Triple therapy improves progression-free survival in patients with advanced RCC versus dual therapy

The first results of the phase 3 COSMIC-313 trial demonstrated that triple therapy (nivolumab plus ipilimumab plus cabozantinib) improved progression-free survival (PFS) versus dual checkpoint inhibition (nivolumab plus ipilimumab) in patients with previously untreated advanced renal cell carcinoma (RCC).

Dual immune checkpoint inhibition with nivolumab plus ipilimumab is the first-line standard-of-care for patients with advanced RCC of IMDC intermediate or poor risk [1]. However, approximately 20% of patients deteriorate to progressive disease as the best response, representing an unmet medical need. Additionally, first-line cabozantinib plus nivolumab has demonstrated clinical effectiveness in patients with advanced RCC [2]. In a phase 1 trial, triplet therapy (nivolumab plus ipilimumab plus cabozantinib) showed clinical activity and manageable toxicity [3]. Based on this background, the COSMIC-313 (NCT03937219) evaluated the efficacy and safety of first-line triple therapy (nivolumab plus ipilimumab plus cabozantinib) in patients with advanced RCC of poor or intermediate IMDC risk. Prof Toni Choueiri (Dana-Farber Cancer Institute, MA, USA) presented the first results [4].

The COSMIC-313 trial randomised 855 previously untreated advanced RCC patients with poor (25%) or intermediate IMDC (75%) risk to receive cabozantinib (40 mg once daily) or placebo plus standard-of-care 4 cycles of nivolumab (3 mg/kg every 4 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 550 first randomised patients. Secondary endpoints were overall survival (OS) in the total intention-to-treat (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, see Figure). PFS rates at 12 months were 57% and 49% for triple and dual therapy, respectively. Triple therapy favoured PFS in all pre-specified subgroups, except participants with IMDC poor risk (HR 1.04). ORR was 43% (3% complete response, 40% partial response) in participants treated with triple therapy versus 36% (3% complete, 33% partial) in participants treated with dual therapy. The median duration of response was not reached in either study arm. 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 consisting of nivolumab plus ipilimumab plus cabozantinib in previously untreated patients with IMDC intermediate risk,” concluded Prof. Toni Choueiri. Follow-up for assessing the OS is ongoing.

1. Motzer RJ, et al. New Engl J Med. 2018;378(14):1277–1290.
2. Choueiri TK, et al. N Eng J Med. 2021;384(9):829–841.
3. Apolo AB, et al. J Clin Oncol. 2020;38(31):3672–3684.
4. Choueiri TK, et al. Phase III study of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in previously untreated advanced renal cell carcinoma (aRCC) of IMDC intermediate or poor risk (COSMIC-313). Abstract LBA8, ESMO Congress 2022, 09–13 September, Paris, France.

Figure: Progression-free survival analysis of the total ITT population [4].



Cabo, cabozantinib. Nivo, nivolumab. Ipi, ipilimumab. NR, not reached. NE, not estimatable.

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Posted on 17 November 20226 September 2023