NCCN Guidelines Insights: Non–Small Cell Lung Cancer, Version 2.2021

Featured Updates to the NCCN Guidelines

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  • 1 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins;
  • 2 Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance;
  • 3 University of Colorado Cancer Center;
  • 4 Huntsman Cancer Institute at the University of Utah;
  • 5 Fox Chase Cancer Center;
  • 6 Robert H. Lurie Comprehensive Cancer Center of Northwestern University;
  • 7 Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute;
  • 8 The University of Texas MD Anderson Cancer Center;
  • 9 Dana-Farber/Brigham and Women’s Cancer Center;
  • 10 Duke Cancer Institute;
  • 11 Moffitt Cancer Center;
  • 12 UT Southwestern Simmons Comprehensive Cancer Center;
  • 13 Yale Cancer Center/Smilow Cancer Hospital;
  • 14 UCSF Helen Diller Family Comprehensive Cancer Center;
  • 15 O'Neal Comprehensive Cancer Center at UAB;
  • 16 Roswell Park Comprehensive Cancer Center;
  • 17 Fred & Pamela Buffett Cancer Center;
  • 18 Massachusetts General Hospital Cancer Center;
  • 19 University of Wisconsin Carbone Cancer Center;
  • 20 University of Michigan Rogel Cancer Center;
  • 21 Stanford Cancer Institute;
  • 22 Vanderbilt-Ingram Cancer Center;
  • 23 City of Hope National Medical Center;
  • 24 Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine;
  • 25 The University of Tennessee Health Science Center;
  • 26 The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute;
  • 27 UC San Diego Moores Cancer Center;
  • 28 Memorial Sloan Kettering Cancer Center;
  • 29 Mayo Clinic Cancer Center;
  • 30 Abramson Cancer Center at the University of Pennsylvania;
  • 31 UCLA Jonsson Comprehensive Cancer Center; and
  • 32 National Comprehensive Cancer Network.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non–Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines regarding targeted therapies, immunotherapies, and their respective biomarkers.

NCCN: Continuing Education

Target Audience: This activity is designed to meet the educational needs of oncologists, nurses, pharmacists, and other healthcare professionals who manage patients with cancer.

Accreditation Statements

In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

Medicine (ACCME): NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nursing (ANCC): NCCN designates this educational activity for a maximum of 1.0 contact hour.

Pharmacy (ACPE): NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-21-006-H01-P

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: (1) review the educational content; (2) take the posttest with a 66% minimum passing score and complete the evaluation at https://education.nccn.org/node/89409; and (3) view/print certificate.

Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please e-mail education@nccn.org.

Release date: March 10, 2021; Expiration date: March 10, 2022

Learning Objectives:

Upon completion of this activity, participants will be able to:

  • Integrate into professional practice the updates to the NCCN Guidelines for Non–Small Cell Lung Cancer
  • Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Non–Small Cell Lung Cancer

Disclosure of Relevant Financial Relationships

The NCCN staff listed below discloses no relevant financial relationships:

Kerrin M. Rosenthal, MA; Kimberly Callan, MS; Genevieve Emberger Hartzman, MA; Erin Hesler; Kristina M. Gregory, RN, MSN, OCN; Rashmi Kumar, PhD; Karen Kanefield; and Kathy Smith.

Individuals Who Provided Content Development and/or Authorship Assistance:

David S. Ettinger, MD, Panel Chair, has disclosed that he is as scientific advisor for BeyondSpring Pharmaceuticals and Takeda Pharmaceuticals North America, Inc.

Miranda Hughes, PhD, Oncology Scientist/Senior Medical Writer, NCCN, has disclosed that she has no relevant financial relationships.

To view all of the conflicts of interest for the NCCN Guidelines panel, go to NCCN.org/disclosures/guidelinepanellisting.aspx.

