As reported at the ASCO20 Virtual Scientific Program by Charles M. Rudin, MD, PhD, and colleagues (Abstract 9001), the phase III KEYNOTE-604 trial has shown that first-line pembrolizumab plus etoposide/platinum significantly prolonged progression-free survival and prolonged overall survival at a near significant level vs placebo plus etoposide/platinum in patients with extensive-stage small cell lung cancer (SCLC). The findings were simultaneously published in the Journal of Clinical Oncology.
Charles M. Rudin, MD, PhD
Study Details
In the double-blind trial, 453 patients were randomly assigned to receive pembrolizumab at 200 mg every 3 weeks (n = 228) or placebo (n = 225) for up to 35 cycles, plus 4 cycles of standard-dose etoposide/platinum, with platinum treatment consisting of investigator’s choice of cisplatin or carboplatin. Patients could have no untreated central nervous system metastases.
Patients with complete or partial response after cycle 4 could receive prophylactic cranial irradiation at investigator discretion. Randomization was stratified by platinum choice (carboplatin vs cisplatin), Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1), and lactate dehydrogenase (LDH) level (≤ upper limit of normal [ULN] vs > ULN).
The primary endpoints were overall survival and progression-free survival on blinded central review using Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. Prespecified efficacy boundaries were one-sided P = .0048 for progression-free survival at second interim analysis, the prespecified primary progression-free survival analysis, and P = .0128 for overall survival at final analysis.
Among all patients, median age was 65 years, 74% had ECOG performance status of 1, and 57% had LDH > ULN. Brain metastases were present in 14% of patients in the pembrolizumab group vs 10% of the control group.
Key Findings
At final analysis, 9% of patients in the pembrolizumab plus etoposide/platinum group and 1% in the placebo plus etoposide/platinum group remained on study treatment. Overall, 12% and 14% had received prophylactic cranial irradiation.
At the time of primary progression-free survival analysis at a median follow-up of 13.5 months, median progression-free survival was 4.5 months in the pembrolizumab group vs 4.3 months in the control group (hazard ratio [HR] = 0.75, 95% confidence interval [CI] = 0.61–0.91, P = .0023).
At final analysis at a median follow-up of 21.6 months, median overall survival was 10.8 months in the pembrolizumab group vs 9.7 months in the control group (HR = 0.80, 95% CI = 0.64–0.98, P = .0164), with the prespecified significance threshold not being met.
“Pembrolizumab plus etoposide/platinum significantly improved progression-free survival and prolonged overall survival compared with placebo plus etoposide/platinum as first-line therapy for patients with extensive-stage SCLC.”— Charles M. Rudin, MD, PhD, and colleagues
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A total of 223 of 228 patients randomly assigned to the pembrolizumab group and 222 of 225 randomly assigned to the control group did not receive any dose of study treatment, and one patient in the pembrolizumab group erroneously received placebo. In a post hoc analysis in the as-treated population, median overall survival was improved in the pembrolizumab vs control group (HR = 0.78, 95% CI = 0.63–0.97, P = .0124), with the P value meeting the significance threshold specified for the intention-to-treat analysis.
Overall response rates at final analysis were 71% vs 62%, with median durations of response of 4.2 months vs 3.7 months.
Adverse events were consistent with those previously observed with the study drugs. Grade 3 or 4 adverse events occurred in 77% vs 75% of patients. Discontinuation of treatment due to adverse events occurred in 15% vs 6%. Adverse events led to death in 6% vs 5% of patients.
The investigators concluded: “Pembrolizumab plus etoposide/platinum significantly improved progression-free survival and prolonged overall survival compared with placebo plus etoposide/platinum as first-line therapy for patients with extensive-stage SCLC. No unexpected toxicities were seen with pembrolizumab plus etoposide/platinum. These data support the benefit of pembrolizumab-containing regimens for extensive-stage SCLC.”
Dr. Rudin, of Memorial Sloan Kettering Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was funded by Merck & Co. For full disclosures of the study authors, visit ascopubs.org.
