FDA Approves Nivolumab Plus Cabozantinib for Advanced RCC


January 22, 2021 - The FDA has approved the combination of nivolumab plus cabozantinib for the frontline treatment of patients with advanced renal cell carcinoma.



The FDA has approved the combination of nivolumab (Opdivo) plus cabozantinib (Cabometyx) for the frontline treatment of patients with advanced renal cell carcinoma (RCC).1

The recommended dose is nivolumab, given at 240 mg every 2 weeks via a 30-minute intravenous (IV) infusion, or at 480 mg every 4 weeks via 30-minute IV infusion, in combination with oral cabozantinib, given at 40 mg once daily without food until either progressive disease or intolerable toxicity.

The regulatory decision was based on findings from the phase 3 CheckMate-9ER trial (NCT03141177), which demonstrated that the doublet led to a 49% reduction in the risk of disease progression or death, significantly improved overall survival (OS), and doubled objective response rates (ORRs) compared with sunitinib (Sutent) in the first-line treatment of patients with RCC.2

At a median follow-up of 18.1 months, the median progression-free survival (PFS) was 16.6 months versus 8.3 months with nivolumab/cabozantinib and sunitinib, respectively (HR, 0.51; 95% CI, 0.41-0.64; P <.0001). The doublet also showed a favorable safety profile with a low incidence of treatment-related discontinuations in patients with advanced prostate cancer.

In the international phase 3 trial, 651 patients with advanced RCC were randomized 1:1 to receive first-line nivolumab in combination with cabozantinib (n = 323) or sunitinib (n = 328). To be eligible for enrollment, patients be treatment naïve and have advanced or metastatic disease, a clear cell component, and any International Metastatic RCC Database Consortium (IMDC) risk score.

Participants in the investigational arm were given intravenous nivolumab at 240 mg every 2 weeks plus oral cabozantinib at a dose of 40 mg daily. Patients in the control arm received oral sunitinib at a dose of 50 mg daily on a 4-weeks-on/2-weeks-off treatment cycle. Treatment was administered until either disease progression or unacceptable toxicity.

The primary end point of the trial was PFS. Secondary end points comrpised OS, ORR, and safety. An exploratory end point of CheckMate-9ER was health-related quality of life (HRQoL).

Data from CheckMate-9ER presented during the 2020 ESMO Virtual Congress demonstrated that the doublet induced activity across several subgroups evaluated, spanning age, sex, PD-L1 expression, bone metastases, IMDC risk group, and geographic region.3

The median OS had not yet been reached in either treatment arm, translating to a 40% reduction in the risk of death with the investigational doublet (HR, 0.60; 95% CI, 0.40-0.89; = .0010).

Additionally, the ORR with nivolumab plus cabozantinib versus sunitinib was 55.7% versus 27.1%, respectively (<.0001). The complete response (CR) rate was 8.0% with the doublet, while 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 and 6.5% were not evaluable or not assessed. The CR, PR, and SD rates were 4.6%, 22.6%, and 42.1%, respectively, in the control arm. A higher percentage of patients experienced progressive disease, at 13.7%, and 17.1% were not evaluable or not assessed.

Regarding safety, any-grade and high-grade treatment-related adverse effects (TRAEs) were similar between the 2 arms. More than half of the participants who received the doublet required dose reductions of cabozantinib due to AEs. Moreover, 15.3% of patients who were given cabozantinib/nivolumab reported TRAEs that resulted in treatment discontinuation; 8.8% of those who were administered sunitinib discontinued treatment due to treatment-related toxicities.

Additionally, 3.1% of patients discontinued both nivolumab and cabozantinib because of toxicities, 5.6% discontinued nivolumab only, and 6.6% discontinued cabozantinib only.

The rate of serious AEs was also similar between the 2 treatment arms, although liver toxicity was found to be more commonly experienced by those who received the doublet. Nineteen percent of participants in the investigational arm required corticosteroids due to immune-associated toxicities; 4% of these patients needed corticosteroids for at least 30 days.

Nivolumab plus cabozantinib was also found to improve HRQoL compared with sunitinib. HRQoL was maintained over time with the doublet versus sunitinib, which had a consistent deterioration per Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI)-19 total score. The between-arm differences were found to be significant at almost all time points.

The combination also improved disease-related symptoms (DRS), while those who were given sunitinib experienced a decline per FKSI-Disease-DRS.

Nivolumab and cabozantinib are both approved in separate indications in RCC. In April 2018, the FDA approved the combination of nivolumab plus ipilimumab (Yervoy) as a frontline treatment for intermediate- and poor-risk patients with advanced RCC. Previously, in 2015, the PD-1 inhibitor was granted regulatory approval for use as a single agent in patients with metastatic RCC following prior antiangiogenic treatment.

In 2017, cabozantinib was granted an approval by the FDA for use in treatment-naïve patients with advanced RCC; the drug initially received approval for the treatment of patients who had progressed on 1 prior antiangiogenic therapy.

WATCH: Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology, director of the Kidney Cancer Center, and senior physician at Dana-Farber Cancer Institute, as well as the Jerome and Nancy Kohlberg chair and professor of medicine at Harvard Medical School, discusses the FDA approval of nivolumab and cabozantinib in advanced RCC.


  1. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. News release. FDA. January 22, 2021. Accessed January 22, 2021. http://bit.ly/2Mjrt1i.
  2. US Food and Drug Administration accepts for priority review applications for Opdivo (nivolumab) in combination with Cabometyx (cabozantinib) in advanced renal cell carcinoma. News release. Bristol Myers Squibb and Exelixis, Inc. October 19, 2020. Accessed December 3, 2020. https://bit.ly/3o5OvY9
  3. 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):S1159. doi:10.1016/j.annonc.2020.08.2257
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