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.
Physicians: NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Nurses: NCCN designates this educational activity for a maximum of 1.0 contact hour.
Pharmacists: NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-23-004-H01-P
PAs: NCCN has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credit for activities planned in accordance with AAPA CME Criteria. This activity is designated for 1.0 AAPA Category 1 CME credit. Approval is valid until April 10, 2024. PAs should only claim credit commensurate with the extent of their participation.
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/92905; 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 email education@nccn.org.
Release date: April 10, 2023; Expiration date: April 10, 2024
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
None of the planners for this educational activity have relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.
Individuals Who Provided Content Development and/or Authorship Assistance:
The faculty listed below have no relevant financial relationship(s) with ineligible companies to disclose.
David S. Ettinger, MD, Panel Chair
Douglas E. Wood, MD, Panel Vice Chair
Kristina M. Gregory, RN, MSN, OCN, Senior Vice President, Clinical Information Programs, NCCN
Miranda Hughes, PhD, Oncology Scientist/Senior Medical Writer, NCCN
To view all of the conflicts of interest for the NCCN Guidelines panel, go to NCCN.org/guidelines/guidelines-panels-and-disclosure/disclosure-panels
This activity is supported by educational grants from AstraZeneca; Exact Sciences; Novartis; and Taiho Oncology, Inc. This activity is supported by an independent educational grant from Daiichi Sankyo. This activity is supported by independent medical education grants from Illumina, Inc. and Regeneron Pharmaceuticals, Inc.
Overview
Much progress has been made recently for lung cancer, such as screening; minimally invasive techniques for diagnosis and treatment; advances in radiation therapy (RT), including stereotactic ablative radiotherapy (SABR); new targeted therapies; and new immunotherapies.1–6 These new treatments are reflected in the improved survival rates for patients with NSCLC. In 2015 to 2016, the 2-year relative survival for NSCLC was 42% compared with 34% in 2009 to 2010.7 From 2010 to 2016, the overall 5-year relative survival rate for NSCLC was 26.5% in the United States.8 From 1990 to 2020, the death rate from lung cancer dropped by 58% in males; from 2002 to 2020, the death rate dropped by 36% in females.9 Since 2006 to 2007, the incidence of lung cancer has decreased annually by almost 2.6% in males and 1.1% in females.9
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non–Small Cell Lung Cancer (NSCLC) provide recommendations for management of disease in patients with NSCLC. The NCCN Guidelines for NSCLC were first published in 1996.10 Subsequently, the NCCN Guidelines have been updated at least once a year by the NCCN NSCLC Panel; there were 6 updates for the 2022 guidelines. These NCCN Guidelines Insights focus on recent updates in the NCCN Guidelines for NSCLC (Versions 1.2023 and 2.2023) in perioperative systemic therapy options for eligible patients with resectable NSCLC. These NCCN Guidelines Insights explain, in greater detail than the parent NCCN Guidelines, the reasons why the panel members recently revised the guidelines, and provide a valuable resource for busy healthcare providers who need to quickly learn about the recent recommendations to provide the best care for their patients with NSCLC.
Neoadjuvant Systemic Therapy
Clinical Trial Data
Several trials suggest that neoadjuvant (also known as preoperative or induction) chemotherapy is beneficial in patients with earlier stage disease.11–13 Trials also suggest that neoadjuvant chemotherapy is beneficial in patients with N2 disease.14–16 Song et al17 published a meta-analysis of 13 randomized clinical trials evaluating neoadjuvant chemotherapy followed by surgery versus surgery alone in resectable NSCLCs (overall survival [OS]: hazard ratio [HR], 0.84; 95% CI, 0.77–0.92; P=.0001). These results are similar to those reported in another meta-analysis (HR, 0.89; 95% CI, 0.81–0.98; P=.02).13 The benefit from neoadjuvant chemotherapy is similar to that attained with adjuvant (also known as postoperative) chemotherapy.13,18,19 The NCCN NSCLC Panel surveyed NCCN Member Institutions in 2021 regarding their approach to patients with N2 disease. One of the results was that 66% of the institutions preferred induction chemotherapy and 33% preferred induction chemoradiation.
