Cabozantinib Plus Nivolumab/Ipilimumab Meets PFS End Point in Untreated Advanced RCC

Toni Choueiri, MD

The addition of cabozantinib (Cabometyx) to nivolumab (Opdivo) and ipilimumab (Yervoy) generated a significant improvement in progression-free survival (PFS) vs nivolumab/ipilimumab alone as a first-line treatment for patients with previously untreated advanced intermediate- or poor-risk renal cell carcinoma (RCC), meeting the primary end point of the phase 3 COSMIC-313 trial (NCT03937219).¹

Data from the primary analysis of the study showed that the cabozantinib-based triplet reduced the risk of disease progression or death by 27% compared with nivolumab/ipilimumab alone (HR, 0.73; 95% CI, 0.57-0.94; P = .01).

“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, stated in a 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.”

Regarding the secondary end point of overall survival (OS), cabozantinib plus nivolumab/ipilimumab did not demonstrate a significant benefit vs nivolumab/ipilimumab alone. The next analysis will continue to evaluate OS.

In April 2018, the FDA approved the combination of nivolumab and ipilimumab as a frontline treatment for intermediate- and poor-risk patients with advanced RCC.² Additionally, in January 2021, the combination of cabozantinib and nivolumab earned FDA approval for the frontline treatment of patients with advanced RCC.³

The multicenter, randomized, double-blinded COSMIC-313 trial evaluated the addition of cabozantinib to the approved nivolumab/ipilimumab regimen vs placebo plus nivolumab/ipilimumab in patients with intermediate- or poor-risk advanced or metastatic RCC.⁴ To enroll, patients were required to have histologically confirmed advanced or metastatic RCC with a clear-cell component. Intermediate- or poor-risk RCC was defined by International Metastatic Database Consortium criteria. Other eligibility criteria included measurable disease per RECIST v1.1 criteria, a Karnofsky performance status of at least 70%, and adequate organ/bone marrow function.

Key exclusion criteria included prior systemic anticancer therapy for unresectable, locally advanced, or metastatic RCC, including investigational agents; uncontrolled, significant intercurrent or recent illness; autoimmune disease that was symptomatic or required treatment within 2 years of randomization; any condition that required systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days of randomization; active infection requiring treatment; a known history of COVID-19 unless the patient had recovered at least 30 days before randomization; major surgery within 4 weeks of randomization; or any other active malignancy at randomization.

Patients were administered 40 mg of cabozantinib or matching placebo once daily, plus 3 mg/kg of nivolumab and 1 mg/kg of ipilimumab once every 3 weeks for 4 total doses. After the conclusion of 4 cycles of nivolumab/ipilimumab, patients in the experimental arm continued with 40 mg of cabozantinib once daily, plus 480 mg/kg of a flat dose infusion of nivolumab once every 4 weeks, for up to 2 years. The control arm received a cabozantinib-matched placebo plus the same nivolumab regimen for up to 2 years.

The safety of all 3 agents was consistent with the known toxicity profiles for each single agent and combination regimen. No new safety signals were detected.

Exelixis will discuss the results with the FDA to determine the next steps for a potential regulatory submission for the triplet as a frontline treatment option for patients with advanced intermediate- or poor-risk RCC.

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

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. Exelixis. July 11, 2022. Accessed July 11, 2022. https://bwnews.pr/3NSar4E
2. FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. News release. FDA. April 16, 2018. Accessed July 11, 2022. https://bit.ly/3c1TnMj
3. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. News release. FDA. January 22, 2021. Accessed July 11, 2022. http://bit.ly/2Mjrt1i
4. 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 11, 2022. https://clinicaltrials.gov/ct2/show/NCT03937219