Integrating immunotherapies will continue to improve patient outcomes and quality of life.
The landscape of adjuvant systemic therapy for non–small cell lung cancer (NSCLC) has witnessed significant advancements with the integration of biomarker testing and the latest updates in clinical guidelines. In the 2023 update, the National Comprehensive Cancer Network (NCCN) panel has made several recommendations for adjuvant therapy options for patients with NSCLC based on clinical trial data and FDA approvals.
The panel expanded the molecular testing criteria to include ALK rearrangements in addition to PD-L1 status and EGFR mutations for stages IB to IIIA or IIIB NSCLC (T3,N2). The guidelines have broadened the application of adjuvant immunotherapy using atezolizumab (Tecentriq; Genentech) and osimertinib (Tagrisso; AstraZeneca) to encompass patients with completely resected stage IIIB (T3,N2) NSCLC.
Osimertinib is recommended for eligible patients with completely resected stage IB to IIIA or IIIB (T3,N2) EGFR mutation–positive NSCLC who have previously received adjuvant chemotherapy or are ineligible for platinum-based chemotherapy. Atezolizumab is recommended as an adjuvant therapy option for eligible patients with PD-L1 levels of at least 1% and completely resected stage IB to IIIA or IIIB (T3,N2), or high-risk stage IIA NSCLC, who have received adjuvant chemotherapy.
Additionally, the NCCN panel added a recommendation for adjuvant pembrolizumab for patients with completely resected stage IIB to IIIA or IIIB (T3,N2), 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. These advancements in biomarker testing and treatment options represent a significant stride toward optimizing personalized care for patients with NSCLC.1
Pembrolizumab (Keytruda; Merck) is a humanized IgG4 k monoclonal antibody designed to specifically target and inhibitthe PD-1 receptor. The randomized, triple-blind, phase 3 PEARLS/KEYNOTE-091 trial (NCT02504372) assessed pembrolizumab as adjuvant therapy for completely resected stage IB to IIIA NSCLC. This study included 1177 patients who had pathologically confirmed stage IB to IIIA NSCLC (of any histology) and underwent complete surgical resection of the tumor with negative margins (R0).
Patients were randomly assigned 1:1 to receive pembrolizumab at 200 mg or placebo every 3 weeks for approximately 1 year, or 18 administrations. Patients were not mandated to receive adjuvant chemotherapy, although it was to be considered for stage IB NSCLC and strongly recommended for stage II to IIIA NSCLC. Patients who did receive adjuvant chemotherapy were to receive no more than 4 chemotherapy cycles.
The median age of the total patient population in the study was 65 years (range, 59-70), with approximately 52% of patients aged 65 years or older. Of the total patient population, 333 (28%) had a PD-L1 tumor proportion score (TPS) of 50% or greater. More than 56% of patients had stage II disease, followed by 28.8% with stage IIIA disease. More than 85% of patients received adjuvant chemotherapy.2
At a median follow-up of 35.6 months (range, 27.1-45.5), the primary end point of disease-free survival (DFS) in the intent-to-treat population was met, with a median DFS of 53.6 months (95% CI, 39.2-not reached [NR]) with pembrolizumab compared with 42 months (95% CI, 31.3-NR) with placebo (HR, 0.76 [95% CI, 0.63-0.91]; P = .0014). In patients with a PD-L1 TPS of 50% or greater, median DFS was not reached among those who were receiving pembrolizumab (95% CI, 44.3 months-NR) or placebo (95% CI, 35.8 months-NR; HR, 0.82 [95% CI, 0.57-1.18]; P = .14). Further, DFS was generally similar across prespecified subgroups, although certain subgroups (current smokers, EGFR-mutated tumors, stage II disease, prior adjuvant chemotherapy, nonsquamous histology, and PD-L1 TPS 1%-49%) with reported benefit with pembrolizumab will require appropriately powered randomized trials to determine benefit of pembrolizumab compared with placebo. Median overall survival (OS) was not reached in either treatment arm (HR, 0.87; 95% CI, 0.67-1.15; P = .17).2
The overall incidence of any-grade adverse events (AEs) was similar between patients who received adjuvant pembrolizumab vs placebo (96% vs 91%). The overall incidence of grade 3 AEs or higher occurred in 34% of patients receiving pembrolizumab compared with 26% receiving placebo. Treatment-related serious AEs occurred in 12% of participants in the pembrolizumab group and 2% in the placebo group. The most common treatment-related serious AEs across both groups included pneumonitis, diarrhea, and colitis. Grade 3 or greater immune-mediated severe AEs, pneumonitis, and hepatitis occurred in at least 5% of patients receiving pembrolizumab. Overall, the AE profile of pembrolizumab was similar to prior studies of pembrolizumab monotherapy. More patients in the pembrolizumab group discontinued treatment due to AEs compared with placebo (20% vs 6%). Lastly, the number of deaths due to AEs attributed to treatment as determined by the investigator was 4 (1%) patients receiving pembrolizumab compared with none in the placebo group.2
