In the phase III KEYNOTE-598 study, the addition of ipilimumab to pembrolizumab increased toxicity without boosting efficacy as first-line therapy for metastatic non–small cell lung cancer (NSCLC) in patients with high expression of PD-L1, according to research presented at International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer Singapore, which was moved to a virtual format and held January 28–31, 2021, in light of the COVID-19 pandemic (Abstract PS01.09), and published simultaneously in the Journal of Clinical Oncology.
The research was presented by Michael Boyer, MBBS, PhD, Clinical Professor of Medicine at the Chris O’Brien Lifehouse and the Central Clinical School of the University of Sydney.
“Nonbinding futility criteria were met, and ipilimumab and placebo were discontinued per the Ethics and Data Monitoring Committee’s recommendation,” said Dr. Boyer. “The addition of ipilimumab to pembrolizumab did not improve efficacy, and it did increase toxicity for first-line therapy for [patients with] NSCLC with high PD-L1 [expression] and no targetable mutations. This means that pembrolizumab monotherapy remains the standard-of-care first-line treatment for this group of patients…. [F]uture research will focus on other ways to improve outcomes.”
“The addition of ipilimumab to pembrolizumab did not improve efficacy, and it did increase toxicity for first-line therapy for [patients with] NSCLC with high PD-L1 [expression] and no targetable mutations. This means that pembrolizumab monotherapy remains the standard-of-care first-line treatment for this group of patients…future research will focus on other ways to improve outcomes.”— Michael Boyer, MBBS, PhD
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KEYNOTE-598 Details
The previous KEYNOTE-024 study showed that pembrolizumab monotherapy significantly improved survival vs platinum-doublet chemotherapy for patients with metastatic NSCLC and a tumor proportion score (TPS) ≥ 50% without targetable EGFR or ALK aberrations. The current randomized, double-blind phase III KEYNOTE-598 study aimed to determine whether adding ipilimumab to pembrolizumab improved efficacy over pembrolizumab alone in such patients.
The trial enrolled 568 patients with high PD-L1 expression from Europe, Asia, and North America, assigning them 1:1 to the combination of pembrolizumab at 200 mg every 3 weeks for up to 35 cycles plus ipilimumab at 1 mg/kg every 6 weeks, or pembrolizumab and placebo. The primary endpoints were overall survival and progression-free survival in the intent-to-treat population.
The protocol-specified first interim analysis (IA1) was to occur upon approximately 255 deaths and approximately 12 months after the last participant was randomly assigned. Nonbinding futility criteria at IA1 were differences in the restricted mean survival time between ipilimumab/pembrolizumab and placebo/pembrolizumab of ≤ 0.2 at the maximum observation time and ≤ 0.1 at 24 months of follow-up.
No Differences in Endpoints
Median overall survival was 21.4 months with ipilimumab/pembrolizumab compared to 21.9 months with pembrolizumab alone (hazard ratio [HR] = 1.08, 95% confidence interval [CI] = 0.85–1.37, P = .74). Restricted mean survival time differences were –0.56 at the maximum observation time and –0.52 at 24 months, which met the futility criteria, according to Dr. Boyer.
Median progression-free survival was 8.2 months with ipilimumab/pembrolizumab compared with 8.4 months for placebo/pembrolizumab (HR = 1.06 95% CI = 0.86–1.30, P = .72). The objective response rate was 45.4% in both arms; median duration of response was 16.1 months with the combination vs 17.3 months with pembrolizumab alone. There were no subgroups who derived benefit from adding ipilimumab, reported Dr. Boyer.
More Toxicity with the Combination
“Safety in the pembrolizumab/ipilimumab and pembrolizumab/placebo groups was as expected,” said Dr. Boyer. The addition of ipilimumab led to increased rates of treatment-related adverse event vs placebo, including:
- Any-grade: 76% vs 68% (immune-related: 45% vs 32%)
- Grade ≥ 3: 35% vs 20% (immune-related: 20% vs 8%)
- Serious adverse events: 28% vs 14% (immune-related: 19% vs 7%)
- Deaths: 2% vs 0 (immune-related: 2% vs 0).
Pruritis, rash, and hypothyroidism were the most common adverse events and were seen in more patients treated with the combination. Patients on the two drugs also had higher rates of treatment discontinuation due adverse events.
Disclosure: For full disclosures of the study authors, visit wclc2020.iaslc.org/disclosures.