This activity is supported by educational grants from Agios Pharmaceuticals; AstraZeneca; Clovis Oncology, Inc.; Daiichi Sankyo; Eisai; Epizyme Inc.; Novartis; and Pharmacyclics LLC, an AbbVie Company and Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC. This activity is supported by an independent medical education grant from Bristol-Myers Squibb, and Regeneron Pharmaceuticals, Inc. and Sanofi Genzyme. This activity is supported by an independent medical educational grant from Mylan Inc. This activity is supported by a medical education grant from Karyopharm Therapeutics. This activity is supported by an independent educational grant from AbbVie.

Overview

Lung cancer is the leading cause of cancer death in the United States.1 In 2021, an estimated 235,760 new cases (119,100 in men and 116,660 in women) of lung and bronchial cancer will be diagnosed, and 131,880 deaths (69,410 in men and 62,470 in women) are estimated to occur.1 Only 26% of all patients with non–small cell lung cancer (NSCLC) are alive ≥5 years after diagnosis.2 The 5-year relative survival rate for metastatic disease is approximately 6% when patients receive historic cytotoxic chemotherapy regimens.2 However, certain patients with metastatic NSCLC who are eligible for newer targeted therapies or immunotherapies are now surviving longer, with 5-year survival rates ranging from 15% to 50%, depending on the biomarker.313

These NCCN Guidelines Insights focus on recent updates in targeted therapies, immunotherapies, and their respective biomarkers for eligible patients with NSCLC. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for NSCLC address all aspects of management for NSCLC. For the 2020 and 2021 updates, several new targeted therapies (or new indications for therapies), including capmatinib, lorlatinib, pralsetinib, selpercatinib, and fam-trastuzumab deruxtecan, are now recommended in the NCCN Guidelines for eligible patients with metastatic NSCLC who have certain actionable biomarkers.1420 These NCCN Guidelines Insights detail the reasons behind the recent revisions and provide a valuable resource for busy healthcare providers who need to quickly learn about the recent recommendations to improve outcomes for their patients with metastatic NSCLC. Unless otherwise indicated, all NCCN recommendations are category 2A (the complete version of these guidelines is available at NCCN.org).

Biomarkers

A predictive (also known as actionable) biomarker has a corresponding specific targeted therapy(ies) that has been shown to improve outcomes in patients with the predictive biomarker (eg, ALK rearrangements are targeted by alectinib, brigatinib, lorlatinib, and other ALK inhibitors). A prognostic biomarker is indicative of patient survival independent of the treatment received, because the biomarker is an indicator of the innate tumor aggressiveness (eg, KRAS mutations). In the NCCN Guidelines, key established predictive molecular biomarkers include ALK rearrangements, BRAF V600E point mutations, sensitizing EGFR mutations, METex14 skipping mutations, NTRK1/2/3 gene fusions, RET rearrangements, and ROS1 rearrangements; PD-L1 expression is a key established immune biomarker (see NSCL-18, page 257). The NCCN NSCLC Panel recommends testing for these key established predictive biomarkers after patients have been diagnosed with metastatic NSCLC and ideally before initial treatment, because effective targeted therapy or immunotherapy is available depending on biomarker test results.14

Emerging predictive biomarkers also have corresponding specific targeted therapies, but fewer data are available to support use of these targeted therapies compared with the targeted therapies for the key established predictive biomarkers (see NSCL-I, page 264). Several emerging biomarkers have become established biomarkers in the NCCN Guidelines after more clinical trial data were published for their corresponding targeted therapies. For example, METex14 skipping mutations and RET rearrangements were moved from the emerging biomarkers section to the established biomarker section of the algorithm for the 2020 update (see NSCL-18, page 257).14,1618 For the version 1.2021 (v1.2021) update, the panel clarified that biomarker testing is recommended in certain patients with metastatic (stage IV) disease, including M1a, M1b, and M1c. The panel also recommends considering biomarker testing for EGFR mutations in surgical tissue or biopsies from patients with completely resected stage IB–IIIA NSCLC to determine whether adjuvant osimertinib can be considered for these patients (see NSCL-4, page 256, and next section).14,21

