Perioperative Pembrolizumab Wins Canadian Approval for Resectable NSCLC

Health Canada has approved pembrolizumab (Keytruda) in combination with platinum-containing chemotherapy as neoadjuvant treatment, then continued as monotherapy in the adjuvant setting, for adult patients with resectable stage II, IIIA, or IIIB (T3-4N2) non-small cell lung cancer (NSCLC).1

The regulatory decision was supported by data from the phase 3 KEYNOTE-671 trial (NCT03425643), which demonstrated that treatment with the experimental regimen led to statistically significant improvements in event-free survival (EFS) and overall survival (OS) compared with neoadjuvant placebo plus chemotherapy, followed by adjuvant placebo monotherapy.

Findings from the trial’s second interim analysis at a median follow-up of 36.6 months (IQR, 27.6-47.8) showed that patients treated with the pembrolizumab regimen (n = 397) achieved an estimated 36-month OS rate of 71% (95% CI, 66%-76%) compared with 64% (95% CI, 58%-69%) for those given the placebo regimen (n = 400; HR, 0.72; 95% CI, 0.56-0.93; one-sided P = .0052).2

Additionally, the experimental regimen generated a median EFS of 47.2 months (95% CI, 32.9-not reached) vs 18.3 months (95% CI, 14.8-22.1) for the placebo regimen (HR, 0.59; 95% CI, 0.48-0.72).

“[Although] we have made significant advancements for patients with advanced lung cancer, it remains the leading cause of cancer-related deaths in Canada. This underscores the importance of addressing lung cancer cases in earlier stages to help improve patient outcomes,” Jonathan Spicer, MD, PhD, thoracic surgeon and scientist at the McGill University Health Centre, scientist in the Cancer Research Program at The Institute, professor of surgery at McGill University, and medical director of the McGill Thoracic Oncology Network, stated in a news release.1 “This recent approval adds another therapeutic option for patients with operable NSCLC.”

In October 2023, the FDA approved pembrolizumab in combination with platinum-containing chemotherapy as neoadjuvant treatment, and as monotherapy during adjuvant treatment for patients with resectable NSCLC.3 This approval was also supported by data from KEYNOTE-671.

KEYNOTE-671 Overview

The multicenter, randomized, double-blind, placebo-controlled trial enrolled patients at least 18 years of age with previously untreated, pathologically confirmed stage II, IIIA, or IIIB (N2) NSCLC that was considered resectable following surgical consultation.2 Patients were required to have an ECOG performance status of 0 or 1, and they needed to provide a tumor sample for PD-L1 analysis.

Key exclusion criteria consisted of active autoimmune disease requiring systemic therapy within 2 years of treatment; a medical condition requiring immunosuppression; and a history of interstitial lung disease (ILD)/pneumonitis requiring steroids.1

Enrolled patients were randomly assigned 1:1 to either treatment arm. In the experimental arm, patients received 200 mg of pembrolizumab on day 1 of each 21-day cycle in combination of 75 mg/m2 of cisplatin on day 1 and either 500 mg/m2 of pemetrexed on day 1 or 1000 mg/m2 of gemcitabine on days 1 and 8 for 4 cycles; after surgery, pembrolizumab was given once every 3 weeks for up to 13 cycles. Patients in the control arm received the same neoadjuvant chemotherapy regimen and placebo in place of pembrolizumab, followed by adjuvant placebo.

Stratification factors included stage (II vs III), tumor PD-L1 tumor proportion score (≥50% vs <50%), histology (squamous vs nonsquamous), and geographic region (East Asia vs non–East Asia).

EFS and OS served as the trial’s dual primary end points. Key secondary end points included pathological complete response rate and major pathological response rate.

Regarding safety, data from the second interim analysis showed that 97% of patients in the pembrolizumab arm (n = 396) experienced any-grade treatment-related adverse effects (TRAEs) compared with 95% of patients in the placebo arm.2 The rates of grade 3 or higher TRAEs were 45% and 38%, respectively.

TRAEs led to death in 1% of patients in both the pembrolizumab arm (n = 4) and the placebo arm (n = 3). TRAEs led to treatment discontinuation of all study treatment in 14% of patients in the experimental arm vs 5% of patients in the control arm.

The most common grade 3 or higher TRAEs reported in at least 5% of patients included decreased neutrophil count (pembrolizumab arm, 21%; placebo arm, 20%), anemia (7%; 6%), decreased platelet count (5%; 6%), and decreased white cell count (5%; 6%).

References

1. Health Canada approves Merck’s Keytruda (pembrolizumab) for the treatment of adult patients with resectable stage II, IIIA, or IIIB (T3-4N2) non-small cell lung carcinoma (NSCLC) in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as monotherapy as adjuvant treatment after surgery. News release. Merch. February 11, 2025. Accessed February 11, 2025. https://www.merck.ca/en/newsroom/keynote-671-trial/
2. Spicer JD, Garassino MC, Wakelee H, et al. Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared with neoadjuvant chemotherapy alone in patients with early-stage non-small-cell lung cancer (KEYNOTE-671): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2024;404(10459):1240-1252. doi:10.1016/S0140-6736(24)01756-2
3. FDA approves neoadjuvant/adjuvant pembrolizumab for resectable non-small cell lung cancer. FDA. October 16, 2023. Accessed February 11, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neoadjuvant-adjuvant-pembrolizumab-resectable-non-small-cell-lung-cancer