As reported in The New England Journal of Medicine by Heather Wakelee, MD, and colleagues, an interim analysis of the phase III KEYNOTE-671 trial showed that the addition of neoadjuvant pembrolizumab to cisplatin-based chemotherapy followed by adjuvant pembrolizumab improved pathologic response and event-free survival in patients undergoing resection of early-stage non–small cell lung cancer (NSCLC).

Heather Wakelee, MD

Study Details

In the international double-blind trial, 797 patients were randomly assigned between April 2018 and December 2021 to receive neoadjuvant pembrolizumab at 200 mg (n = 397) or placebo (n = 400) every 3 weeks with cisplatin-based chemotherapy for four cycles; following surgery, patients received adjuvant pembrolizumab at 200 mg or placebo every 3 weeks for up to 13 cycles. The co-primary endpoints were event-free survival and overall survival.  

Survival and Response Rates

At the prespecified first interim analysis, median follow-up was 25.2 months (range = 7.5–50.6 months). Event-free survival at 24 months was 62.4% (95% confidence interval [CI] = 56.8%–67.5%) in the pembrolizumab group vs 40.6% (95% CI = 34.8%–46.3%) in the control group. Median event-free survival was not reached (95% CI = 34.1 months to not reached) in the pembrolizumab group vs 17.0 months (95% CI = 14.3–22.0 months) in the control group (hazard ratio = 0.58, 95% CI = 0.46–0.72, P < .001).

Estimated 24-month overall survival was 80.9% (95% CI = 76.2%–84.7%) in the pembrolizumab group and 77.6% (95% CI = 72.5%–81.9%) in the control group. Median overall survival was not reached in the pembrolizumab group vs 45.5 months (95% CI = 42.0 months to not reached) in the control group (P = .02, which did not meet the significance criterion for interim analysis).

Major pathologic response occurred in 30.2% of patients in the pembrolizumab group vs 11.0% of the placebo group (difference = 19.2 percentage points, 95% CI = 13.9–24.7 percentage points, P < .0001). Pathologic complete response occurred in 18.1% of patients in the pembrolizumab group vs 4.0% of the placebo group (difference = 14.2 percentage points, 95% CI= 10.1–18.7 percentage points, P < .0001).

Adverse Events

Across all treatment phases, treatment-related grade ≥ 3 adverse events occurred in 44.9% of those in the pembrolizumab group vs 37.3% of the control group, most commonly hematologic adverse events. Treatment-related serious adverse events occurred in 17.7% vs 14.3% of patients, and treatment-related adverse events led to discontinuation of treatment in 12.6% vs 5.3%. Treatment-related death occurred in four patients (1.0%) in the pembrolizumab group, due to immune-mediated lung disease, pneumonia, and sudden cardiac death in one patient each during the neoadjuvant/surgery phase and atrial fibrillation in one patient during the adjuvant phase.

Treatment-related death occurred in three patients (0.8%) in the control group, due to acute coronary syndrome, pneumonia, and pulmonary hemorrhage during the neoadjuvant/surgery phase.

The investigators concluded, “Among patients with resectable, early-stage NSCLC, neoadjuvant pembrolizumab plus chemotherapy followed by resection and adjuvant pembrolizumab significantly improved event-free survival, major pathological response, and pathological complete response as compared with neoadjuvant chemotherapy alone followed by surgery. Overall survival did not differ significantly between the groups in this analysis.”  

Dr. Wakelee, of the Division of Oncology, Stanford University School of Medicine, Stanford Cancer Institute, is the corresponding author for The New England Journal of Medicine article.

Disclosure: The study was funded by Merck Sharp and Dohme. For full disclosures of the study authors, visit nejm.org.