Molecular Biomarkers

The panel recommends molecular testing using a validated test(s) that assesses a minimum of the following potential genetic variants: ALK rearrangements (category 1), BRAF mutations, EGFR mutations (category 1), METex14 skipping mutations, NTRK1/2/3 gene fusions, RET rearrangements, and ROS1 rearrangements.14 Both FDA-approved companion diagnostics and laboratory-developed test platforms are available to evaluate for these and other analytes. The NCCN Guidelines for NSCLC provide recommendations for specific biomarkers that should be assessed in patients who have been diagnosed with NSCLC, and recommend testing techniques for the key established biomarkers, but do not endorse any specific commercially available biomarker assays. For the 2020 update, the panel recommends that molecular testing be performed via a broad, panel-based approach, most typically performed by next-generation sequencing (NGS), so that testing is done for all of the actionable biomarkers at the same time, including the established and emerging biomarkers. This testing technique helps ensure that there is sufficient tissue to test for all of the actionable biomarkers. However, some gene fusions are difficult to detect using DNA-based NGS. For patients who, in broad panel testing, do not have identifiable driver oncogenes (especially never smokers), RNA-based NGS should be considered, if not already performed, to maximize detection of fusion events.22

ALK, EGFR, BRAF, METex14, NTRK1/2/3, RET, and ROS1 status should be known before deciding whether to use either targeted therapy or immunotherapy with or without chemotherapy regimens. If it is not feasible to perform molecular testing, then patients are treated as though they do not have driver oncogenes.2327 Note that the panel recommends that testing for PD-L1 expression levels, which is an immune biomarker, be performed using an immunohistochemistry test that is an FDA companion diagnostic or has been shown to have equivalent performance to an approved companion diagnostic.28,29 The immunohistochemical evaluation of PD-L1 that guides use of pembrolizumab is based on tumor proportion score (TPS), which is the percentage of viable tumor cells showing partial or complete membrane staining at any intensity.

For the 2021 and 2020 updates, new content was added for EGFR mutations and NTRK1/2/3 gene fusions; recommended testing techniques were added for METex14 skipping mutations, NTRK1/2/3 gene fusions, and RET fusions (see NSCL-H 2 and 4, pages 263 and 264)14; and content was revised for the key established biomarkers, such as EGFR mutations, and for the emerging biomarkers, such as tumor mutational burden (TMB) (see NSCL-18 and NSCL-I, pages 257 and 264). For the v1.2021 update, the panel decided that routine molecular testing should be considered in all patients with metastatic NSCLC squamous cell carcinoma (see NSCL-18, page 257).14 Therefore, characteristics—such as smoking status, small biopsy specimens, and mixed histology—should no longer be used when considering whether to perform biomarker testing on patients with metastatic NSCLC squamous cell carcinoma. This decision is based on recent data showing that patients with metastatic squamous cell carcinoma also have actionable biomarkers, such as EGFR mutations, although at a lower incidence than those with metastatic NSCLC adenocarcinoma.23,3032 The cumulative incidence of actionable alterations in tumors carrying a diagnosis of metastatic squamous cell carcinoma is sufficient to justify consideration of molecular testing. The panel now feels that molecular testing should be considered in patients with metastatic squamous cell carcinoma based on the effectiveness of targeted therapies.23,32 The panel also clarified that NTRK1/2/3 gene fusions are established predictive molecular biomarkers for the 2021 update. Typically, the key established molecular biomarkers do not overlap; most patients with actionable mutations only have one actionable mutation.23,32 Although KRAS mutations are not actionable at this time, inclusion on panel-based testing is informative, because it generally excludes the presence of an actionable alteration.

Immunotherapy with or without chemotherapy is recommended for patients who do not have actionable molecular biomarkers. If patients have both a molecular biomarker and high PD-L1 expression levels, targeted therapy is usually recommended over immunotherapy with or without chemotherapy based on data showing that targeted therapy yields higher response rates compared with immunotherapy in the first-line setting, targeted therapy is better tolerated, and most patients with an actionable molecular biomarker will only have a modest or slight response to immunotherapy.2327 Response rates for immunotherapy are lower in patients with EGFR and ALK variants; however, pembrolizumab with or without chemotherapy may be considered for a heavy smoker with PD-L1 levels of 100% and a BRAF V600E mutation.

