FDA grants nivolumab/cabozantinib combo priority review in kidney cancer

The FDA is reviewing data from the phase 3 CheckMate-9ER trial, which showed that the combination significantly improved progression-free and overall survival compared with sunitinib in frontline renal cell carcinoma.

The FDA has granted a priority review designation to supplemental applications for the combination regimen of nivolumab (Opdivo) plus cabozantinib (Cabometyx) as a treatment for patients with advanced renal cell carcinoma (RCC).1

The applications for the regimen—which comprise a supplemental biologics license application for the PD-1 inhibitor nivolumab and a supplemental new drug application for the multikinase inhibitor cabozantinib—are based on findings from the phase 3 CheckMate-9ER trial (NCT03141177). Study results showed that the combination reduced the risk of disease progression or death by 49% versus sunitinib (Sutent) in treatment-naïve patients with advanced RCC, with a median progression-free survival of 16.6 months versus 8.3 months, respectively (HR, 0.51; P <.0001).2

Additional findings showed that, at a median follow-up of 18.1 months, the median overall survival was not reached in either arm, and there was a 40% reduction in the risk of death with the combination (HR, 0.60; P = .0010).

The priority designation expedites the FDA’s review of these applications. Under the Prescription Drug User Fee Act, the FDA is now scheduled to make its decision on the applications by February 20, 2021.

“With their complementary mechanisms of action and evidence that Cabometyx may promote a more immune-permissive environment, we believe there is opportunity for additive or synergistic effects with this potential combination regimen,” Gisela Schwab, MD, president, product development and medical affairs and chief medical officer, Exelixis, the developer of cabozantinib, stated in a press release.

In the international, randomized, phase 3 CheckMate-9ER trial, 651 patients with advanced RCC received the combination of nivolumab and cabozantinib (n = 323) or sunitinib (n = 328) in the first-line setting. Patients must have had previously untreated advanced or metastatic disease, a clear cell component, and any International Metastatic RCC Database Consortium (IMDC) risk score.

The combination demonstrated a benefit across numerous subgroups, including age, sex, PD-L1 expression, bone metastases, IMDC risk group, and geographic region.

The objective response rate (ORR) was also doubled with nivolumab/cabozantinib in this setting compared with sunitinib, at 55.7% versus 27.1%, respectively (P <.0001). In the combination arm, the complete response (CR) rate was 8.0%, the partial response (PR) rate was 47.7%, and the stable disease (SD) rate was 32.2%. Additionally, 5.6% of patients had progressive disease (PD) and 6.5% were not evaluable or not assessed. In the sunitinib arm, the CR, PR, and SD rates were 4.6%, 22.6%, and 42.1%, respectively. Moreover, 13.7% of patients had PD and 17.1% of patients were not evaluable or not assessed.

Regarding safety, the incidence of the most common, any-grade and high-grade treatment-related adverse events (TRAEs) were similar in both arms. More than 50% of patients on the combination required dose reductions of cabozantinib due to adverse effects (AEs). TRAEs led to treatment discontinuations in 15.3% of those in the nivolumab/cabozantinib arm and in 8.8% of those on sunitinib. Specifically, 3.1% of patients discontinued both nivolumab and cabozantinib due to AEs, 5.6% discontinued only nivolumab, and 6.6% discontinued only cabozantinib.

The overall rate of serious AEs was similar between the 2 groups; however, liver toxicity was more common with cabozantinib/nivolumab. Nineteen percent of patients on the combination required corticosteroids due to immune-related AEs, 4% of whom needed corticosteroids for at least 30 days.

“We have witnessed practice-changing advancements in the treatment of renal cell carcinoma in recent years, but we recognize the importance of providing patients and physicians with additional options that can help them take control of the disease,” Mark Rutstein, vice president, development program lead, Opdivo, Bristol Myers Squibb, stated in the press release. “In the CheckMate-9ER trial, combining Opdivo and Cabometyx, 2 proven agents with strong clinical legacies in advanced renal cell carcinoma, led to superior efficacy across all end points.”

Cabozantinib was approved by the FDA in December 2017 for use in previously untreated patients with advanced RCC. The FDA approved nivolumab in November 2015 for use in patients with metastatic RCC who progressed on an angiogenesis inhibitor. Nivolumab also has an FDA-approved RCC indication in the frontline setting for use in combination with ipilimumab (Yervoy) as a treatment for intermediate- and poor-risk patients with advanced disease.


1. U.S. Food and Drug Administration Accepts for Priority Review Applications for OPDIVO® (nivolumab) in Combination with CABOMETYX® (cabozantinib) in Advanced Renal Cell Carcinoma. https://bit.ly/3jgfbBM Published October 19, 2020. Accessed October 19, 2020.

2. Choueiri TK, Powles T, Burotto M, et al. Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: first results from the randomized phase 3 CheckMate 9ER trial. Ann Oncol. 2020;31(4). Abstract 696O.

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