CheckMate 816, a phase III randomized trial, assessed neoadjuvant therapy with nivolumab + platinum-doublet chemotherapy versus chemotherapy alone in 358 patients with resectable (tumors ≥4 cm or node-positive) NSCLC (stage IB–IIIA NSCLC using AJCC staging, 7th edition).20 Nivolumab is an immune checkpoint inhibitor (ICI) that inhibits PD-1 receptors. Chemotherapy regimens included (1) cisplatin + either pemetrexed (nonsquamous only) or gemcitabine (squamous only); or (2) carboplatin + paclitaxel (any histology). If their patients could not tolerate cisplatin, clinicians could substitute carboplatin-based regimens. Patients had good performance status (0–1) and did not have known EGFR mutations or ALK fusions. Median event-free survival was 31.6 months (95% CI, 30.2 to not reached) for nivolumab + chemotherapy versus 20.8 months (95% CI, 14.0–26.7) for chemotherapy alone (HR, 0.63; 97% CI, 0.43–0.91; P=.005). The pathologic complete response was 24% (95% CI, 18%–31%) with nivolumab + chemotherapy versus 2.2% (95% CI, 0.6%–5.6%) with chemotherapy alone (odds ratio 13.9; 99% CI, 3.49–55.7; P<.001). The major pathologic response was 36.9% with nivolumab + chemotherapy versus 8.9% with chemotherapy alone (major pathologic response, ≤10% viable tumor in lung and lymph nodes). The overall response rate was 53.6% for nivolumab + chemotherapy versus 37.4% with chemotherapy alone. Surgery was performed for 83% of patients receiving nivolumab + chemotherapy versus 75% of those receiving chemotherapy alone. Grade 3 to 4 treatment-related adverse events occurred in 33.5% of patients receiving nivolumab + chemotherapy versus 36.9% of those receiving chemotherapy alone. No deaths were reported in the nivolumab + chemotherapy group; 3 deaths (1.7% [3/176]) were reported in the chemotherapy alone group.
NADIM, a single-arm phase II study, assessed neoadjuvant therapy with nivolumab + carboplatin + paclitaxel in 46 patients with resectable stage IIIA NSCLC; 41 patients had resection.21,22 At 36 months, updated results show that OS was 81.9% (95% CI, 66.8%–90.6%).21 Tumor mutational burden and PD-L1 levels were not predictive of survival. Grade 3 or worse treatment-related adverse events were reported in 30% (14/46) of patients; the most common events were increased lipase and febrile neutropenia (7% [3/46] for both).22 None of the adverse events were associated with death or delays in surgery.
NCCN Recommendations
Based on the clinical trial data, the NCCN panel recommends that certain patients with resectable NSCLC who are likely to receive adjuvant chemotherapy may instead be treated with neoadjuvant systemic therapy after surgical evaluation (see NSCL-3, NSCL-5, NSCL-7, NSCL-8, and NSCL-10, pages 342–348; and NSCL-9, available in the complete version of these guidelines at NCCN.org). The panel recommends nivolumab + platinum-doublet chemotherapy as a neoadjuvant systemic therapy option for eligible patients with resectable (tumors ≥4 cm or node-positive) NSCLC and no contraindications to treatment with PD-1/PD-L1 inhibitors based on clinical trial data and the FDA approval (see NSCL-E 1 of 3, page 349).20–22 Chemotherapy regimens that may be used with neoadjuvant nivolumab include (1) cisplatin + either pemetrexed (nonsquamous only), gemcitabine (squamous only), or paclitaxel (any histology); or (2) carboplatin + either pemetrexed (nonsquamous only), gemcitabine (squamous only), or paclitaxel (any histology) (see NSCL-E 1 of 3, page 349).20 For the 2023 update (Version 1.2023), the panel added a recommendation that all patients should be evaluated for neoadjuvant therapy, with strong consideration for patients with node-positive disease or tumors ≥4 cm and who have no contraindications for ICIs. Neoadjuvant therapy should not be used to attempt to induce resectability in patients who do not already meet criteria for resectability on initial evaluation.
Contraindications for treatment with PD-1/PD-L1 inhibitors may include active or previously documented autoimmune disease and/or current use of immunosuppressive agents; some oncogenic drivers (eg, EGFR exon 19 deletions, EGFR exon 21 L858R mutations, or ALK fusions) have been shown to be associated with less benefit from PD-1/PD-L1 inhibitors.23 Testing for PD-L1 status, EGFR mutations, and ALK fusions is recommended before administering neoadjuvant nivolumab + platinum-doublet chemotherapy in eligible patients with stage IB (only T = 4 cm) to IIIA and stage IIIB (only T3N2). For the 2023 update (Version 1.2023), the panel expanded the criteria to include patients with stage IIIB (only T3N2) disease based on differences between the AJCC staging systems for the 7th and 8th editions (see Table 3 in the complete version of these NCCN Guidelines, available at NCCN.org [page ST-3]).24 Although the 8th edition of the AJCC staging manual is currently being used, the clinical trials used the 7th edition.
