As reported by Martin Reck, MD, PhD, and colleagues in the Journal of Clinical Oncology, the 5-year follow-up of the pivotal phase III KEYNOTE-024 trial shows maintained overall survival benefit in patients treated with pembrolizumab vs chemotherapy—despite substantial crossover to the immunotherapy group—in previously untreated patients with non–small cell lung cancer (NSCLC) and a PD-L1 tumor proportion score (TPS) ≥ 50%.
The study supported the October 2016 approval of pembrolizumab in this setting, with the immunotherapy being associated with improved progression-free and overall survival. The authors noted that the report is the first 5-year follow-up of any first-line phase III immunotherapy trial for NSCLC.
Martin Reck, MD, PhD
Study Details
In the trial, 305 patients with TPS ≥ 50% and no sensitizing EGFR or ALK alterations were randomly assigned to receive pembrolizumab at 200 mg once every 3 weeks for up to 35 cycles (n = 154) or platinum-based chemotherapy (n = 151). Patients with disease progression in the chemotherapy group could cross over to receive pembrolizumab. The primary endpoint was progression-free survival, with overall survival as a secondary endpoint.
Key Findings
Median time from random assignment to data cutoff in June 2020 was 59.9 months (range = 55.1–68.4 months). Among patients initially assigned to chemotherapy, 99 (66.0%) received subsequent anti–PD-1 or PD-L1 therapy (including 83 who crossed over to pembrolizumab on study), representing a 66.0% effective crossover rate. A total of 80 patients (52.9%) in the pembrolizumab group received additional anticancer therapy, including 12 who received a second course of pembrolizumab on study.
Median overall survival was 26.3 months (95% confidence interval [CI] = 18.3–40.4 months) in the pembrolizumab group vs 13.4 months (95% CI = 9.4–18.3 months) in the chemotherapy group (hazard ratio [HR] = 0.62, 95% CI = 0.48–0.81). Kaplan-Meier estimates for rates at 3, 4, and 5 years were 43.7% vs 23.7%, 35.8% vs 19.8%, and 31.9% vs 16.3%.
Median progression-free survival was 7.7 months (95% CI = 6.1–10.2 months) in the pembrolizumab group vs 5.5 months (95% CI = 4.2–6.2 months) in the chemotherapy group (HR = 0.50, 95% CI = 0.39–0.65). Estimates of progression-free survival rates at 3, 4, and 5 years were 22.8% vs 4.1%, 16.4% vs 1.4%, and 12.8% vs no evaluable patients.
Pembrolizumab provides a durable, clinically meaningful long-term overall survival benefit vs chemotherapy as first-line therapy for metastatic NSCLC with PD-L1 tumor proportion score of at least 50%.— Martin Reck, MD, PhD, and colleagues
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Median progression-free survival–2 (ie, time from randomization to subsequent disease progression after initiation of new anticancer therapy or death from any cause) was 24.1 months (95% CI = 15.0–31.4 months) in patients initially randomly assigned to pembrolizumab vs 8.5 months (95% CI = 7.3–11.4 months) among those initially randomly assigned to chemotherapy (HR = 0.51, 95% CI = 0.39–0.67). Estimated rates at 3, 4, and 5 years were 39.5% vs 15.0%, 31.4% vs 14.0%, and 26.3% vs 13.0%.
A total of 39 patients (25.8%) in the pembrolizumab group completed 35 cycles of treatment. At data cutoff, 32 were alive, and the overall survival rate at 36 months from completion of 35 cycles (approximately 5 years) was 81.4%. A total of 18 patients (46.2%) were alive without disease progression or subsequent therapy for NSCLC. Among patients who completed 35 cycles, treatment-related adverse events occurred in 87.2% (grade 3–4 in 15.4%), consistent with the overall as-treated population.
A total of 12 patients received a second course of pembrolizumab on study after investigator-assessed disease progression. Median time from last dose of second course to data cutoff was 15.2 months (range = 0.4–29.6 months). Among these patients, eight (66.7%) were alive at data cutoff; five (41.7%) were alive without disease progression, and three (25.0%) had not received subsequent therapy. Objective response was observed in four patients and stable disease was observed in six. Five patients (41.7%) had treatment-related adverse events during the second course; all were grade 1 or 2, including grade 1 hyperthyroidism in one patient.
No new safety signals were identified in long-term follow-up. Exposure-adjusted adverse event rates in the total study population decreased over time in both treatment groups for treatment-related adverse events, immune-mediated adverse events, and infusion-related reactions.
The investigators concluded, “Pembrolizumab provides a durable, clinically meaningful long-term overall survival benefit vs chemotherapy as first-line therapy for metastatic NSCLC with PD-L1 tumor proportion score of at least 50%.”
Dr. Reck, of the Lung Clinic Grosshansdorf, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc. For full disclosures of the study authors, visit ascopubs.org.