Recent data show that certain patients with completely resected early-stage NSCLC who have sensitizing EGFR mutations have longer duration of disease-free survival if they receive adjuvant osimertinib versus placebo.21 ADAURA, a phase III randomized trial in 682 patients, showed that 90% (95% CI, 84%–93%) of patients with stage II–IIIA NSCLC receiving osimertinib were alive and disease-free at 24 months compared with 44% (95% CI, 37%–51%) receiving placebo (HR, 0.17; 99.06% CI, 0.11–0.26; P<.001).21 Disease-free survival was also improved in patients who received adjuvant chemotherapy before osimertinib compared with placebo. Nine patients in the osimertinib group and 20 in the placebo group died. It will be interesting to see whether patients with other actionable molecular biomarkers, such as ALK rearrangements, also have improved survival with targeted agents in the same setting. For the v1.2021 update, the panel recommends considering adjuvant osimertinib for patients with completely resected EGFR mutation–positive stage IIB–IIIA and high-risk stage IB–IIA NSCLC who received previous adjuvant chemotherapy or are ineligible to receive platinum chemotherapy based on FDA approval and clinical trial results (see NSCL-E, page 261).21 High-risk features are described in the algorithm (see NSCL-4, page 256).

For the version 2.2021 (v2.2021) update, the panel now recommends lorlatinib (category 1) as another preferred first-line therapy option for patients with ALK rearrangement–positive metastatic NSCLC (see NSCL-23, page 258).15 The panel revised the preference stratification for brigatinib (category 1) to a preferred first-line therapy option for patients with ALK rearrangement–positive metastatic NSCLC in the v1.2021 update (see NSCL-23, page 258).33,34 The panel clarified that entrectinib may be better for patients with ROS1 rearrangement–positive metastatic NSCLC who have brain metastases, and entrectinib is now recommended as a subsequent therapy option for patients with ROS1-positive disease who have CNS progression after crizotinib (see NSCL-26, page 259).35,36 Entrectinib was designed to cross the blood–brain barrier.35 However, entrectinib is less effective for certain resistant ROS1 variants.35 For the v1.2021 update, the panel added capmatinib as a treatment option for patients with high-level MET amplification, which is an emerging biomarker (see NSCL-I, page 264).16 The panel also added fam-trastuzumab deruxtecan as a treatment option for patients with ERBB2 (HER2) mutation–positive metastatic NSCLC, which is another emerging biomarker (see NSCL-I, page 264).19 The panel deleted single-agent dabrafenib as a treatment option for patients with BRAF V600E mutation–positive metastatic NSCLC who cannot tolerate combination therapy with dabrafenib + trametinib; single-agent vemurafenib remains an option in this setting.37,38 Although less toxic, dabrafenib monotherapy is less effective than combination therapy with dabrafenib + trametinib.39

For the 2020 updates, the panel added selpercatinib and pralsetinib as preferred first-line therapy options for patients with RET rearrangement–positive metastatic NSCLC.17,18 Selpercatinib and pralsetinib are also recommended as preferred subsequent therapy options in this setting if RET inhibitors have not been previously given as first-line therapy. The panel also added capmatinib as a preferred first-line therapy option for patients with METex14 skipping mutations.16 Likewise, capmatinib is also recommended as a preferred subsequent therapy option in this setting if MET inhibitors have not been previously given as first-line therapy.

Immune Biomarkers

Several immune biomarkers, including PD-L1 expression levels and TMB, have been assessed in clinical trials to see if they are useful for predicting whether patients with metastatic NSCLC will respond to various immunotherapy regimens, such as single-agent pembrolizumab or nivolumab + ipilimumab.4043 The response rate to immune checkpoint inhibitors varies depending on the regimen and setting. The highest response rates occur in patients with PD-L1 levels ≥50% in the first-line setting and no actionable molecular biomarkers (approximately 40% response rate to single-agent immunotherapy; approximately 60% to chemoimmunotherapy).40,41,4446 However, only approximately 30% of patients with metastatic NSCLC have PD-L1 levels ≥50%.44,47 Although PD-L1 expression level is widely used as an immune biomarker, it is not an ideal biomarker because some patients with low PD-L1 expression levels respond to immunotherapy and others with high levels do not respond to immunotherapy.48,49 PD-L1 expression levels are useful for deciding whether to use single-agent immunotherapy or combination immunotherapy.

