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Adding a CTLA-4 checkpoint inhibitor to pembrolizumab (Keytruda) failed to improve survival in previously untreated patients with metastatic non-small cell lung cancer (NSCLC) and high PD-L1 expression levels, a phase III trial found.

In KEYNOTE 598, the PD-1 checkpoint inhibitor pembrolizumab plus ipilimumab (Yervoy) yielded a median overall survival (OS) of 21.4 months in patients with a tumor proportion score (TPS) of 50% or greater, as compared to 21.9 months with pembrolizumab plus placebo (HR 1.08, 95% CI 0.85-1.37, P=0.74), reported Michael Boyer, MBBS, PhD, of the University of Sydney.

Median progression-free survival was also no different, at 8.2 months with ipilimumab versus 8.4 months with placebo (HR 1.06, 95% CI 0.86-1.30, P=0.72), according to findings presented at the virtual World Conference on Lung Cancer (WCLC) and published simultaneously in the .

"The addition of ipilimumab to pembrolizumab did not improve efficacy, and it did increase toxicity for first-line therapy for non-small cell lung cancer with high PD-L1 and no targetable mutations," said Boyer. "This means that pembrolizumab monotherapy remains the standard-of-care first-line treatment for this group of patients."

While the combination strategy failed in patients with high PD-L1 expression, dual checkpoint inhibition with anti-PD-1 nivolumab (Opdivo) plus ipilimumab is already approved as a first-line treatment option in NSCLC, in combination with a limited course of therapy regardless of PD-L1 status (based on CheckMate 9LA), or as a chemo-free regimen for PD-L1-positive (≥1%) patients (based on CheckMate 227). Both trials showed improved survival compared with standard chemotherapy options.

WCLC discussant Fan Yun, MD, of the Zhejiang Cancer Hospital in Hangzhou, China, suggested that NSCLC patients with low PD-L1 expression and those with high tumor mutational burden (TMB) may in fact derive the most benefit from dual checkpoint inhibition.

She said the negative results of KEYNOTE 598 may be explained by the influence of increased toxicity with the combination, which led to higher rates of treatment discontinuation, as well as the patient population selected.

"CTLA-4 blockade allows for activation and proliferation of extra T-cell clones," said Yun. However, high PD-L1 expressors (≥50%) present "with higher levels of pre-activated CD8-positive T cells in the microenvironment. Hence, additional CTLA-4 blockade may not bring clinical benefits as expected."

Ongoing combination trials involving anti-PD-1/L1 plus other drugs -- including tiragolumab or lenvatinib (Lenvima) -- will help clarify the role of additional treatment in this population, Yun said.

KEYNOTE 598 was a phase III trial that randomized 568 metastatic NSCLC patients without EGFR or ALK mutations to continuous pembrolizumab (200 mg every 3 weeks) plus either ipilimumab (1 mg/kg every 6 weeks for up to 18 doses) or placebo. All patients had a TPS score ≥50%.

Both groups had an overall response rate of 45.4%, including complete responses in 4.6% of patients in the combination arm and 2.8% of those on single-agent pembrolizumab. Median durations of response were 16.1 and 17.3 months, respectively.

The 1-year OS rate was 63.6% for the pembrolizumab-ipilimumab group and 67.9% for the group receiving pembrolizumab-placebo. At an interim analysis, an external data safety and monitoring board recommended the study be discontinued for futility.

Across the board, the addition of ipilimumab led to increased rates of treatment-related adverse event (AEs) versus placebo:

• Any-grade AEs: 76.2% vs 68.3% (immune-related: 44.7% vs 32.4%)
• Grade ≥3 AEs: 35.1% vs 19.6% (immune-related: 20.2% vs 7.8%)
• Serious AEs: 27.7% vs 13.9% (immune-related: 19.1% vs 7.1%)
• Deaths: 2.5% vs 0 (immune-related: 2.1% vs 0)

Common AEs with ipilimumab or placebo included pruritis (20.6% vs 14.9%), rash (17.4% vs 10.7%), and hypothyroidism (14.2% vs 11.4%).

Combination treatment led to higher rates of treatment discontinuation -- 30.9% for both drugs and ipilimumab alone in 6.4%. In the placebo group, 17.1% of patients discontinued pembrolizumab while 3.2% discontinued placebo. Treatment delays occurred in 40.1% of patients in the ipilimumab arm and 26.3% of those in placebo arm.