Pembrolizumab–ipilimumab disappoints in PD-L1-high metastatic NSCLC
medwireNews: Adding ipilimumab to pembrolizumab does not boost the efficacy of the PD-1 inhibitor in untreated patients with metastatic non-small-cell lung cancer (NSCLC) and high PD-L1 expression, but leads to worse toxicity, shows the KEYNOTE-598 trial.
Therefore “pembrolizumab monotherapy remains a standard of care, first-line treatment for [NSCLC] with a tumor proportion score of at least 50% and no targetable EGFR or ALK aberrations,” said study author Michael Boyer, from the University of Sydney in New South Wales, Australia.
Speaking at the IASLC 2020 World Conference on Lung Cancer, he explained that dual checkpoint blockade with nivolumab plus the CTLA-4 inhibitor ipilimumab is a standard option for advanced melanoma and renal cell carcinoma, and the combination has demonstrated better overall survival (OS) versus doublet chemotherapy in metastatic NSCLC.
The team therefore investigated the combination of pembrolizumab and ipilimumab in 568 patients with treatment-naïve, stage IV NSCLC, randomly assigning them to receive pembrolizumab 200 mg every 3 weeks either alongside ipilimumab 1 mg/kg every 6 weeks or placebo.
After a median follow-up of 20.6 months, there was no significant difference between the combination and pembrolizumab alone groups in the co-primary endpoints of OS and progression-free survival, at medians of 21.4 versus 21.9 months and 8.2 versus 8.4 months, respectively.
“The restricted mean survival time difference at 24 months was –0.52 and at the maximum observation time was –0.56, thus the futility boundaries were crossed and the study was terminated,” reported Boyer.
He added that “adverse events were generally more common” in the combination than pembrolizumab alone arm, with grade 3–5 events occurring in 35.1% and 19.6% of participants, respectively, and serious events in 27.7% and 13.9%.
A total of 7.5% of patients who received pembrolizumab–ipilimumab discontinued both drugs due to toxicity, as did 4.3% of those given pembrolizumab plus placebo.
Discussant Yun Fan (Zhejiang Cancer Hospital, Hangzhou, China) proposed two possible explanations for the negative results of the trial, namely the choice of experimental population and the influence of adverse events with dual immunotherapy.
“CTLA-4 blockade allows for activation and proliferation of extra T-cell clones,” she explained, but noted that patients with at least 50% PD-L1 expression already have high levels of pre-activated CD8+ T cells in the tumor microenvironment, and therefore “additional CTLA-blockade may not bring clinical benefit as expected.”
Furthermore, the greater toxicity and higher discontinuation rate with combination versus single-agent immunotherapy, adversely influences the efficacy, commented Fan.
The KEYNOTE-598 results are simultaneously published in the Journal of Clinical Oncology.
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