Cabozantinib Combination Yields Improvement in PFS for Advanced RCC


The primary end point of progression-free survival was met in the phase 3 COSMIC-313 trial which investigated cabozantinib, nivolumab, and ipilimumab in previously untreated, advanced intermediate- or poor-risk renal cell carcinoma.

The combination of cabozantinib (Cabometyx), nivolumab (Opdivo), and ipilimumab (Yervoy) demonstrated significant improvement in progression-free survival (PFS) for patients with previously untreated, advanced intermediate- or poor-risk renal cell carcinoma (RCC), according to results from the phase 3 COSMIC-313 trial (NCT03937219).1,2

This significant improvement in PFS met the trial’s primary end point. At the interim analysis, investigators reported that the cabozantinib arm compared with nivolumab plus ipilimumab did not experience a significant improvement in overall survival (OS), the study’s secondary end point. Due to this, the trial is set to continue to the next OS analysis.

“As the treatment landscape continues to evolve, resulting in more options for advanced kidney cancer, there is still a need for additional effective first-line treatment options for patients with intermediate- or poor-risk disease,” Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and the Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School, said in the press release. “These initial findings from COSMIC-313 suggest that the triplet combination of cabozantinib, nivolumab, and ipilimumab may have the potential to serve as an additional option for this patient population.”

The triple-blind trial enrolled 855 patients who were randomized 1:1, and. In the combination arm, patients received 40 mg of cabozantinib daily, nivolumab at 3 mg/kg once every 3 weeks for 4 doses, and ipilimumab at 1 mg/kg every 3 weeks for 4 doses, which was followed by 40 mg of cabozantinib once daily and a 480 mg/kg flat dose of nivolumab once every 4 weeks for up to 2 years. In the control arm, patients received matched placebo plus nivolumab and ipilimumab in the same dosing regimen as the combination arm.

Eligibility criteria for this trial included having histologically confirmed advanced or metastatic RCC with a clear cell component and intermediate- or poor-risk RCC, measurable disease via RECIST 1.1 criteria and determined by the investigator, Karnofsky Performance Status of 70% or more, and adequate organ and marrow function.

Exclusion criteria included having prior systemic anti-cancer therapy; uncontrolled, significant intercurrent, or recent illness; major surgery; or an active malignancy at the time of randomization or diagnosis of another malignancy within 3 years that requires active treatment.

The combination was found to significantly reduce the risk of disease progression or death vs the control arm (HR, 0.73; 95% CI, 0.57-0.94; P = .01). The safety profile remained similar to what has previously been observed with each agent.

Moving forward, investigators have plans for a potential regulatory submission, with additional research being presented at a future medical meeting.

“COSMIC-313 is the first trial to show that a tyrosine kinase inhibitor added to dual checkpoint inhibition can improve [PFS] in patients with advanced kidney cancer,” Vicki L. Goodman, MD, executive vice president of Product Development and Medical Affairs and chief medical officer at Exelixis, concluded. “With these findings in hand, we look forward to discussing the results with the FDA and presenting the data at a future medical meeting.”


  1. Exelixis announces cabozantinib in combination with nivolumab and ipilimumab significantly improved progression-free survival in phase 3 COSMIC-313 pivotal trial in patients with previously untreated advanced kidney cancer. News Release. Exelixis. July 11, 2022. Accessed July 12, 2022.
  2. Choueiri TK, Albiges L, Powles T, Scheffold C, Wang F, Motzer R. A phase III study (COSMIC-313) of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in patients (pts) with previously untreated advanced renal cell carcinoma (aRCC) of intermediate or poor risk. J Clin Oncol. 2020;38(suppl 6). doi:10.1200/JCO.2020.38.6_suppl.TPS767

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