Phase 3 data for cabozantinib triplet in kidney cancer published in NEJM

Findings from the phase 3 COSMIC-313 trial, which showed that adding cabozantinib (Cabometyx) to nivolumab (Opdivo) and ipilimumab (Yervoy) in the first-line setting significantly improved progression-free survival (PFS) in patients with intermediate- or poor-risk renal cell cancer (RCC), have been published in the New England Journal of Medicine.¹

“This is the first study to evaluate a triplet therapy against a contemporary immune-oncology doublet control and it was designed to answer an important question of whether adding cabozantinib to dual checkpoint inhibition can improve outcomes for this patient population,” said Toni Choueiri, MD.

In the study, treatment with the triplet of cabozantinib plus nivolumab/ipilimumab reduced the risk of death by 27% versus nivolumab/ipilimumab alone (HR, 0.73; 95% CI, 0.57-0.94; P = .01). At a median follow-up of between 17.7 and 20 months, the median PFS was not yet reached in the cabozantinib arm vs 11.3 months in the control arm. The objective response rates were 43% vs 36% respectively.¹

“This is the first study to evaluate a triplet therapy against a contemporary immune-oncology doublet control and it was designed to answer an important question of whether adding cabozantinib to dual checkpoint inhibition can improve outcomes for this patient population,” Toni Choueiri, MD, director of the Lank Center for Genitourinary Cancer at Dana-Farber Cancer Institute, and lead author of the COSMIC-313 study, stated in a press release.² “The initial findings provide a clear look at the efficacy and safety profile of this triplet therapy and demonstrate a significant progression-free survival benefit.”

Overall, the study randomized 855 patients to either the cabozantinib triplet (n = 428) or the control arm (n = 427). At the time of the PFS analysis, there was not a significant overall survival (OS) benefit observed with the triplet regimen; accordingly, the trial is continuing to the next OS analysis.

Regarding safety, the incidence of grade 3/4 adverse events (AEs) was higher in the experimental arm at a rate of 79% vs 56% in the control arm. Of further note, discontinuation of any study treatment due to AEs occurred in 45% of patients receiving the cabozantinib triplet compared with 24% of patients receiving nivolumab/ipilimumab alone.

Due to this safety disparity between the 2 treatment arms, Robert Motzer, MD, co-corresponding and senior author of the study, is still not sure exactly where the triplet regimen will end up in the kidney cancer treatment paradigm.

“Because of the severity of the side effects, it’s too early to determine whether this new combination will become a standard treatment. Longer follow-up is needed to see if patients will live longer following treatment with the addition of the targeted drug compared to the standard immunotherapy program. Future research will focus on determining who is most likely to benefit from the addition of cabozantinib,” Motzer, who is section head, kidney cancer, Genitourinary Oncology Service, and Jack and Dorothy Byrne Chair in Clinical Oncology, Memorial Sloan Kettering Cancer Center, stated in a press release.³

References

1. Choueiri TK, Powles T, Albiges L, et al. Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma. N Engl J Med. 2023;388(19):1767-1778. doi: 10.1056/NEJMoa2212851

2. Three-drug combination slows progression of advanced kidney cancer. Published online May 10, 2023. https://www.newswise.com/articles/three-drug-combination-slows-progression-of-advanced-kidney-cancer2

3. New Combination Drug Treatment Helps Some People With Stage 4 Kidney Cancer. Published online May 10, 2023. https://www.mskcc.org/news/new-combination-drug-treatment-helps-some-people-with-stage-4-kidney