Continuation of Pembrolizumab with Additional Chemotherapy after Progression with PD-1/PD-L1 Inhibitor Monotherapy in Patients with Advanced NSCLC: A Randomized, Placebo-Controlled Phase II Study

Abstract Purpose: Although programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors have shown survival benefits in patients with non–small cell lung cancer (NSCLC), most patients progress. This study evaluated whether continuing pembrolizumab with additional chemotherapy after failure of prior PD-1/PD-L1 inhibitor extends survival. Patients and Methods: This placebo-controlled, double-blind, randomized phase II study enrolled patients with NSCLC who received one or two cytotoxic chemotherapy, including at least one platinum-doublet regimen, and progressed on second- or third-line PD-1/PD-L1 inhibitor monotherapy as the last systemic therapy. Patients were randomized (1:1) to pembrolizumab or placebo plus chemotherapy, stratified by histology and clinical outcomes to prior PD-1/PD-L1 inhibitor. The primary endpoint was progression-free survival (PFS). Results: A total of 98 patients were randomized to the pembrolizumab-chemotherapy (N = 47) and placebo-chemotherapy arm (N = 51). At the median follow-up duration of 10.5 months, there was no statistical difference in PFS [median 4.1 months vs. 5.9 months; HR = 1.06; 95% confidence interval (CI), 0.69–1.62; P = 0.78) and overall survival (median 11.5 months vs. 12.0 months; HR = 1.09; 95% CI, 0.66–1.83; P = 0.73) between the pembrolizumab-chemotherapy and placebo-chemotherapy arms. In a subgroup with PD-L1 expression in ≥50% of tumor cells and favorable clinical outcomes to prior PD-1/PD-L1 inhibitor (partial response or 6 months or longer of stable disease), the pembrolizumab-chemotherapy arm showed a higher 24-month survival rate than the placebo-chemotherapy arm (74% vs. 38%; HR = 0.52; 95% CI, 0.13–2.1; P = 0.34). Conclusions: This study did not show a survival benefit with the continuation of pembrolizumab with chemotherapy in patients whose NSCLC progressed on second- or third-line PD-1/PD-L1 inhibitors. See related commentary by Tseng and Gainor, p. 2206