Frontline Nivolumab/Cabozantinib Approved in Europe for Advanced RCC

The European Commission has approved the combination of nivolumab and cabozantinib as a frontline treatment in patients with advanced renal cell carcinoma.

The European Commission has approved the combination of nivolumab (Opdivo) and cabozantinib (Cabometyx) as a frontline treatment in patients with advanced renal cell carcinoma (RCC).1

The regulatory decision was based on data from the phase 3 CheckMate-9ER trial (NCT03141177), where the doublet showcased superior efficacy over sunitinib (Sutent) in terms of progression-free survival (PFS), overall survival (OS), and objective response rate (ORR).

Nivolumab/cabozantinib resulted in a 49% reduction in the risk of disease progression or death. At a median follow-up of 18.1 months, the median PFS was 16.6 months vs 8.3 months with the doublet vs single-agent sunitinib, respectively (HR, 0.51; 95% CI, 0.41-0.64; P <.0001).2

Although the median OS had not yet been reached in either of the arms, but a 40% reduction in the risk of death was observed with the combination (HR, 0.60; P = .0010). Moreover, the doublet elicited an ORR of 55.7% vs 27.1% with sunitinib (P <.0001).

“With this approval, we can now offer patients 2 different [nivolumab]-based combinations that have demonstrated significant survival benefits vs sunitinib,” Dana Walker, MD, MSCE, vice president and development program lead, genitourinary cancers, at Bristol Myers Squibb, stated in a press release. “Today’s milestone builds on our heritage of developing and delivering novel treatments for patients with advanced RCC, first with the only dual immunotherapy option, [nivolumab] plus ipilimumab [Yervoy], and now with a new immunotherapy and TKI inhibitor regimen.”

In the phase 3 trial, investigators enrolled 651 patients with advanced RCC. To be eligible for inclusion, patients needed to have previously untreated advanced or metastatic disease with a clear cell component. Notably, patients could have any International Metastatic RCC Database Consortium (IMDC) risk score.

Study patients were randomized in a 1:1 fashion to either frontline nivolumab/cabozantinib (n = 323) or sunitinib monotherapy (n = 328). Intravenous nivolumab was delivered at a dose of 240 mg every 2 weeks, while oral cabozantinib was given at 40 mg daily. Oral sunitinib was administered at 50 mg daily on a 4-weeks-on/2-weeks-off cycle. Patients continued to receive treatment until they had progressive disease or experienced unacceptable toxicity.

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

Additional results from the trial showed that of the patients who responded to nivolumab/cabozantinib, 8.0% achieved a complete response (CR), 47.7% had a partial response (PR), and 32.2% experienced stable disease. Additionally, 5.6% of patients had progressive disease (PD) and 6.5% were determined unevaluable or were not assessed. Of those who received sunitinib, the CR rate was 4.6%, the PR rate was 22.6%, and the stable disease rate was 42.1%; 13.7% of patients had PD and 17.1% were either not evaluable or not assessed.

Moreover, HRQoL was noted to be improved in the group of patients who received the doublet vs those who received the monotherapy. HRQoL was maintained over time with nivolumab/cabozantinib vs sunitinib, which had a consistent deterioration per Functional Assessment of Cancer Therapy-Kidney Symptom Index-19 total score. The differences between arms were significant at all time points evaluated. Disease-related symptoms were also noted to be improved in those within the investigative arm vs those in the control arm.

Regarding safety, any-grade and high-grade treatment-related adverse effects (TRAEs) were comparable between the treatment arms. More than half of the patients in the investigative arm required dose reductions of cabozantinib due to toxicity. Moreover, about 15% of those given the doublet had a TRAE that led to discontinuation vs 8.8% of those who received single-agent sunitinib. About 3% of patients stopped treatment with both nivolumab and cabozantinib due to AEs, 5.6% just discontinued nivolumab, and 6.6% just discontinued cabozantinib.

Serious AEs were comparable between the 2 arms. However, liver toxicities were noted to be more common with nivolumab/cabozantinib vs sunitinib alone. Nineteen percent of patients who received the doublet required corticosteroids due to immune-related toxicities and 4% needed these agents for at least 30 days.

“The combination of cabozantinib and nivolumab was a natural extension of our work together with TKI/immunotherapy [combinations,” Robert J. Motzer, MD, Kidney Cancer section head in the genitourinary oncology service and Jack and Dorothy Byrne chair in Clinical Oncology at Memorial Sloan Kettering Cancer Center, told OncLive in a recent interview on CheckMate-9ER. “The next step, which Toni K. Choueiri, MD, has led, is the COSMIC-313 trial [NCT03937219], which compares the triplet of cabozantinib plus nivolumab and ipilimumab with nivolumab/ipilimumab plus placebo.”

In January 2021, the FDA approved nivolumab plus cabozantinib for the frontline treatment of patients with advanced RCC based on CheckMate-9ER data. Both agents also have approvals in separate indications within RCC. In 2015, the immunotherapy was given the green light by the FDA for use as a single agent in patients with metastatic RCC following prior antiangiogenic therapy.

Two years later, in 2017, the FDA approved cabozantinib for treatment-naïve patients with advanced RCC and the initial approval was for use in patients who experienced disease progression on 1 prior antiangiogenic therapy. A year later, in April 2018, the FDA approved nivolumab plus ipilimumab for the frontline treatment of patients with intermediate- and poor-risk, advanced RCC.


  1. Bristol Myers Squibb receives European Commission approval for Opdivo (nivolumab) in combination with Cabometyx (cabozantinib) as first-line treatment for patients with advanced renal cell carcinoma. News release. Bristol Myers Squibb. April 14, 2021. Accessed April 14, 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