Cabozantinib/Nivolumab Approaches EU Approval for Frontline Advanced RCC

The European Medicines Agency’s Committee for Medicinal Products for Human Use has adopted a positive opinion for the combination of cabozantinib plus nivolumab for use as a frontline treatment in patients with advanced renal cell carcinoma.

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for the combination of cabozantinib (Cabometyx) plus nivolumab (Opdivo) for use as a frontline treatment in patients with advanced renal cell carcinoma (RCC).1

The decision was based on data from the phase 3 CheckMate-9ER trial (NCT03141177), where the frontline regimen reduced the risk of disease progression or death by 49% and significantly improved overall survival, while doubling objective response rates (ORRs) vs sunitinib (Sutent) in this patient population.2

At a median follow-up of 18.1 months, the median progression-free survival (PFS) was 16.6 months with cabozantinib/nivolumab vs 8.3 months with sunitinib, which translated to a hazard ratio (HR) of 0.51 (95% CI, 0.41-0.64; P <.0001). 

“On the heels of the FDA approval of [cabozantinib] in combination with [nivolumab] in the United States, we are excited that this CHMP recommendation brings our partner Ipsen one step closer to making this combination regimen available as a first-line treatment option for patients with advanced kidney cancer in Europe,” Gisela Schwab, MD, president of Product Development and Medical Affairs and chief medical officer of Exelixis, stated in a press release.1

The international, phase 3 CheckMate-9ER trial enrolled a total of 651 patients who had advanced RCC. To be eligible for enrollment, patients had to have previously untreated advanced or metastatic disease and a clear cell component. Patients could have any International Metastatic RCC Database Consortium (IMDC) risk score.

Participants were randomized 1:1 to receive either frontline cabozantinib/nivolumab (n = 323) or sunitinib (n = 328). Those in the investigative arm received intravenous nivolumab at 240 mg every 2 weeks plus oral cabozantinib at a daily dose of 40 mg. Patients in the control arm were given oral sunitinib at a daily dose of 50 mg on a 4-weeks-on/2-weeks-off cycle. Participants were administered treatment until either progressive disease or intolerable toxicity.

The primary end point of the trial was PFS, and key secondary end points comprised OS, ORR, and safety. Investigators also evaluated health-related quality of life (HRQoL) as an exploratory end point for the study.

Notably, the doublet induced benefit across several subgroups analyzed in the trial, including age, sex, PD-L1 expression, bone metastases, IMDC risk group, and geographic region.

Additional results from CheckMate-9ER demonstrated that the median OS had not yet been reached in either of the treatment groups, leading to a 40% reduction in the risk of death with the combination (HR, 0.60; P = .0010).

Moreover, the ORR elicited with cabozantinib/nivolumab was 55.7% vs 27.1% with sunitinib (P <.0001). Patients in the investigative arm had a complete response (CR) rate of 8.0%, a partial response (PR) rate of 47.7%, and 32.2% of patients achieved disease stability; 5.6% of patients experienced disease progression (PD), and 6.5% were not evaluable or not assessed. Those in the control arm experienced a CR rate of 4.6%, a PR rate of 22.6%, and a stable disease rate of 42.1%. In this arm, 13.7% experienced PD and 17.1% were not evaluable or were not assessed.

The doublet was also found to improve HRQoL vs sunitinib. Specifically, HRQoL was maintained over time with the doublet vs sunitinib, which had a consistent deterioration per Functional Assessment of Cancer Therapy-Kidney Symptom Index-19 total score. The differences between arms proved to be significant at all time points assessed. Moreover, disease-related symptoms were also improved in patients who received cabozantinib/nivolumab vs those given sunitinib. 

The incidence of the most frequent any-grade and high-grade treatment-related toxicities proved to be comparable between the arms. More than half of those who received the doublet needed dose reductions of cabozantinib because of toxicity.

Approximately 15% of patient who received cabozantinib/nivolumab experienced treatment-related adverse effects (TRAEs) that resulted in discontinuations vs 8.8% of those who were given sunitinib. About 3% of patients stopped treatment with both nivolumab and cabozantinib because of toxicity, while 5.6% only discontinued nivolumab and 6.6% only discontinued cabozantinib.

Rates of serious toxicities proved to be comparable between the treatment arms, although liver toxicity was more frequently reported with the doublet vs sunitinib. Nineteen percent off patients who receive cabozantinib/nivolumab needed treatment with corticosteroids because of immune-related AEs and 4% of these patients needed corticosteroids for at least 30 days.

In January 2021, the FDA approved cabozantinib/nivolumab for use in the first-line treatment of patients with advanced RCC based on data from CheckMate-9ER.

Nivolumab and cabozantinib also have approval in separate indications in RCC. In 2015, nivolumab was approved for use as a monotherapy in patients with metastatic RCC after previous antiangiogenic therapy. In 2017, the FDA approved cabozantinib for use in treatment-naïve patients with advanced RCC; the initial approval was for use in patients who had progressed on 1 previous antiangiogenic therapy. In April 2018, the FDA gave the green light to nivolumab plus ipilimumab (Yervoy) for use as a first-line treatment in patients with intermediate- and poor-risk, advanced RCC.


  1. Exelixis’ partner Ipsen receives positive CHMP opinion for CABOMETYX (cabozantinib) in combination with OPDIVO (nivolumab) as a first-line treatment for patients with advanced renal cell carcinoma. News release. Exelixis, Inc. February 26, 2021. Accessed February 26, 2021.
  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(suppl 4):S1159. doi:10.1016/j.annonc.2020.08.2257
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