/carboplatin/paclitaxel/bevacizumab given.

If nivolumab + ipilimumab ± chemotherapy given.

If atezolizumab/carboplatin/albumin-bound paclitaxel given.

If pembrolizumab/carboplatin/(paclitaxel or albumin-bound paclitaxel) given.

ADENOCARCINOMA, LARGE CELL, NSCLC NOS

Continuation maintenance

• Bevacizumab (category 1)

• Pemetrexed (category 1)

• Bevacizumab/pemetrexed

• Pembrolizumab/pemetrexed (category 1)

• Atezolizumab/bevacizumab (category 1)

• Nivolumab/ipilimumab

• Atezolizumab

• Gemcitabine (category 2B)

Switch maintenance

• Pemetrexed

SQUAMOUS CELL CARCINOMA (PS 0–2)

Continuation maintenance

• Pembrolizumab

• Nivolumab/ipilimumab

• Gemcitabine (category 2B)

Switch maintenance

(category 2B)

• Docetaxel

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-K

4 OF 5

SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE –

PROGRESSION

ADENOCARCINOMA, LARGE CELL, NSCLC NOS

(PS 0–2)

Preferred (no previous IO):

Systemic immune checkpoint inhibitors

o,d

• Nivolumab (category 1)

• Pembrolizumab

(category 1)

• Atezolizumab (category 1)

Other Recommended (no previous IO or previous IO):

• Docetaxel

• Pemetrexed

• Gemcitabine

• Ramucirumab/docetaxel

SQUAMOUS CELL CARCINOMA (PS 0–2)

Preferred (no previous IO):

Systemic immune checkpoint inhibitors

o,d

• Nivolumab (category 1)

• Pembrolizumab

(category 1)

• Atezolizumab (category 1)

Other Recommended (no previous IO or previous IO):

• Docetaxel

• Gemcitabine

• Ramucirumab/docetaxel

If progression on PD-1/PD-L1 inhibitor, using a PD-1/PD-L1 inhibitor is not recommended.

The data in the second-line setting suggest that PD-1/PD-L1 inhibitor monotherapy is less effective, irrespective of PD-L1 expression, in EGFR+/ALK+/RET+ NSCLC.

Pembrolizumab is approved for patients with NSCLC tumors with PD-L1 expression levels ≥1%, as determined by an FDA-approved test.

If not previously given.

SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE –

SUBSEQUENT SYSTEMIC THERAPY OPTIONS

ADENOCARCINOMA, LARGE CELL, NSCLC NOS

d,r

• PS 0–2: nivolumab, pembrolizumab, or atezolizumab,

docetaxel (category 2B), pemetrexed (category 2B), gemcitabine

(category 2B), or ramucirumab/docetaxel (category 2B)

• PS 3–4: Best supportive care

• Options for further progression are best supportive care or clinical

trial.

SQUAMOUS CELL CARCINOMA

d,r

• PS 0–2: nivolumab, pembrolizumab, or atezolizumab,

docetaxel (category 2B), gemcitabine (category 2B),

or ramucirumab/docetaxel (category 2B)

• PS 3–4: Best supportive care

• Options for further progression are best supportive care or clinical

trial.

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

NSCL-K

5 OF 5

Langer CJ, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-

squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021

study. Lancet Oncol. 2016;17:1497-1508.

Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non-

small-cell lung cancer. N Engl J Med 2018;378:2078-2092.

Socinski M, Jotte R, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous

NSCLC. N Engl J Med 2018;378:2288-2301.

West H, McCleod M, Hussein M, et al. West H, McCleod M, Hussein M, et al. Atezolizumab in combination

with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line

treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre,

randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20:924-937

Hellmann MD, Paz-Ares L, Bernabe Caro, R, et al. Nivolumab plus ipilimumab in advanced non-small-cell

lung cancer. N Eng J Med 2019;381:2020-2031.

Paz-Ares L, Ciuleanu TE, Cobo M, et al. First-line nivolumab plus ipilimumab combined with two cycles of

chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised,

open-label, phase 3 trial. Lancet Oncol 2021;22:198-211.

Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small cell

lung cancer. N Engl J Med 2006;355:2542-2550.

Patel JD, Socinski MA, Garon EB, et al. Pointbreak: a randomized phase III study of pemetrexed plus

carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel

plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV

nonsquamous non-small cell lung cancer. J Clin Oncol 2013;31:4349-4357.

Barlesi F, Scherpereel A, Rittmeywr A, et al. Randomized phase III trial of maintenance bevacizumab with

or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced

nonsquamous non-small cell lung cancer: AVAPERL. J Clin Oncol 2013;31:3004-3011.

Socinski MA, Bondarenko I, Karaseva NA, et al. Weekly nab-paclitaxel in combination with carboplatin

versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small

cell lung cancer: final results of a phase III trial. J Clin Oncol 2012:30:2055-2062.

Fossella F, Periera JR, von Pawel J, et al. Randomized, multinational, phase III study of docetaxel plus

platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX

326 study group. J Clin Oncol 2003;21(16):3016-3024.

Klastersky J, Sculier JP, Lacroix H, et al. A randomized study comparing cisplatin or carboplatin with

etoposide in patients with advanced non-small cell lung cancer: European Organization for Research and

Treatment of Cancer Protocol 07861. J Clin Oncol 1990;8:1556-1562.

Frasci G, Comella P, Panza N, eta l. Carboplatin-oral etoposide personalized dosing in elderly non-small

cell lung cancer patients. Gruppo Oncologico Cooperativo Sud-Italia. Eur J Cancer 1998;34:1710-1714.

Danson S, Middleton MR, O’Byrne KJ, et al. Phase III trial of gemcitabine and carboplatin versus

mitomycin, ifosfamide, and cisplatin or mitomycin, vinblastine, and ciplatin in patients with advanced non-

small cell lung carcinoma. Cancer 2003;98:542-553.

Ohe Y, Ohashi Y, Kubota K, et al. Randomized phase III study of cisplatin plus irinotecan versus

carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-

small-cell lung cancer: Four-Arm Cooperative Study in Japan. Ann Oncol 2007;18:317-323.

Scagliotti GV, Kortsik C, Dark GG, et al. Pemetrexed combined with oxaliplatin or carboplatin as first-line

treatment in advanced non-small cell lung cancer: a multicenter, randomized, phase II trial. Clin Cancer

Res 2005;11:690-696.

Cardenal F, Lopez-Cabrerizo MP, Anton A, et al. Randomized phase III study of gemcitabine-cisplatin

versus etoposide-cisplatin in the treatment of locally advanced or metastatic non-small cell lung cancer. J

Clin Oncol 1999;17:12-18.

Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with

cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage NSCLC. J Clin Oncol

2008;26:3543-3551.

Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced

non-small cell lung cancer. N Engl J Med 2002;346:92-98.

Pujol JL, Breton JL, Gervais R, et al. Gemcitabine-docetaxel versus cisplatin-vinorelbine in advanced

or metastatic non-small-cell lung cancer: a phase III study addressing the case for cisplatin. Ann Oncol

2005;16:602-610.

Tan EH, Szczesna A, Krzakowski M, et al. Randomized study of vinorelbine--gemcitabine versus

vinorelbine--carboplatin in patients with advanced non-small cell lung cancer. Lung Cancer 2005;49:233-

240.

Green M, Manikhas G, Orlov S, et al. Abraxane®, a novel Cremophor® -free, albumin-bound particle

form of paclitaxel for the treatment of advanced non-small-cell lung cancer. Ann Oncol 2006;17:1263-

1268.

Rizvi N, Riely G, Azzoli C, et al. Phase I/II trial of weekly intravenous 130-nm albumin-bound paclitaxel as

initial chemotherapy in patients with atage IV non-small-cell lung cancer. J Clin Oncol 2008;26:639-643.

Socinski MA, Bondarenko I, Karaseva NA, et al. Weekly nab-paclitaxel in combination with carboplatin

versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small

cell lung cancer: final results of a phase III trial. J Clin Oncol 2012:30:2055-2062.