TMB is an approximate measure of the total number of somatic mutations.50 Theoretically, high TMB levels will correlate with high neoantigen levels that will activate an antitumor immune response.48 TMB levels are typically high in patients with NSCLC who are smokers or former smokers. Low TMB is more commonly detected in never-smokers.22,51 Preliminary data for progression-free survival from CheckMate 227, a phase III randomized trial with a complex design, suggested that TMB might be a useful immune biomarker for deciding whether to use immunotherapy in patients with metastatic NSCLC.42 However, updated data from this trial showed that overall survival was improved with nivolumab + ipilimumab regardless of TMB or PD-L1 expression levels.43 In addition, combining TMB with PD-L1 expression level also did not correlate with overall survival.

Several trials have shown that high TMB levels do not correlate with PD-L1 expression levels in patients with NSCLC.42,43,52,53 KEYNOTE-158, a phase II trial, assessed TMB levels in patients with solid tumors who received pembrolizumab as second-line therapy; however, none of the patients had NSCLC.54 TMB does not identify patients who will respond to chemotherapy; therefore, it has limited value for assessing combination immunotherapy + chemotherapy regimens.48 TMB is also not an ideal immune biomarker, because some patients with low levels experience a response to immunotherapy and others with high levels do not.48

In addition to the lack of clinical data to support use of TMB as an immune biomarker, there are technical problems with measuring TMB,50 including lack of agreement on the definition of a cutoff for designating high TMB levels and lack of standardization of TMB measurements across laboratories.50 PD-L1 expression level is a more useful immune biomarker than TMB for deciding how to use immunotherapy, because test results are obtained more quickly, less tissue is needed for testing, and data demonstrate relative reproducibility across platforms and individuals. For the v1.2021 update, the panel decided to remove TMB as an emerging immune biomarker for patients with metastatic NSCLC based on clinical trial data, concerns about variable TMB measurements, and other issues as previously described (see NSCL-I, page 264).14,43,50 Currently, the NCCN Guidelines do not recommend measurement of TMB levels before deciding whether to use nivolumab + ipilimumab combined with or without chemotherapy or to use other immune checkpoint inhibitors, such as pembrolizumab.14

For the v1.2021 update, the panel added a recommendation (category 2A) for consolidation immunotherapy with single-agent durvalumab for patients with unresectable stage II NSCLC who have not experienced disease progression after definitive concurrent chemoradiation. Previously, the durvalumab recommendation had been restricted to patients with unresectable stage III NSCLC (category 1) (see NSCL-F, page 262).55 The panel also revised the recommendation for atezolizumab monotherapy to category 1 (from category 2A) as a preferred treatment option for patients with PD-L1 expression levels of ≥50% and negative for actionable biomarkers (see NSCL-31, page 260).45 The recommendation for nivolumab + ipilimumab was also revised to category 1 (from category 2A) for patients with PD-L1 expression levels of ≥1% and negative for actionable biomarkers (see NSCL-31, page 260).

