Approval Sought for Cabozantinib/Nivolumab for Unresectable, Advanced, or Metastatic RCC in Japan

A supplemental application was submitted to the Japanese Ministry of Health, Labour, and Welfare for Manufacturing and Marketing approval of the combination of cabozantinib plus nivolumab for the treatment of patients with unresectable, advanced, or metastatic renal cell carcinoma.

A supplemental application was submitted to the Japanese Ministry of Health, Labour, and Welfare for Manufacturing and Marketing approval of the combination of cabozantinib (Cabometyx) plus nivolumab (Opdivo) for the treatment of patients with unresectable, advanced, or metastatic renal cell carcinoma (RCC).1

The submission is based on data from the phase 3 CheckMate-9ER trial (NCT03141177), which demonstrated that the regimen led to a 49% reduction in the risk of disease progression or death, markedly improved overall survival (OS), and doubled objective response rates (ORRs) compared with sunitinib (Sutent) in the up-front treatment of patients with RCC.2

At a median follow-up of 18.1 months, the median progression-free survival (PFS) with cabozantinib/nivolumab was 16.6 months versus 8.3 months with sunitinib (HR, 0.51; P <.0001). The combination was also found to have an acceptable safety profile, with a low rate of treatment-related discontinuations in those with advanced disease.

“Following our recent announcement that the US FDA accepted and granted priority review to our supplemental new drug application for [cabozantinib] in combination with [nivolumab] for the treatment of [patients with] advanced RCC, we’re excited that our partner Takeda along with Ono have also advanced this combination regimen toward potential regulatory approval in Japan,” Gisela Schwab, MD, stated in a press release. “The results of the CheckMate-9ER trial suggest [cabozantinib] in combination with [nivolumab] may become an important new treatment option for patients with advanced kidney cancer in need of new therapies.”

A total of 651 patients with advanced RCC were enrolled to the international phase 3 CheckMate-9ER trial. Participants were randomized 1:1 to either the combination regimen (n = 323) or sunitinib (n = 328) as first-line treatment. Patients needed to be treatment naïve, have advanced or metastatic disease, a clear cell component, and any International Metastatic RCC Database Consortium (IMDC) risk score to be eligible for inclusion.

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

PFS served as the primary end point of the trial, while secondary end points comprised OS, ORR, and safety. Health-related quality of life (HRQoL) was an exploratory end point.

Results from CheckMate-9ER presented during the 2020 ESMO Virtual Congress demonstrated that the combination had efficacy across many subgroups evaluated, including age, sex, PD-L1 expression, bone metastases, IMDC risk group, and geographic region.

At the time of the presentation, the median OS had not yet been reached in either arm; this translated to a 40% reduction in the risk of death with the combination regimen (HR, 0.60; P =.0010).

Additional results showed that the combination elicited an ORR of 55.7% versus 27.1% with sunitinib (P <.0001). The complete response (CR) rate with nivolumab/cabozantinib was 8.0%, with a 47.7% partial response (PR) rate, and a 32.2% stable disease (SD) rate. Moreover, 5.6% of patients experienced progressive disease and 6.5% of participants were determined to be unevaluable or were not assessed. In the sunitinib arm, the CR, PR, and SD rates were 4.6%, 22.6%, and 42.1%, respectively. In this arm, 13.7% of patients had disease progression and 17.1% were not evaluable or not assessed.

With regard to safety, any-grade and high-grade treatment-related toxicities were similar between the 2 arms analyzed. Over half of patients on cabozantinib/nivolumab required dose reductions of cabozantinib due to toxicities. Moreover, 15.3% of patients who were given the combination regimen had treatment-related adverse effects that resulted in treatment discontinuation versus 8.8% of those who were given sunitinib. About 3% of patients discontinued both nivolumab and cabozantinib due to toxicities, 5.6% stopped nivolumab only, and 6.6% stopped cabozantinib only.

The rate of serious toxicities was also found to be similar between the 2 arms; however, liver toxicity was more commonly reported with the combination regimen. Additionally, 19% of participants on nivolumab/cabozantinib required treatment with corticosteroids due to immune-associated toxicities; of these patients, 4% needed corticosteroids for at least 30 days.

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

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

Nivolumab and cabozantinib are currently approved in separate indications in RCC. In April 2018, the FDA approved nivolumab/ipilimumab (Yervoy) for use as an up-front treatment for intermediate- and poor-risk patients with advanced RCC. In 2015, the PD-1 inhibitor received regulatory approval for use as a single agent in the treatment of patients with metastatic RCC following prior antiangiogenic therapy.

In 2017, cabozantinib received regulatory approval from the FDA for the treatment of treatment-naïve patients with advanced RCC; the agent was initially approved for use in those who had progressed on 1 prior antiangiogenic treatment.


1. Exelixis announces Takeda and Ono submit supplemental application for Cabometyx (cabozantinib) in combination with Opdivo (nivolumab) for the treatment of unresectable, advanced, or metastatic renal cell carcinoma. News release. Exelixis, Inc.October 27, 2020. Accessed October 27, 2020.

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 October 27, 2020.

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). Abstract 696O.