KEYNOTE-598 Rules Out Pembrolizumab–Ipilimumab For PD–L1-Positive Metastatic NSCLC

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: KEYNOTE-598 study findings do not support the use of ipilimumab in combination with pembrolizumab for the first-line treatment of metastatic non-small-lung cancer (NSCLC) with a PD-L1 tumour proportion score (TPS) of at least 50% and no sensitising EGFR or ALK mutations. 

The phase III trial results were presented at the IASLC 2020 World Conference on Lung Cancer Singapore Worldwide Virtual Event by Michael Boyer, from the Chris O’Brien Lifehouse and University of Sydney in New South Wales, Australia, and simultaneously published in the Journal of Clinical Oncology. 

The co-primary endpoint of median overall survival (OS) was 21.4 months for the 284 patients who were randomly assigned to receive pembrolizumab 200 mg every 3 weeks for up to 35 doses plus ipilimumab 1 mg/kg every 6 weeks. 

This did not significantly differ from the median 21.9 months OS achieved by the 284 patients who instead received pembrolizumab plus placebo, the researchers report. 

The second co-primary endpoint of median progression-free survival was also comparable with pembrolizumab plus ipilimumab versus pembrolizumab plus placebo, at 8.2 and 8.4 months, respectively. 

“There was no subgroup for which pembrolizumab-ipilimumab improved efficacy versus pembrolizumab-placebo as the 95% CIs for all subgroups, including age, sex, and tumor histologic features, overlapped the 95% CI of the overall population”, the team emphasizes. 

Furthermore, pembrolizumab plus ipilimumab was associated with a higher rate of grade 3–5 adverse events (AEs), affecting 62.4% of patients versus 50.2% of those given pembrolizumab plus placebo, as well as a higher rate of grade 3–5 immune-mediated AEs, at 20.2% versus 7.8%. 

In particular, patients given pembrolizumab plus ipilimumab were more likely to develop grade 3 or more severe diarrhoea, rash and colitis than those given pembrolizumab plus placebo. 

Treatment discontinuation because of AEs in the pembrolizumab plus ipilimumab arm was required for both agents in 30.9% of patients and for ipilimumab only in 6.4%, whereas in the control arm discontinuation of pembrolizumab and placebo and of placebo only occurred in 17.1% and 3.2%, respectively.  

Immune-mediated AEs resulted in discontinuation of all treatment in 12.1% of those given pembrolizumab plus ipilimumab and 4.3% of those given pembrolizumab plus placebo, with discontinuation of ipilimumab or placebo only in 1.8% and 1.1%, respectively. 

Moreover, there was a higher rate of death with pembrolizumab plus ipilimumab, at 13.1% versus 7.5% for controls, with these events considered treatment-related in 2.5% and 0.0% of cases, respectively. 

“The external data and safety monitoring committee recommended that the study be stopped for futility and that participants discontinue ipilimumab and placebo”, say the authors who conclude that their findings “do not support the use of pembrolizumab–ipilimumab in place of pembrolizumab monotherapy in this population.” 

The investigators say their findings are “consistent” with both the KEYNOTE-024 and KEYNOTE-042 trials of patients with a TPS of at least 50%, as well as the nivolumab plus ipilimumab arm of the CheckMate 227 trial and other trials of cemiplimab and atezolizumab, all of which were performed in a similar patient population. 

“Although cross-trial comparisons should be undertaken with caution, these findings suggest that the lack of benefit for pembrolizumab-ipilimumab cannot be explained by overperformance of the pembrolizumab-placebo group or underperformance of the pembrolizumab-ipilimumab group”, Michael Boyer and co-authors conclude. 

“It is plausible that despite having different targets and mechanisms of action, combined CTLA-4 and PD-1 inhibition may not provide benefit beyond PD-1 inhibition alone in this NSCLC population most likely to benefit from immunotherapy.” 

References  

Boyer M, Şendur 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; Advance online publication 29 January 2021. DOI: 10.1200/JCO.20.03579  

PS02.09 - Boyer M, et al. Pembrolizumab Plus Ipilimumab vs Pembrolizumab Plus Placebo as 1L Therapy for Metastatic NSCLC of PD-L1 TPS ≥50%: KEYNOTE-598. IASLC 2020 World Conference on Lung Cancer (January 28-31, 2020).