Dual immune checkpoint inhibition with nivolumab plus ipilimumab is a first-line standard-of-care for patients with aRCC of IMDC intermediate or poor risk1. However, approximately 20% of patients experience progressive disease as best response, representing an unmet medical need. In addition, first-line cabozantinib plus nivolumab has demonstrated clinical effectiveness in patients with aRCC2. In a phase 1 trial, triplet therapy (nivolumab/ipilimumab/cabozantinib) showed clinical activity and manageable toxicity3.
Based on this background, the phase 3 COSMIC-313 trial (NCT03937219) evaluated the efficacy and safety of first-line triple therapy (nivolumab/ipilimumab/cabozantinib) in patients with aRCC of poor or intermediate risk. Dr Toni Choueiri (Dana-Farber Cancer Institute, MA, USA) presented the first results4.
COSMIC-313 randomised 855 previously untreated aRCC patients with poor (25%) or intermediate (75%) risk to receive cabozantinib (40 mg once daily) or placebo plus 4 cycles of nivolumab (3 mg/kg every 3 weeks) and ipilimumab (1 mg/kg every 3 weeks) followed by nivolumab (480 mg every 3 weeks) up to 2 years. The primary endpoint of the study was PFS in the primary intention-to-treat population (PITT), defined as the 550 first randomised patients. Secondary endpoints were overall survival (OS) in the ITT population, objective response rate (ORR), duration of response, and safety.
Triple therapy significantly improved median PFS versus dual therapy (not reached vs 11.3 months; HR 0.73; P=0.013). PFS rates at 12 months were 57% and 49% with triple and dual therapy, respectively. Triple therapy favoured PFS in all pre-specified subgroups, except patients with IMDC poor risk (HR 1.04). ORR was 43% (3% complete response, 40% partial response) in patients treated with triple therapy versus 36% (3% complete, 33% partial) in patients treated with dual therapy. Median duration of response was not reached in both study arms. The safety profile of the triple therapy was generally manageable and consistent with the profiles of the treatment components.
“This first study to use dual immune checkpoint inhibition as the control demonstrated a significant benefit in PFS for triple therapy with cabozantinib/nivolumab/ipilimumab in previously untreated patients with IMDC intermediate risk,” concluded Dr Choueiri. Follow-up for OS in ongoing.