Healthcare providers should be aware of the spectrum of potential immune-mediated adverse events, know how to manage the adverse events, and educate their patients about possible side effects (see the NCCN Guidelines for Management of Immunotherapy-Related Toxicities, available at NCCN.org).25–28 Nivolumab should be discontinued for patients with severe or life-threatening pneumonitis and should be withheld or discontinued for other severe or life-threatening immune-mediated adverse events when indicated (see prescribing information).
Adjuvant Systemic Therapy
Targeted Therapy
Clinical Trial Data
ADAURA, a phase III randomized trial, assessed adjuvant therapy with osimertinib versus placebo in 682 patients with resected stage IB–IIIA EGFR mutation–positive NSCLC (staging based on AJCC 7th edition).29 At 24 months, 89% (95% CI, 85%–92%) of the osimertinib group and 52% (95% CI, 46%–58%) of the placebo group were alive and disease-free (overall HR for disease recurrence or death, 0.20; 99.12% CI, 0.14–0.30; P<.001). At 24 months, 98% (95% CI, 95%–99%) of the osimertinib group and 85% (95% CI, 80%–89%) of the placebo group were alive and did not have central nervous system disease (overall HR for disease recurrence or death, 0.18; 95% CI, 0.10–0.33). For patients with stage IB NSCLC, 88% (95% CI, 78%–94%) of the osimertinib group and 71% (95% CI, 60%–80%) of the placebo group were alive and disease-free at 24 months (overall HR for disease recurrence or death, 0.39; 95% CI, 0.18–0.76). For patients with stage II NSCLC, 91% (95% CI, 82%–95%) of the osimertinib group and 56% (95% CI, 45%–65%) of the placebo group were alive and disease-free at 24 months (overall HR, 0.17; 95% CI, 0.08–0.31). For those with stage IIIA NSCLC, 88% (95% CI, 79%–94%) of the osimertinib group and 32% (95% CI, 23%–41%) of the placebo group were alive and disease-free at 24 months (overall HR, 0.12; 95% CI, 0.07–0.20). Data were also reported for those who received adjuvant chemotherapy and those who did not. OS data are not available yet. Serious adverse events were reported in 16% (54/339) of patients receiving osimertinib versus 12% (42/343) receiving placebo. Ten (3%) patients receiving osimertinib had interstitial lung disease versus no patients in the placebo group. There were no deaths in the osimertinib group versus 1 in the placebo group.
NCCN Recommendations
The NCCN panel recommends osimertinib as an adjuvant (also known as postoperative) therapy option for eligible patients with completely resected (R0) stage IB (only T = 4 cm) to IIIA and stage IIIB (only T3N2) EGFR mutation–positive NSCLC who have previously received adjuvant chemotherapy or are ineligible to receive platinum-based chemotherapy based on clinical trial data and the FDA approval (see NSCL-4, NSCL-4A, NSCL-7, NSCL-10, and NSCL-E 2 of 3, pages 343–350; and NSCL-6, available in the complete version of these guidelines at NCCN.org).29 For the 2023 update (Version 1.2023), the NCCN panel expanded the criteria to include patients with stage IIIB (only T3N2) disease, as previously described.24 Osimertinib is recommended in these settings for EGFR exon 19 deletions or EGFR exon 21 L858R mutations, which are the most common EGFR mutations. Although it is technically easier to use a resected specimen for molecular testing, it is also acceptable to use initial diagnostic biopsy specimens. However, plasma cell-free/circulating tumor (cf/ct) DNA testing is not recommended in this setting, because tissue is available and it is difficult to detect mutations in peripheral blood in patients with early-stage disease. The NCCN Guidelines include a caveat that if patients have oncogenic driver mutations and high PD-L1 levels, they should receive appropriate targeted therapy, such as osimertinib, and not ICIs and not both. Targeted therapies are associated with higher response rates and less toxicity than ICIs.
