Cabozantinib Plus Nivolumab Approved in Japan for Unresectable or Metastatic RCC


The Japanese Ministry of Health, Labor, and Welfare has approved the combination of cabozantinib and nivolumab for the treatment of patients with unresectable or metastatic renal cell carcinoma.

Michael M. Morrissey, PhD

Michael M. Morrissey, PhD

The Japanese Ministry of Health, Labor, and Welfare has approved the combination of cabozantinib (Cabometyx) and nivolumab (Opdivo) for the treatment of patients with unresectable or metastatic renal cell carcinoma (RCC).1

The regulatory decision was based on data from the phase 3 CheckMate-9ER trial (NCT03141177), which showed that the median progression-free survival (PFS) with the doublet was 16.6 months (95% CI, 12.5-24.9) vs 8.3 months (95% CI, 7.0-9.7) with sunitinib (Sutent; HR, 0.51; 95% CI, 0.41-0.64; P < .001).2

Cabozantinib/nivolumab also showcased a significant overall survival (OS) benefit over sunitinib. The probability of OS at 12 months with the doublet and sunitinib was 85.7% (95% CI, 81.3%-89.1%) and 75.6% (95% CI, 70.5%-80.0%), respectively (HR, 0.60; 98.89% CI, 0.40-0.89; P = .001). The median OS had not yet been reached in either arm.

“We’re excited our partner Takeda, along with Ono, will be able to bring [cabozantinib] in combination with [nivolumab] to patients with advanced kidney cancer in Japan following regulatory approvals as a first-line treatment in the United States and European Union earlier this year,” Michael M. Morrissey, PhD, president and chief executive officer at Exelixis, Inc., stated in a press release. “With approximately 25,000 new cases of kidney cancer diagnosed in Japan annually, we’re pleased that this important new treatment option will now be available to Japanese patients in need of new therapies.”

The open-label, phase 3 trial enrolled patients with previously untreated advanced RCC with a clear-cell component. Patients had to have a Karnofsky performance status score of at least 70 and measurable disease per RECIST v1.1 criteria. Patients could have any International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk score, but they could not have received prior systemic therapy for their disease.

If they had active central nervous system metastases or active autoimmune disease or received systemic treatment with either glucocorticoids or other immunosuppressive medications within 14 days prior to randomization, they were excluded.

A total of 651 participants were randomized 1:1 to receive either nivolumab at 240 mg every 2 weeks plus cabozantinib at a once-daily dose of 40 mg (n = 323) or sunitinib at a once-daily dose of 50 mg for 4 weeks of each 6-week cycle (n = 328).

The primary end point of the trial was PFS among all randomized patients. The key secondary end points of the trial were OS and objective response rate in this population and safety in those who received at least 1 dose of trial treatment.

Among those in this population, 22.4% had IMDC favorable risk prognostic features, 57.8% had intermediate risk, and 19.8% had poor risk. Moreover, 25.5% of patients had a PD-L1 tumor expression of at least 1% and 74.5% had an expression of less than 1% at the time of stratification.

Notably, patient characteristics at baseline proved to be representative of a population with previously untreated advanced RCC and were balanced in the 2 treatment arms.

According to independent review, 55.7% (95% CI, 50.1%-61.2%) of patients who received the doublet experienced an objective response vs 27.1% (95% CI, 22.4%-32.3%) of those who were given sunitinib (P < .001). Moreover, a complete response was experienced by 8.0% and 4.6% of patients in the investigative and control arms, respectively.

The median time to response was 2.8 months with the doublet vs 4.2 months with sunitinib. In the investigative and control arms, the median duration of response was 20.2 months and 11.5 months, respectively. In the doublet arm, the probability of response at 12 months was 71.1% vs 40.9% in the monotherapy arm.

Of a total of 284 patients with evaluable data in the nivolumab/cabozantinib arm, 94.7% experienced a reduction in the sum of their target-lesion diameters; in 70.4% of patients, the reduction was at least 30%. In the sunitinib arm, 84.9% experienced any reduction and 42.5% experienced a reduction of at least 30%.

The PFS, OS, and objective response rate benefits proved to be consistent across the subsets of patients analyzed, including IMDC risk status, PD-L1 expression, and irrespective of bone metastases.

The median duration of treatment in the investigative arm was 14.3 months (range, 0.2-27.3) vs 9.2 months (range, 0.8-27.6) in the control arm. The median duration of treatment with nivolumab was 13.3 months (range, 0-24.0) and 13.8 months (range, 0.2-27.3) with cabozantinib.

Regarding safety, toxicities of any cause during treatment occurred in 99.7% of patients who received the doublet and in 99.1% of those who were given sunitinib. Adverse effects of any cause that were grade 3 or higher were experienced by 75.3% and 70.6% of those on the investigative and control arms, respectively.

Treatment-related toxicities were reported in 96.6% of those in the doublet arm vs 93.1% of those in the sunitinib arm. Grade 3 or higher treatment-related adverse effects (AEs) were experienced by 60.6% of those in the investigative arm vs 50.9% of those in the control arm.

Additionally, 19.7% of those in the doublet arm experienced AEs of any cause that resulted in treatment discontinuation vs 16.9% of those in the monotherapy arm. One death on the nivolumab/cabozantinib arm was related to treatment vs 2 deaths on the sunitinib arm.


  1. Exelixis announces partner Takeda and Ono receive approval in Japan for CABOMETYX (cabozantinib) in combination with OPDIVO (nivolumab) for the treatment of unresectable or metastatic renal cell carcinoma. News release. Exelixis, Inc. August 25, 2021. Accessed August 25, 2021.
  2. Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384(9):829-841. doi:10.1056/NEJMoa2026982
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