Fossella FV, DeVore R, Kerr RN, et al. Randomized phase III trial of docetaxel versus vinorelbine

or ifosfamide in patients with advanced non-small cell lung cancer previously treated with platinum-

containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol

2000;18:2354-2362.

Fidias PM, Dakhil SR, Lyss AP, et al. Phase III study of immmediate compared with delayed docetaxel

after front-line therapy with gemcitabine plus carboplatin in advanced non-small cell lung cancer. J Clin

Oncol 2009;27:591-598.

Zatloukal P, Kanitz E, Magyar P, et al Gemcitabine in locally advanced and metastatic non-small cell lung

cancer: the Central European phase II study. Lung Cancer 1998;22:243-250.

Sederholm C, Hillerdal G, Lamberg K, et al. Phase III trial of gemcitabine plus carboplatin versus single

agent gemcitabine in the treatment of locally advanced or metastatic non-small cell lung cancer: the

Swedish Lung Cancer Study group. J Clin Oncol 2005;23:8380-8288.

Perol M, Chouaid C, Perol D, et al. Randomized, phase III study of gemcitabine or erlotinib maintenance

therapy versus observation, with predefined second-line treatment, after cisplatin-gemcitabine induction

chemotherapy in advanced non-small celll lung cancer. J Clin Oncol 2012;30:3516-3524.

Lilenbaum RC, Herndon JE, List MA, et al. Single-agent versus combination chemotherapy in advanced

non-small cell lung cancer: the cancer and leukemia group B (study 9730). J Clin Oncol 2005;23:190-196.

Ceresoli GL, Gregorc V, Cordio S, et al. Phase II study of weekly paclitaxel as second-line therapy in

patients wit h advanced non-small cell lung cancer. Lung Cancer 2004;44:231-239.

Yasuda K, Igishi T, Kawasaki Y, et al. Phase II study of weekly paclitaxel in patients with non-small cell

lung cancer who have failed previous treatments. Oncology 2004;66:347-352.

Hanna NH, Sheperd FA, Fossella FV, et al. Randomized phase III study of pemetrexed versus

docetaxel in patients with non-small cell lung cancer previously treated with chemotherapy. J Clin Oncol

2004;22:1589-1597.

Paz-Ares L. Luft A, Vincente D, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell

lung cancer. N Engl J Med 2018;379:2040-2051.

SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

ST-1

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition

(2017) published by Springer International Publishing.

Table 1. Denitions for T, N, M

T Primary Tumor

TX Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not

visualized by imaging or bronchoscopy

T0 No evidence of primary tumor

Tis Carcinoma in situ

Squamous cell carcinoma in situ (SCIS)

Adenocarcinoma in situ (AIS): adenocarcinoma with pure lepidic pattern, ≤3 cm in greatest dimension

T1 Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more

proximal than the lobar bronchus (i.e., not in the main bronchus)

T1mi Minimally invasive adenocarcinoma: adenocarcinoma (≤3 cm in greatest dimension) with a predominantly lepidic pattern and ≤5 mm

invasion in greatest dimension

T1a Tumor ≤1 cm in greatest dimension. A supercial, spreading tumor of any size whose invasive component is limited to the bronchial

wall and may extend proximal to the main bronchus also is classied as T1a, but these tumors are uncommon.

T1b Tumor >1 cm but ≤2 cm in greatest dimension

T1c Tumor >2 cm but ≤3 cm in greatest dimension

T2 Tumor >3 cm but ≤5 cm or having any of the following features: (1) Involves the main bronchus, regardless of distance to the

carina, but without involvement of the carina; (2) Invades visceral pleura (PL1 or PL2); (3) Associated with atelectasis or obstructive

pneumonitis that extends to the hilar region, involving part or all of the lung

T2a Tumor >3 cm but ≤4 cm in greatest dimension

T2b Tumor >4 cm but ≤5 cm in greatest dimension

T3 Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall (including

superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary

T4 Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea,

recurrent laryngeal nerve, esophagus, vertebral body, carina; separate tumor nodule(s) in an ipsilateral lobe dierent from that of the

primary

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

ST-2

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition

(2017) published by Springer International Publishing.