Durvalumab (Imfinzi; AstraZeneca) is a humanized IgG1 monoclonal antibody directed against PD-L1 and is being studied for its efficacy as adjuvant therapy for completely resected stage IB to IIIA NSCLC in the ongoing randomized, double-blind, phase 3 BR31 trial (NCT02273375). This study has recruited 1415 patients who have histologically confirmed stage IB to IIIA NSCLC and underwent complete surgical resection of the primary tumor with negative margins. Only standard postoperative adjuvant chemotherapy is allowed.3 Further, patients are randomly assigned 2:1 to receive intravenous (IV) infusions of durvalumab or placebo at 10 mg/kg every 2 weeks for 6 months, followed by IV infusions of durvalumab or placebo at 20 mg/kg every 4 weeks for 6 months.4
The primary outcome measure is DFS in patients with PD-L1-positive NSCLC with no EGFR mutation or ALK gene rearrangement. Key secondary outcome measures include DFS in patients with different PD-L1 genetic expression levels and EGFR mutations or ALK gene rearrangement, as well as OS in patients with different PD-L1 and EGFR mutations over a period of 8 years. The safety of durvalumab and incidence of AEs will be monitored every 6 months. Participants will then be followed up for a maximum of 10 years to assess OS and DFS. The study completion date is estimated to be January 2026.3
Nivolumab (Opdivo; Bristol Myers Squibb) is a humanized IgG4 PD-1 immune checkpoint inhibitor monoclonal antibody that is also being studied for its efficacy as adjuvant therapy for completely resected stage IB to IIIA NSCLC. The ongoing phase 3, randomized, open-label ANVIL trial (NCT02595944) is in the arm of the ALCHEMIST trial, a National Cancer Institute–sponsored National Clinical Trials Network initiative investigating adjuvant nivolumab in patients not eligible for EGFR- or ALK-targeted therapy.5
In the ANVIL study, 903 patients with completely resected NSCLC (stage IB-IIIA NSCLC without EGFR or ALK mutations) and negative surgical margins at baseline will be randomly assigned 1:1 to nivolumab vs observation. Adjuvant chemotherapy and/or radiation is allowed but not required. Patients randomly assigned to the treatment arm will receive nivolumab 480 mg IV over 30 minutes every 4 weeks for up to 1 year, whereas patients randomly assigned to the control arm will be followed serially with CT and/or PET/CT imaging for up to 1 year.6,7
The primary objectives of this study are to assess DFS and OS for up to 10 years. Key secondary objectives are to evaluate DFS and OS by stage or stratification factor and in patients with tumors who have high mutational load. After completion of study treatment, patients are followed up at 6 weeks, every 3 months for 2 years, every 6 months for 2 years, and then every 12 months for 6 years. The estimated primary completion date is December 2025.7
The advancements in adjuvant immunotherapy and biomarker testing represent a substantial step forward in the adjuvant therapy space for resectable NSCLC. Specifically, pembrolizumab showed promising results in the PEARLS/KEYNOTE-091 trial. The study demonstrated a significant improvement in DFS for patients with completely resected stage IB to IIIA NSCLC treated with pembrolizumab compared with placebo. Of note, in both the pembrolizumab and placebo groups, median DFS for patients in the PD-L1 TPS of 50% or greater and median OS were not reached in the interim analysis. However, as this only provides may not capture the complete picture of long-term survival.2 The ongoing trials evaluating other immunotherapies, such as durvalumab and nivolumab, will provide further insights into their efficacy as adjuvant therapies in the future.3,7
As research continues and more data from ongoing trials become available, the hope is that the integration of these immunotherapies will continue to improve outcomes and enhance the quality of life for patients with resectable NSCLC. Overall, the future of adjuvant immunotherapy in resectable NSCLC appears promising, and these findings pave the way for a more personalized and effective treatment approach.
1. NCCN. Clinical Practice Guidelines in Oncology. Non–small cell lung cancer, version 3.2023. Accessed July 18, 2023. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
2. O’Brien M, Paz-Ares L, Marreaud S, et al. Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial. Lancet Oncol. 2022;23(10):1274-1286. doi:10.1016/S1470-2045(22)00518-6
3. Double blind placebo controlled controlled study of adjuvant MEDI4736 in completely resected NSCLC. ClinicalTrials.gov. October 24, 2014. Accessed July 18, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT02273375
4. BR.31: a phase III prospective double blind placebo controlled randomized study of adjuvant MEDI4736 in completely resected non-small cell lung cancer. Victorian Cancer Trials. Accessed July 18, 2023. https://trials.cancervic.org.au/details.aspx?ID=vctl_actrn12615000323527
5. The ALCHEMIST lung cancer trials. National Cancer Institute. Updated July 24, 2017. Accessed July 18, 2023. https://www.cancer.gov/types/lung/research/alchemist
6. EA5142. South Georgia Medical Center. Accessed July 18, 2023. www.sgmc.org/our-locations/cancer-treatment/clinical-trials/ea5142/
7. Nivolumab after surgery and chemotherapy in treating patients with stage IB-IIIA non-small cell lung cancer (an ALCHEMIST treatment trial) (ANVIL). ClinicalTrials.gov. Posted November 4, 2015. Accessed July 18, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT02595944
About the Authors
Yuxi Lei is a PharmD candidate at Rutgers University Ernest Mario School of Pharmacy in Piscataway, New Jersey.
Rebecca Pokorny, PharmD, BCPS, BCOP, is a clinical oncology pharmacist at Huntsman Cancer Institute in Salt Lake City, Utah.
Luisa Giannangelo, MBA, RPh, is a pharmacist and medical writer in High Point, North Carolina.