Immunotherapy
Clinical Trial Data
IMpower010, a phase III randomized trial, assessed adjuvant therapy with atezolizumab versus best supportive care in 1,005 patients with completely resected stage IB–IIIA NSCLC (staging based on AJCC 7th edition) and various PD-L1 levels.30 Atezolizumab is an ICI that inhibits PD-L1. All patients received adjuvant platinum-based chemotherapy after resection. In patients with resected stage II–IIIA NSCLC and PD-L1 of ≥1%, disease-free survival (DFS) was improved in those receiving adjuvant atezolizumab compared with best supportive care (HR, 0.66; 95% CI, 0.50–0.88; P=.0039). Treatment-related grade 3 and 4 adverse events were reported in 11% (53/495) of patients; 4 deaths occurred (1% [4/495]).
PEARLS/KEYNOTE 091, a phase III randomized trial, assessed adjuvant therapy with pembrolizumab versus placebo in 1,177 patients with completely resected stage IB–IIIA NSCLC (staging based on AJCC 7th edition).31 Pembrolizumab is an ICI that inhibits PD-1 receptors. Most patients (86%) received adjuvant platinum-based chemotherapy after resection but had not received neoadjuvant chemotherapy or RT. In patients who received adjuvant chemotherapy after resection, the median DFS in the overall population was 53.6 months (95% CI, 39.2 to not reached) in those receiving adjuvant pembrolizumab versus 42.0 months (95% CI, 31.3 to not reached) in those receiving placebo (HR, 0.76, 95% CI, 0.63–0.91; P=.0014). In patients with PD-L1 levels of ≥50%, the median DFS was similar in both groups (HR, 0.82; 95% CI, 0.57–1.18; P=.14). OS data are not available yet. Grade 3 or worse events included hypertension (6%) and pneumonia (2%) in patients receiving pembrolizumab, and hypertension (6%) and increased body weight (2%) in those receiving placebo. In patients receiving pembrolizumab, 4 (1%) treatment-related deaths occurred from myocarditis and cardiogenic shock; myocarditis and septic shock; pneumonia; and sudden death. In patients receiving placebo, there were no treatment-related deaths.
NCCN Recommendations
The NCCN NSCLC Panel recommends atezolizumab as an adjuvant therapy option for eligible patients with PD-L1 of ≥1% and completely resected (R0) stage IIB–IIIA, stage IIIB (only T3N2), or high-risk stage IIA NSCLC who are negative for EGFR exon 19 deletions, EGFR exon 21 L858R mutations, or ALK fusions and who have previously received adjuvant chemotherapy based on clinical trial data and the FDA approval (see NSCL-4, NSCL-7, NSCL-10, and NSCL-E 2 of 3, pages 343–350; and NSCL-6, available in the complete version of these guidelines at NCCN.org).30
For the 2023 update (Version 2.2023), the NCCN panel added a recommendation for adjuvant pembrolizumab for eligible patients with completely resected (R0) stage IIB–IIIA, stage IIIB (only T3N2), or high-risk stage IIA NSCLC who are negative for EGFR exon 19 deletions, EGFR exon 21 L858R mutations, or ALK fusions and who have previously received adjuvant chemotherapy based on clinical trial data and the FDA approval (see NSCL-4, NSCL-7, NSCL-10, and NSCL-E 2 of 3, pages 343–350; and NSCL-6, available in the complete version of these guidelines at NCCN.org).31 High-risk factors may include poorly differentiated tumors, vascular invasion, wedge resection, visceral pleural involvement, and unknown lymph node status (Nx). The panel added a caveat that the benefit of adjuvant pembrolizumab is unclear for patients with PD-L1 levels <1% (HR, 0.78; 95% CI, 0.58–1.03). For the 2023 update (Version 1.2023), the panel expanded the criteria to include patients with stage IIIB (only T3N2) disease, as previously described. In addition, the panel added a recommendation that patients should be evaluated for perioperative (neoadjuvant or adjuvant) therapy before surgery (see NSCL-3, NSCL-5, and NSCL-8, pages 342–347).
