Introduction
In KEYNOTE-024, pembrolizumab monotherapy significantly improved survival versus platinum-doublet chemotherapy in patients with metastatic NSCLC with PD-L1 TPS ≥50% and no targetable EGFR or ALK aberrations. We conducted the randomized, double-blind, phase 3 KEYNOTE-598 study (NCT03302234) to determine whether adding ipilimumab to pembrolizumab improved efficacy over pembrolizumab alone in this population.
Methods
Eligible patients were randomized 1:1 to ipilimumab 1 mg/kg Q6W or saline placebo for up to 18 cycles; patients in both arms received pembrolizumab 200 mg Q3W for up to 35 cycles. Randomization was stratified by ECOG PS (0 vs 1), region (East Asia vs not East Asia), and histology (squamous vs nonsquamous). Treatment differences in the primary endpoints of OS and PFS (RECIST v1.1; blinded, independent central review) were assessed by the stratified log-rank test in the ITT population. The protocol-specified first interim analysis (IA1) was planned to occur when ∼255 deaths occurred and ∼12 months after the last participant was randomized. Nonbinding futility criteria at IA1 were differences in the restricted mean survival time (RMST) between pembro–ipi and pembro–placebo of ≤0.2 at the maximum observation time and ≤0.1 at 24 months of follow-up.
Results
Between 12-January-2018 and 22-August-2019, 568 participants were randomized to pembro–ipi (n=284; 282 treated) and pembro–placebo (n=284; 281 treated). As of 01-September-2020, median (range) study follow-up was 20.6 months (12.4-31.7), treatment was ongoing in 21.3% in the pembro–ipi arm vs 23.8% in the pembro–placebo arm, and median number of treatment cycles was 10 vs 15. Baseline characteristics were balanced between arms. With 272 deaths, median OS was 21.4 months for pembro–ipi vs 21.9 months for pembro–placebo (HR, 1.08 [95% CI, 0.85-1.37]; P = 0.74). RMST differences were –0.56 at the maximum observation time and –0.52 at 24 months, which met the futility criteria. With 372 events, median PFS was 8.2 months for pembro–ipi vs 8.4 months for pembro–placebo (HR, 1.06 [95% CI, 0.86-1.30]; P = 0.72). ORR was 45.4% in both arms; median DOR was 16.1 months for pembro–ipi vs 17.3 months for pembro–placebo. Treatment-related AEs occurred in 76.2% of pembro–ipi recipients vs 68.3% of pembro–placebo recipients, were of grade 3-5 in 35.1% vs 19.6%, led to death in 2.5% vs 0%, and led to discontinuation of any treatment in 25.2% vs 10.7%. Immune-mediated AEs and infusion reactions occurred in 44.7% of pembro–ipi recipients vs 32.4% of pembro–placebo recipients, were grade 3-5 in 20.2% vs 7.8%, led to death in 2.1% vs 0%, and led to discontinuation of any treatment in 14.9% vs 5.3%. Based on the observed efficacy and safety, the external data monitoring committee recommended that the study be stopped due to futility and that participants discontinue ipi/placebo.
Conclusion
Adding ipilimumab to pembrolizumab does not improve efficacy and is associated with greater toxicity than pembrolizumab alone as first-line therapy for metastatic NSCLC with PD-L1 TPS ≥50% and no targetable EGFR or ALK aberrations. These data confirm pembrolizumab monotherapy as a standard-of-care for this population.
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