A triplet regimen of nivolumab, ipilimumab, and cabozantinib (NIVO+IPI+CABO), which combines dual immunotherapy with antiangiogenic therapy, shows efficacy in untreated advanced renal cell carcinoma (RCC), but adverse events are common and often lead to treatment adjustments, according to study findings reported at IKCS Europe 2022.

In an exploratory cohort of the CheckMate 9ER trial (NCT03141177), investigators randomly assigned 50 patients to receive NIVO (3 mg/kg), an anti-PD-1 antibody, plus IPI (1 mg/kg), an anti-CTLA-4 antibody, every 3 weeks for 4 cycles with once-daily CABO (40 mg), a tyrosine kinase inhibitor. The regimen was followed by NIVO (240 mg) every 2 weeks with once-daily CABO (40 mg). The study arm was later discontinued.

Median progression-free survival (PFS) was 9.9 months by blinded independent central review – the study’s primary endpoint –and 15.7 months by investigator assessment in a post hoc analysis, according to Andrea Apolo, MD, of the National Cancer Institute in Bethesda, Maryland, and colleagues. The objective response rate was 44.0% by both methods with 8.0% of patients achieving complete response. Median duration of response and median overall survival were not reached.

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NIVO, IPI, and CABO dose delays were reported in 78.0%, 38.0%, and 79.6% of patients, respectively, and CABO dose reductions in 63.3%. Most dose adjustments were due to adverse events (AEs), the investigators pointed out. Treatment-related AEs occurred in 96.0% of patients, including grade 3-4 treatment-related AEs in 80.0%. Treatment-related AEs led to discontinuation of 1 or more drugs in 26.0% of patients. A total of 8.0% of patients discontinued NIVO and/or IPI only, 6.0% discontinued CABO only, 10.0% discontinued NIVO+IPI+CABO, and 2.0% discontinued unassigned drugs.

Despite clinical activity in untreated advanced RCC, use of the triplet regimen was affected by patient characteristics and AEs, the investigators highlighted.

The ongoing phase 3 COSMIC-313 trial (NCT03937219) including approximately 840 patients is expected to provide definitive answers on the relative risks and benefits of NIVO+IPI+CABO.

Disclosure: The CheckMate 9ER trial was supported by Bristol-Myers Squibb. Please see the original references for a full list of disclosures.


Apolo A, Motzer R, Choueiri T, et al. Nivolumab plus ipilimumab plus cabozantinib for previously untreated advanced renal cell carcinoma: results from a discontinued study arm of CheckMate 9ER. Presented at: IKCS 2022 in Antwerp, Belgium; April 22-24, 2022. Abstract 1.