Patients with ALK fusions, EGFR exon 19 deletions, or EGFR exon 21 L858R mutations have less benefit from ICIs.23 Testing for PD-L1 status, EGFR mutations, and ALK fusions is recommended before administering atezolizumab or pembrolizumab as adjuvant therapy. For the 2023 update (Version 1.2023), the panel expanded the molecular testing criteria to include ALK fusions. Although it is technically easier to use a resected specimen for molecular testing, it is also acceptable to use initial diagnostic biopsy specimens. However, plasma cf/ct DNA testing is not recommended in this setting, because tissue is available and it is difficult to detect mutations in peripheral blood in patients with early-stage disease. As previously mentioned, ICIs are associated with unique immune-mediated adverse events.25,26 Atezolizumab or pembrolizumab should be discontinued for patients with severe or life-threatening pneumonitis and should be withheld or discontinued for other severe or life-threatening immune-mediated adverse events when indicated (see prescribing information).
Summary
These NCCN Guidelines Insights focus on neoadjuvant and adjuvant (also known as perioperative) systemic therapy options for eligible patients with resectable NSCLC. The NCCN Guidelines Insights explain, in greater detail than the parent NCCN Guidelines, the reasons why the panel members recently revised the guidelines, and provide a valuable resource for busy healthcare providers who need to quickly learn about the recent recommendations to provide the best care for their patients with NSCLC.
For the 2023 update (Version 1.2023), the NCCN panel added a recommendation that patients should be evaluated for perioperative (neoadjuvant or adjuvant) therapy before surgery (see NSCL-3, NSCL-5, and NSCL-8, pages 342–347). The panel recommends nivolumab + platinum-doublet chemotherapy as a neoadjuvant (also known as preoperative or induction) systemic therapy option for eligible patients with resectable (tumors ≥4 cm or node-positive) NSCLC based on clinical trial data and the FDA approval (see NSCL-E 1 of 3, page 349).20–22 For the 2023 update (Version 1.2023), the panel added a recommendation that all patients should be evaluated for neoadjuvant therapy, with strong consideration for patients with node-positive disease or tumors ≥4 cm and who have no contraindications for ICIs. Neoadjuvant therapy should not be used to attempt to induce resectability in patients who do not already meet criteria for resectability on initial evaluation.
The NCCN panel recommends osimertinib as an adjuvant (also known as postoperative) therapy option for eligible patients with completely resected (R0) stage IB (only T = 4 cm) to IIIA and stage IIIB (only T3N2) EGFR mutation–positive NSCLC who have previously received adjuvant chemotherapy or are ineligible to receive platinum-based chemotherapy based on clinical trial data and the FDA approval (see NSCL-4, NSCL-7, NSCL-10, NSCL-E 2 of 3, pages 343–350; and NSCL-6, available in the complete version of these guidelines at NCCN.org).29 The panel recommends atezolizumab as an adjuvant therapy option for eligible patients with PD-L1 levels ≥1% and completely resected stage IIB–IIIA, stage IIIB (only T3N2), or high-risk stage IIA NSCLC who have previously received adjuvant chemotherapy based on clinical trial data and the FDA approval (see NSCL-4, NSCL-7, NSCL-10, NSCL-E 2 of 3, pages 343–350; and NSCL-6, available in the complete version of these guidelines at NCCN.org).30
For the 2023 update (Version 2.2023), the panel added a recommendation for adjuvant pembrolizumab for eligible patients with completely resected (R0) stage IIB–IIIA, stage IIIB (only T3N2), or high-risk stage IIA NSCLC who are negative for EGFR exon 19 deletions, EGFR exon 21 L858R mutations, or ALK fusions and who have previously received adjuvant chemotherapy based on clinical trial data and the FDA approval (see NSCL-4, NSCL-7, NSCL-10, NSCL-E 2 of 3, pages 343–350; and NSCL-6, available in the complete version of these guidelines at NCCN.org).31 The panel added a caveat that the benefit of adjuvant pembrolizumab is unclear for patients with PD-L1 levels <1% (HR, 0.78; 95% CI, 0.58–1.03). For the 2023 update (Version 1.2023), the panel expanded the criteria to include patients with stage IIIB (only T3N2) disease based on differences between the AJCC staging systems for the 7th and 8th editions (see Table 3 in the complete version of these NCCN Guidelines, available at NCCN.org [page ST-3]).24 Although the 8th edition of the AJCC staging manual is currently being used, the clinical trials used the 7th edition. The NCCN panel also expanded the molecular testing criteria to include ALK fusions, because patients with ALK fusions, EGFR exon 19 deletions, or EGFR exon 21 L858R mutations experience less benefit from ICIs.23
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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 NCCN Guidelines is available free of charge at NCCN.org.
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