Cabozantinib in Combination With Nivolumab and Ipilimumab Met Primary End Point in the Phase 3 COSMIC-313 Trial

Cabozantinib (Cabometyx; Exelixis), used in a triple regimen with nivolumab (Opdivo; Bristol Myers Squibb) and ipilimumab (Yervoy; Bristol Myers Squibb), met its primary end point of progression-free survival (PFS) in patients with previously untreated intermediate or poor-risk (based on International Metastatic Renal Cell Carcinoma Database Consortium [IMDC] criteria) advanced renal cell carcinoma (aRCC). The final results of the phase 3 COSMIC-313 trial (NCT03937219) were presented at the 2025 ASCO Genitourinary Cancers Symposium.¹

Depction of renal cancer | Image Credit: © Ahmet Aglamaz - stock.adobe.com

RCC is the most common kidney cancer, and although it is typically diagnosed in early stages, approximately one-third of diagnoses happen at advanced stages. By these late stages, prognoses are poor, with a 5-year survival rate of 10%, despite treatment advancements in the field. Regimens utilizing multiple therapies, known as double-, triple-, and even quadruple-therapies, have greatly improved outcomes, as seen in the phase 3 COSMIC-313 trial.²

Cabozantinib is a tyrosine kinase inhibitor that received FDA approval in 2017 as a monotherapy for the treatment of patients with aRCC. This was followed by an additional approval for its use in combination with nivolumab. Emerging data suggest the clinical benefit of combining cabozantinib with nivolumab plus ipilimumab, showing significant improvements in PFS.^2,3

COSMIC-313 is a multicenter, randomized, double-blinded, controlled phase 3 trial evaluating cabozantinib in combination with nivolumab and ipilimumab (C+N+I) vs nivolumab and ipilimumab in combination with matched placebo (P+N+I). A total of 855 patients were randomized 1:1 to receive either a placebo or cabozantinib at 40 mg once daily; nivolumab at 3 mg per kg intravenously every 3 weeks; and ipilimumab at 1 mg per kg intravenously every 3 weeks for 4 cycles. This was followed by 480 mg of nivolumab given intravenously every 4 weeks for a maximum of 2 years. The primary end point was PFS by blinded independent central review per RECIST 1.1 in the first 550 randomized patients. The secondary end point was overall survival (OS) in all randomized patients. Of the participants, 75% had an intermediate IMDC risk and 25% had a poor IMDC risk.³

Patients receiving C+N+I (n=428) maintained improved PFS at the median follow-up of 45 months compared with P+N+I (n=427). Neither the ITT population nor the IMDC risk group showed a significant difference in OS between C+N+I and P+N+I. As the best response, C+N+I had a greater overall response rate and a lower incidence of PD.³

“The addition of cabozantinib on top of nivolumab plus ipilimumab seems to overcome an M2-like macrophage-mediated immune suppression,” said Laurence Albiges, MD, PhD, of the Institut Gustave Roussy, Université Paris Saclay.³

Treatment-emergent adverse events (TEAEs) of grade 3 and 4 occurred in 81% (C+N+I) vs 62% (P+N+I) of patients. The most common grade 3 and 4 TEAEs were raised ALT (27% vs. 6%) and high AST (20% vs. 5%). In each group, 1% of patients had a grade 5 treatment-related adverse event (TRAE). OS results did not differ significantly based on baseline c-Met or PD-L1 levels.³

These findings from the COSMIC-313 trial reinforce the potential of triplet therapy with cabozantinib, nivolumab, and ipilimumab in extending PFS for patients with advanced RCC, particularly those at intermediate or poor risk. While OS benefits remain inconclusive, the improved response rates and disease control highlight the evolving role of combination therapies in the treatment landscape. Future research will be crucial in refining patient selection and optimizing treatment strategies to balance efficacy and safety.

REFERENCES

1. Study of cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced or metastatic renal cell carcinoma (COSMIC-313). Updated February 11, 2025. Accessed February 17, 2025. https://clinicaltrials.gov/study/NCT03937219

2. Cabozantinib extends survival in RCC patients with untreated brain metastases. Pharmacy Times. February 15, 2025. Accessed February 17, 2025. https://www.pharmacytimes.com/view/cabozantinib-extends-survival-in-rcc-patients-with-untreated-brain-metastases

3. Albiges L, Motzer R, Trevino S, et al. Cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in previously untreated advanced renal cell carcinoma (aRCC): Final results of COSMIC-313. 2025 ASCO Genitourinary Cancers Symposium. February 13, 2025, to February 15, 2025. San Francisco, CA. Abstract 438.