Summary

These NCCN Guidelines Insights focus on recent updates in targeted therapies, immunotherapies, and their respective biomarkers for eligible patients with NSCLC. For a list of the recent updates, see the complete version of these guidelines at NCCN.org. The NCCN Guidelines for NSCLC address all aspects of management for NSCLC. For the 2020 and 2021 updates, several new targeted therapies or new indications for therapies, including capmatinib, lorlatinib, pralsetinib, selpercatinib, and fam-trastuzumab deruxtecan, are now recommended in the NCCN Guidelines for eligible patients with metastatic NSCLC who have certain actionable biomarkers.14,1620 For the v2.2021 update, the panel now recommends lorlatinib (category 1) as another preferred first-line therapy option for patients with ALK rearrangement–positive metastatic NSCLC.15 For the v1.2021 update, the panel recommends considering adjuvant osimertinib for patients with completely resected EGFR mutation–positive stage IIB–IIIA and high-risk stage IB–IIA NSCLC who received previous adjuvant chemotherapy or are ineligible to receive platinum chemotherapy.14,21

The panel revised the preference stratification for brigatinib (category 1) to a preferred first-line therapy option for patients with ALK rearrangement–positive metastatic NSCLC.33,34 The panel clarified that entrectinib may be better for patients with ROS1 rearrangement–positive metastatic NSCLC who have brain metastases; entrectinib is recommended as a subsequent therapy option for patients with ROS1-positive disease who have central nervous system progression after crizotinib.35,36 For the v1.2021 update, the panel decided that routine molecular biomarker testing should be considered in all patients with metastatic NSCLC squamous cell carcinoma; EGFR mutation biomarker testing can also be considered for patients with completely resected stage IB–IIIA NSCLC.14,21,30,31 Content was revised for the key established biomarkers, such as EGFR mutations. TMB, which is an immune biomarker, was deleted from the NCCN Guidelines based on clinical trial data, concerns about variable TMB measurements, and other issues.14,43,50 TMB was previously listed as an emerging biomarker. Currently, the NCCN Guidelines do not recommend measurement of TMB levels before deciding on the use of nivolumab + ipilimumab combined with or without chemotherapy or the use of other immune checkpoint inhibitors, such as pembrolizumab.14

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    Borghaei H, Langer CJ, Paz-Ares L, . Pembrolizumab plus chemotherapy versus chemotherapy alone in patients with advanced non-small cell lung cancer without tumor PD-L1 expression: a pooled analysis of 3 randomized controlled trials. Cancer 2020;126:48674877.

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    Sholl LM, Hirsch FR, Hwang D, . The promises and challenges of tumor mutation burden as an immunotherapy biomarker: a perspective from the International Association for the Study of Lung Cancer Pathology Committee. J Thorac Oncol 2020;15:14091424.

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    Offin M, Rizvi H, Tenet M, . Tumor mutation burden and efficacy of EGFR-tyrosine kinase inhibitors in patients with EGFR-mutant lung cancers. Clin Cancer Res 2019;25:10631069.

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    Rizvi H, Sanchez-Vega F, La K, . Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing. J Clin Oncol 2018;36:633641.

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    Carbone DP, Reck M, Paz-Ares L, . First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med 2017;376:24152426.

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    Antonia SJ, Villegas A, Daniel D, . Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med 2018;379:23422350.

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 noted.

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.

PLEASE NOTE

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. The NCCN Guidelines Insights highlight important changes in the NCCN Guidelines recommendations from previous versions. Colored markings in the algorithm show changes and the discussion aims to further the understanding of these changes by summarizing salient portions of the panel's discussion, including the literature reviewed.

The NCCN Guidelines Insights do not represent the full NCCN Guidelines; further, the National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application of the NCCN Guidelines and NCCN Guidelines Insights and disclaims any responsibility for their application or use in any way.

The complete and most recent version of these guidelines is available free of charge at NCCN.org.

© National Comprehensive Cancer Network, Inc. 2021. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.

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    Offin M, Rizvi H, Tenet M, . Tumor mutation burden and efficacy of EGFR-tyrosine kinase inhibitors in patients with EGFR-mutant lung cancers. Clin Cancer Res 2019;25:10631069.

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    Rizvi H, Sanchez-Vega F, La K, . Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing. J Clin Oncol 2018;36:633641.

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    Carbone DP, Reck M, Paz-Ares L, . First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med 2017;376:24152426.

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    Marabelle A, Fakih M, Lopez J, . Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol 2020;21:13531365.

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    Antonia SJ, Villegas A, Daniel D, . Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med 2018;379:23422350.

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