In patients with extensive-stage SCLC, pembrolizumab combined with platinum-based chemotherapy significantly improves progression-free survival compared with first-line use of doublet chemotherapy.
KEYNOTE-604 is a double-blind, phase 3 study of pembrolizumab (Keytruda) combined with etoposide and platinum (EP) therapy compared with placebo plus EP as first-line therapy for patients with extensive-stage SCLC.1 Patients who were eligible to enroll in KEYNOTE-604 had previously untreated extensive-stage SCLC and no untreated central nervous system metastases. They were randomized to receive either pembrolizumab (200 mg every 3 weeks) or placebo for up to 35 cycles combined with 4 cycles of standard-dose EP.1 Patients with complete response or partial response after cycle 4 could receive PCI at the investigator’s discretion. Patient randomization was stratified by platinum choice (carboplatin vs cisplatin), performance status (Eastern Cooperative Oncology Group [ECOG] performance score 0 vs 1), and lactate dehydrogenase levels (≥upper limit of normal [ULN] vs >ULN).1
The primary end points of KEYNOTE-604 were OS and PFS using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria and blinded central review in the intent-to-treat (ITT) population. ORR, duration of response (DOR), and safety were secondary end points.1
A total of 453 patients were randomized: 223 of 228 patients assigned to pembrolizumab plus EP received treatment and 222 of 225 patients assigned to placebo plus EP received treatment.1 One patient who was assigned to pembrolizumab plus EP received placebo plus EP in error.1 The median age of patients receiving pembrolizumab plus EP was 64 years, 74% had ECOG performance score 1, and 56% had lactate dehydrogenase levels >ULN.1 More patients in the pembrolizumab plus EP arm had baseline brain metastases (15% vs 10%).1
At the final analysis, with median follow-up of 21.6 months, 9% of patients in the pembrolizumab plus EP arm and 1% in the placebo plus EP arm remained on study treatment; 12% and 14% received PCI.1 At the second interim analysis, with median follow-up of 13.5 months, pembrolizumab plus EP significantly improved PFS in the ITT population (HR, 0.75; 95% CI, 0.61-0.91; P = .002; median, 4.5 vs 4.3 months).1
At the final analysis, pembrolizumab plus EP prolonged OS in the ITT population, but the significance threshold was not met (HR, 0.80; 95% CI, 0.64-0.98; P = .016; median, 10.8 vs 9.7 months).1 In a post-hoc analysis of OS in the as-treated population, the nominal P value was less than the significance threshold (HR, 0.78; 95% CI, 0.63-0.97; P = .012).1 ORR was 71% for pembrolizumab plus EP compared with 62% for placebo plus EP.1 Median DOR was 4.2 months versus 3.7 months, respectively.1
Observed AEs were as expected; any-cause AEs were grade 3/4 in 77% of patients receiving pembrolizumab plus EP compared with 75% of patients receiving placebo plus EP.1 AEs led to drug discontinuation of any treatment in 15% and 6% of patients, respectively.1 Death caused by AEs occurred in 6% and 5% of patients, respectively.1
In summary, pembrolizumab plus EP significantly improved PFS compared with placebo plus EP as first-line therapy for patients with extensive-stage SCLC. No unexpected toxicities were seen with pembrolizumab plus EP. These data support the benefit of pembrolizumab-containing regimens for extensive-stage SCLC.1
1. Rudin CM, Awad MM, Navarro A, et al; for the KEYNOTE-604 Investigators. Pembrolizumab or placebo plus etoposide and platinum as first-line therapy for extensive-stage small-cell lung cancer: randomized, double-blind, phase III KEYNOTE-604 study. J Clin Oncol. 2020;38:2369-2379.