Cabozantinib Combination Improves PFS in Patients with Untreated RCC

Results from the primary analysis of the phase 3 COSMIC-313 trial showed significant improvement in progression-free survival in patients with renal cell carcinoma receiving the combination of cabozantinib, nivolumab, and ipilimumab.

Significant improvement in progression-free survival (PFS) was demonstrated in patients with previously untreated, advanced, intermediate- or poor-risk renal cell carcinoma (RCC) receiving the combination of cabozantinib (Cabometyx), nivolumab (Opdivo), and ipilimumab (Yervoy), meeting the primary end point of the ongoing phase 3 COSMIC-313 trial(NCT03937219).1

Results from the primary analysis were announced by Exelixis Inc. and showed that while the study met primary end point of PFS, the combination did not demonstrate overall survival (OS) benefit, the study’s secondary end point.

"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," said Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and the Jerome and Nancy Kohlberg Chair and Professor of Medicine at Harvard Medical School, in the press release. "These initial findings from COSMIC-313 suggest that the triplet combination of cabozantinib, nivolumab and ipilimumab may have potential to serve as an additional option for this patient population."

This multicenter, randomized, double-blinded, phase 3 study enrolled 855 patients from 177 sites around the world. Investigators randomized patients 1:1 to receive the cabozantinib, nivolumab, and ipilimumab combination, the experimental arm, or to receive nivolumab plus ipilimumab, the control arm.

In the experimental arm, patients received 40 mg of cabozantinib daily in combination with 3 mg/kg of nivolumab once every 3 weeks for 4 total doses and with 1 mg/kg of ipilimumab once every 3 weeks for 4 total doses followed by 40 mg of daily cabozantinib plus 480 mg/kg of nivolumab once every 4 weeks for up to 2 years. The control arm received placebo plus 3 mg/kg of nivolumab once every 3 weeks for 4 total doses and 1 mg/kg of ipilimumab once every 3 weeks for 4 total doses followed by placebo plus 480 mg/kg of nivolumab once every 4 weeks for up to 2 years. The study’s primary end point is PFS, and the secondary endpoint in OS.

To be included in the study, patients must have had histologically confirmed advanced or metastatic renal cell carcinoma with a clear-cell component, not amenable to curative surgery or radiation therapy. Those with intermediate- or poor-risk RCC, measurable disease per RECIST 1.1 as determined by the Investigator, a Karnofsky performance status ≥ 70%, and adequate organ and marrow function were eligible for enrollment in the trial.2

Patients were excluded from the study if they received prior anticancer for unresectable or locally advanced RCC, had major surgery within 4 weeks prior to the study’s randomization, or had an uncontrolled, significant, recent illness or malignancy at the time of randomization.

Results showed that the primary analysis of PFS, per RECIST 1.1 as assessed by a blinded independent radiology committee, reduced the risk of disease progression or death significantly more in patients receiving the combination treatment than in patients in the control arm (HR, 0.73; 95% CI, 0.57-0.94; P = .01). No new safety signals were reported, and the safety profile reflected the known profiles for each individual agent and for the combinations as well.

The company, Exelixis, will share results with the FDA to determine a path for a possible regulatory submission for this combination in patients with previously untreated, advanced, intermediate- or poor-risk RCC. More findings will be presented at future meetings.

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

The trial will continue evaluating this experimental combination for OS in the next analysis.

References
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. Yahoo Finance; July 11, 2022. Accessed July 13, 2022. https://yhoo.it/3yF5ypY
2. Study of cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced or metastatic renal cell carcinoma (COSMIC-313). ClinicalTrials.gov. Updated March 10, 2022. Accessed July 13, 2022. https://bit.ly/3IAsg7i