Keynote-604: Phase 3 randomized, double-blind trial of pembrolizumab/placebo plus etoposide/platinum for extensive stage-SCLC

Background: Therapeutic options for small‐cell lung cancer (SCLC) remain limited, with etoposide/platinum (EP) as the standard first‐line chemotherapy regimen. However, patients with extensive‐stage (ES)‐SCLC experience high relapse rates within months after initial therapy. Pembrolizumab, a humanized monoclonal antibody against PD‐1, has shown antitumor activity as monotherapy in heavily pretreated patients with PD‐L1epositive SCLC in the phase 1b KEYNOTE‐028 study. KEYNOTE‐604 (ClinicalTrials.gov, NCT03066778) evaluates EP plus either pembrolizumab or placebo as first‐line therapy for ES‐SCLC. Method: Not applicable. Result: Not applicable. Conclusion: In this international, double‐blind, phase 3 trial, adults with newly diagnosed ES‐SCLC, ECOG PS ≤1, and no previous systemic therapy for SCLC are randomized 1:1 to receive either EP plus a 200‐mg fixed dose of pembrolizumab intravenously (IV) once every 3 weeks (Q3W) or EP plus placebo IV Q3W. Randomization is stratified by the chosen platinum therapy (carboplatin vs cisplatin), ECOG PS (0 vs 1), and baseline lactate dehydrogenase concentration (≤ upper limit of normal [ULN] vs > ULN). Study treatment includes a total of 4 cycles of EP and 2 years of pembrolizumab/placebo and continues until documented PD, intolerable toxicity, or withdrawal of consent. Patients with a response after 4 cycles of EP plus placebo or pembrolizumab may receive prophylactic cranial irradiation. Patients who complete 2 years of pembrolizumab treatment or stop pembrolizumab for reasons other than PD/intolerability, but subsequently have documented PD confirmed by blinded independent review, may receive an additional 1 year of pembrolizumab provided that no other systemic therapy has been administered. Patients must meet the eligibility criteria for retreatment; patients in the placebo arm are not eligible for treatment with pembrolizumab at the time of PD. Tumor response is assessed every 6 weeks for 48 weeks, and every 9 weeks thereafter by RECIST version 1.1 by blinded independent central review. AEs occurring during treatment and 30 days thereafter (90 days for serious AEs) are graded per Common Terminology Criteria for Adverse Events, version 4.0. Primary endpoints are PFS and OS. Secondary endpoints are ORR, duration of response, safety, and patient‐reported outcomes. Approximately 430 patients will be enrolled.