The addition of ipilimumab to pembrolizumab does not significantly improve efficacy and is associated with greater toxicity compared to pembrolizumab monotherapy as first-line treatment for metastatic NSCLC with PD-L1 TPS ≥ 50% and no targetable EGFR or ALK aberration, according to data recently published in the Journal of Clinical Oncology.

According to the study from Michael Boyer, MBBS, PhD, of the Chris O’Brien Lifehouse and the University of Sydney in Sydney, Australia, and colleagues, pembrolizumab-ipilimumab should not be used in place of pembrolizumab monotherapy in this population.

“PD-L1 expression on tumor and/or immune cells helps identify patients with NSCLC who experience better outcomes with this treatment class. For patients with the highest PD-L1 expression levels, defined as a tumor proportion score (TPS) ≥ 50%, pembrolizumab monotherapy is a widely approved and accepted standard of care based on results of KEYNOTE-024, in which pembrolizumab significantly improved overall survival, progression-free survival, and objective response rate vs platinum-doublet chemotherapy,” O’Brien and colleagues wrote.  “Despite the effectiveness of pembrolizumab monotherapy in this population, which was confirmed in KEYNOTE-042, almost 50% of patients die within 2 years and more effective therapies are needed.”

The researchers conducted a randomized, double-blind, placebo-controlled phase 3 study at 171 sites in 24 countries. 

Eligibility criteria included patients ≥ 18 years with histologically and cytologically confirmed stage IV NSCLC, PD-L1 TPS ≥ 50%, no previous systematic therapy for metastatic NSCLC, an Eastern Cooperative Oncology Group performance status score of 0 or 1 and ≥ 1 lesion measurable per RECIST v1.1.

A total of 568 patients were randomized 1:1 to ipilimumab 1 mg/kg (N = 284) or placebo (N = 284) every 6 weeks for up to 18 doses. 

All patients included in the study received pembrolizumab 200 mg every 3 weeks for up to 35 doses. 

The primary endpoints were overall survival and progression free survival. 

According to the study, median overall survival was 21.4 months for pembrolizumab-ipilimumab vs 21.9 months for pembrolizumab-placebo (HR = 1.08; 95% CI, 0.85-1.37; P = .74).

Median progression-free survival was 8.2 months for pembrolizumab-ipilimumab vs 8.4 months for pembrolizumab-placebo (HR = 1.06; 95% CI, 0.86-1.30; P = .72). 

Grade 3-5 adverse events occurred in 62.4% of patients who received pembrolizumab-ipilimumab compared with 50.2% of patients in the pembrolizumab-placebo group.

The adverse events led to death in 13.1% of those who received pembrolizumab-ipilimumab and 7.5% of those in the pembrolizumab-placebo cohort. 

The study was stopped at the recommendation of the external data and safety monitoring committee due to futility.

“Immune checkpoint inhibition is an important component of first-line treatment for metastatic NSCLC in patients without actionable driver mutations. Our findings do not support the use of dual checkpoint inhibition with pembrolizumab and ipilimumab in place of pembrolizumab monotherapy in patients with metastatic NSCLC with programmed death ligand 1 tumor proportion score ≥ 50% and no actionable driver mutations.”

Disclosure: Boyer reports receiving honoraria from AstraZeneca, consulting and advisory fees from AstraZeneca, Bristol-Myers Squibb, Janssen and Merck Sharp & Dohme and travel accommodations from Merck Sharp & Dohme and Genetech/Roche. Please see the full study for a complete list of author disclosures.