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

Abstract

PURPOSE Pembrolizumab monotherapy is standard first-line therapy for metastatic non–small-cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1) tumor proportion score (TPS) ≥ 50% without actionable driver mutations. It is not known whether adding ipilimumab to pembrolizumab improves efficacy over pembrolizumab alone in this population. METHODS In the randomized, double-blind, phase III KEYNOTE-598 trial (ClinicalTrials.gov identifier: NCT03302234 ), eligible patients with previously untreated metastatic NSCLC with PD-L1 TPS ≥ 50% and no sensitizing EGFR or ALK aberrations were randomly allocated 1:1 to ipilimumab 1 mg/kg or placebo every 6 weeks for up to 18 doses; all participants received pembrolizumab 200 mg every 3 weeks for up to 35 doses. Primary end points were overall survival and progression-free survival. RESULTS Of the 568 participants, 284 were randomly allocated to each group. Median overall survival was 21.4 months for pembrolizumab-ipilimumab versus 21.9 months for pembrolizumab-placebo (hazard ratio, 1.08; 95% CI, 0.85 to 1.37; P = .74). Median progression-free survival was 8.2 months for pembrolizumab-ipilimumab versus 8.4 months for pembrolizumab-placebo (hazard ratio, 1.06; 95% CI, 0.86 to 1.30; P = .72). Grade 3-5 adverse events occurred in 62.4% of pembrolizumab-ipilimumab recipients versus 50.2% of pembrolizumab-placebo recipients and led to death in 13.1% versus 7.5%. The external data and safety monitoring committee recommended that the study be stopped for futility and that participants discontinue ipilimumab and placebo. CONCLUSION Adding ipilimumab to pembrolizumab does not improve efficacy and is associated with greater toxicity than pembrolizumab monotherapy as first-line treatment for metastatic NSCLC with PD-L1 TPS ≥ 50% and no targetable EGFR or ALK aberrations. These data do not support use of pembrolizumab-ipilimumab in place of pembrolizumab monotherapy in this population.

A vision of immuno-oncology: the Siena think tank of the Italian network for tumor biotherapy (NIBIT) foundation

“…Fourth, combinations of novel or current IO therapies may also improve current treatment options. Surprisingly, the combination of ipilimumab and pembrolizumab in patient with more than 50% PD-L1 expression did not result in an improvement in OS [29]. The lack of detecting a benefit may perhaps be more due to the toxicity of combining pembrolizumab and ipilimumab and thus limit the potential of delivering an improved benefit to patients.…”

“…To consider intermittent or alternating combination therapies with novel agents, it is important to first [4] Cemiplimab for > 50% PDL1 [25] Atezolizumab for > 50% PDL1 [7] Pembrolizumab +chemotherapy for < 50% PDL1 [5,6] Nivolumab/Ipilimumab + 2 cycles chemotherapy [20] Atezolizumab + tiragolumab [30] Pembrolizumab + ipilimumab (No Improvement in > 50% PD-L1 + Patients) [29] Cutaneous Melanoma…”

Stay on Target: Reengaging Cancer Vaccines in Combination Immunotherapy

“…A recent phase III clinical trial of pembrolizumab plus ipilimumab in metastatic NSCLC (NCT03302234) found that patients receiving the combination had an OS of 21.4 months while those receiving pembrolizumab alone had an OS of 21.9 months. Furthermore, patients receiving pembrolizumab plus ipilimumab reported greater toxicity, leading to death in 13.1% of patients versus 7.5% of patients in the monotherapy arm [ 22 ]. These findings clarify that, even in combination, the efficacy of immune checkpoint blockade therapy is not universal.…”

Two Complementarity Immunotherapeutics in Non-Small-Cell Lung Cancer Patients—Mechanism of Action and Future Concepts

“…Moreover, this therapy was associated with greater toxicity than pembrolizumab monotherapy. However, in patients with high PD-L1 expression on tumor cells, immunotherapy alone appears to be a better therapeutic option [ 25 ].…”