Table 2. AJCC Prognostic Groups

T N M

Occult

Carcinoma

TX N0 M0

Stage 0 Tis N0 M0

Stage IA1 T1mi N0 M0

T1a N0 M0

Stage IA2 T1b N0 M0

Stage IA3 T1c N0 M0

Stage IB T2a N0 M0

Stage IIA T2b N0 M0

Stage IIB T1a N1 M0

T1b N1 M0

T1c N1 M0

T2a N1 M0

T2b N1 M0

T3 N0 M0

Stage IIIA T1a N2 M0

T1b N2 M0

T1c N2 M0

T2a N2 M0

T2b N2 M0

T3 N1 M0

T4 N0 M0

T4 N1 M0

T N M

Stage IIIB T1a N3 M0

T1b N3 M0

T1c N3 M0

T2a N3 M0

T2b N3 M0

T3 N2 M0

T4 N2 M0

Stage IIIC T3 N3 M0

T4 N3 M0

Stage IVA Any T Any N M1a

Any T Any N M1b

Stage IVB Any T Any N M1c

Table 1. Denitions for T, N, M (continued)

N Regional Lymph Nodes

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

N1 Metastasis in ipsilateral peribronchial and/or ipsilateral

hilar lymph nodes and intrapulmonary nodes, including

involvement by direct extension

N2 Metastasis in ipsilateral mediastinal and/or subcarinal

lymph node(s)

N3 Metastasis in contralateral mediastinal, contralateral hilar,

ipsilateral or contralateral scalene, or supraclavicular lymph

node(s)

M Distant Metastasis

M0 No distant metastasis

M1 Distant metastasis

M1a Separate tumor nodule(s) in a contralateral lobe; tumor

with pleural or pericardial nodules or malignant pleural or

pericardial eusion

M1b Single extrathoracic metastasis in a single organ (including

involvement of a single nonregional node)

M1c Multiple extrathoracic metastases in a single organ or in

multiple organs

Most pleural (pericardial) effusions with lung cancer are a result of the tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for

tumor, and the fluid is nonbloody and not an exudate. If these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a

staging descriptor.

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

*Rami-Porta R, Asamura H, Travis WD, Rusch VW. Lung cancer - major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin 2017;67:138-155.

Table 3. Comparison of the Descriptors in the Eighth Edition of the TNM Classication of Lung Cancer Compared with the Seventh Edition*

ST-3

Descriptor 7th Edition T/N/M 8th Edition T/N/M

T component

0 cm (pure lepidic adenocarcinoma

≤3 cm in total size)

T1a if ≤2 cm; T1b if >2-3 cm Tis (AIS)

≤0.5 cm invasive size (lepidic predominant

adenocarcinoma ≤3 cm total size)

T1a if ≤2 cm; T1b if >2-3 cm T1mi

≤1 cm T1a T1a

>1-2 cm T1a T1b

>2-3 cm T1b T1c

>3-4 cm T2a T2a

>4-5 cm T2a T2b

>5-7 cm T2b T3

>7 cm T3 T4

Bronchus <2 cm from carina T3 T2

Total atelectasis/pneumonitis T3 T2

Invasion of diaphragm T3 T4

Invasion of mediastinal pleura T3 —

N component

No assessment, no involvement, or

involvement of regional lymph nodes

NX, N0, N1, N2, N3 No change

M component

Metastasis within the thoracic cavity M1a M1a

Single extrathoracic metastasis M1b M1b

Multiple extrathoracic metastasis M1b M1c

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

NCCN Categories of Evidence and Consensus

Category 1 Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3 Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise indicated.

NCCN Categories of Preference

Preferred intervention

Interventions that are based on superior ecacy, safety, and evidence; and, when appropriate,

aordability.

Other recommended

intervention

Other interventions that may be somewhat less ecacious, more toxic, or based on less mature data;

or signicantly less aordable for similar outcomes.

Useful in certain

circumstances

Other interventions that may be used for selected patient populations (dened with recommendation).

All recommendations are considered appropriate.

CAT-1

NCCN Guidelines Version 5.2021

Non-Small Cell Lung Cancer

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion