Survival was not improved with the immunotherapy combination of pembrolizumab and ipilimumab in comparison with pembrolizumab monotherapy in the first-line treatment of patients with metastatic non–small cell lung cancer who had high PD-L1 expression and did not harbor EGFR or ALK aberrations, findings from the phase 3 KEYNOTE-598 trial showed.
Survival was not improved with the immunotherapy combination of pembrolizumab (Keytruda) and ipilimumab (Yervoy) in comparison with pembrolizumab monotherapy in the first-line treatment of patients with metastatic non–small cell lung cancer (NSCLC) who had high PD-L1 expression (tumor proportion score [TPS], ≥50%) and did not harbor EGFR or ALK aberrations, findings from the phase 3 KEYNOTE-598 trial showed. Additionally, higher toxicity rates were observed with the combination regimen.1,2
Results presented at the International Association for the Study of Lung Cancer's 2020 World Conference on Lung Cancer showed that the median overall survival (OS) was 21.4 months for patients who received pembrolizumab/ipilimumab versus 21.9 months for those who received the PD-1 inhibitor alone (HR, 1.08; 95% CI, 0.85-1.37; P = .74). The restricted mean survival time differences were –0.56 at the maximum observation time and –0.52 at 2 years, which met the study’s futility criteria.
Additionally, the median progression-free survival (PFS) was 8.2 months and 8.4 months for the combination and monotherapy arms, respectively (HR, 1.06; 95% CI, 0.86-1.30; P = .72).
Based on the observed efficacy and safety, an external data monitoring committee recommended that the study be stopped due to futility and that patients discontinue treatment from both ipilimumab and placebo, explained lead study author Michael Boyer, MBBS, FRACP, PhD.
"This means that pembrolizumab monotherapy remains a standard of care first-line treatment for this group of patients,” said Boyer, clinical professor of medicine at the Chris O’Brien Lifehouse and the Central Clinical School of the University of Sydney, in Sydney, Australia.
In the multicenter, phase 3 KEYNOTE-598 trial (NCT03302234), which was comprised of centers in North America, Europe, and Asia, investigators sought to determine whether the addition of ipilimumab to pembrolizumab could improve efficacy versus single-agent pembrolizumab in patients with metastatic NSCLC whose PD-L1 TPS was at least 50% and did not harbor EGFR or ALK aberrations.
To be eligible for enrollment, patients had stage IV NSCLC, could not have received prior systemic therapy, no known untreated central nervous system metastases, and no more than 1 measurable lesion per RECIST v1.1 criteria.
Patients were randomized 1:1 to receive pembrolizumab at 200 mg every 3 weeks for up to 35 cycles with ipilimumab at 1 mg/kg every 6 weeks (n = 284) or saline placebo (n = 284) for up to 6 cycles.
Stratification factors included ECOG performance score (0 vs 1), region (East Asia vs not East Asia), and histology (squamous vs nonsquamous). The primary end points were PFS and OS, both of which were assessed by the stratified log-rank test in the intent-to-treat population. Key secondary end points were objective response rate (ORR) and duration of response (DOR) per RECIST v1.1 criteria by blinded independent central review and safety.
The protocol-specified first interim analysis was set to occur when approximately 255 deaths occurred and an estimated 1 year had passed since the last patient was randomized to treatment. Nonbinding futility criteria at this analysis were differences in the restricted mean survival time between the combination and pembrolizumab/placebo of less than or equal to 0.2 at the maximum observation time and less than or equal to 0.1 at 2 years of follow-up.
Additionally, 372 events occurred for PFS and 272 deaths at this time point.
The PFS and OS data in patient subgroups were consistent with the overall trial results, Boyer added. However, he noted that tumor mutational burden has not yet been studied as a subgroup.
Further data showed that the ORR was 45.4% in both arms. The median DOR was 16.1 months and 17.3 months for the ipilimumab/pembrolizumab and placebo/pembrolizumab groups, respectively.
Regarding safety, there were 76.2% of treatment-related adverse events (AEs) in the ipilimumab/pembrolizumab group compared with 68.3% for the pembrolizumab/placebo arm, the most common of which were pruritus (20.6% with pembrolizumab/ipilimumab vs 14.9% with pembrolizumab/placebo), rash (17.4% vs 10.7%, respectively), and hypothyroidism (14.2% vs 11.4%). Immune-mediated AEs occurred in 20.2% of pembrolizumab/ipilimumab-treated patients and 7.8% of pembrolizumab/placebo-treated patients.
AEs of grades 3 to 5 occurred in 35.1% and 19.6% of patients, respectively; and serious AEs were in 27.7% and 13.9% of patients, respectively. AEs led to death in 7 patients on pembrolizumab/ipilimumab versus 0 in the single-agent pembrolizumab arm.
Patients were on a median 5.6 months with ipilimumab versus 8.8 months with placebo; the median number of 3-week cycles was 10 with the combination versus 15 with the pembrolizumab/placebo arm.
1. Boyer M. Pembrolizumab plus ipilimumab vs pembrolizumab plus placebo as 1L therapy for metastatic NSCLC of PD-L1 TPS ≥50%: KEYNOTE-598. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; virtual. Abstract PS01.09
2. Boyer M, Sendur MAN, Rodríguez-Abreu D, et al. Pembrolizumab plus ipilimumab or placebo for metastatic non–small-cell lung cancer with PD-L1 tumor proportion score ≥ 50%: randomized, double-blind phase III KEYNOTE-598 study. J Clin Oncol. Published online January 29, 2021. doi:10.1200/JCO.20.03579