FDA Grants Priority Review to Nivolumab Plus Cabozantinib in Advanced RCC

The FDA has granted a priority review designation to a supplemental biologics license application and supplemental new drug application for nivolumab (Opdivo) plus cabozantinib (Cabometyx) for the treatment of patients with advanced renal cell carcinoma, according to Bristol Myers Squibb and Exelixis, Inc.¹

The applications are based on data from the phase 3 CheckMate-9ER trial, which showed that the combination resulted in a 49% reduction in the risk of disease progression or death, significantly improved overall survival (OS), and doubled objective response rates (ORRs) versus sunitinib (Sutent) when used as a frontline treatment in patients with RCC.²

Specifically, the median progression-free survival (PFS) was 16.6 months with nivolumab plus cabozantinib versus 8.3 months with sunitinib at a median follow-up of 18.1 months (HR, 0.51; P <.0001). The combination also demonstrated a tolerable toxicity profile, with a low rate of drug-related discontinuations in patients with advanced disease.

Under the Prescription Drug User Fee Act, the FDA must make a decision on the applications by February 20, 2021.

“We have witnessed practice-changing advancements in the treatment of RCC in recent years, but we recognize the importance of providing patients and physicians with additional options that can help them take control of the disease,” said Mark Rutstein, vice president and development program lead of Opdivo at Bristol Myers Squibb.1 “In the CheckMate-9ER, combining [nivolumab] and [cabozantinib], 2 proven agents with strong clinical legacies in advanced RCC, led to superior efficacy across all end points. We look forward to working with the FDA to bring this potential treatment option to physicians and their patients who choose an immunotherapy plus TKI regimen.”

In the international phase 3 trial, a total of 651 patients with advanced RCC were randomized to receive either nivolumab/cabozantinib (n = 323) or sunitinib (n = 328) as frontline treatment. To be eligible for participation, they had to have treatment-naïve advanced or metastatic disease, a clear cell component, and any International Metastatic RCC Database Consortium (IMDC) risk score.

Participants were randomized in a 1:1 fashion. Those in the combination arm received intravenous nivolumab at 240 mg every 2 weeks in combination with oral cabozantinib at a daily dose of 40 mg. In the control arm, patients were given oral sunitinib at a daily dose of 50 mg on a 4-weeks-on/2-weeks-off cycle. Patients received treatment until progressive disease or intolerable toxicity.

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

Results from CheckMate-9ER presented during the 2020 ESMO Virtual Congress showed that the combination proved beneficial across several subgroups analyzed, including age, sex, PD-L1 expression, bone metastases, IMDC risk group, and geographic region.

The median OS had not yet been reached in either treatment arm, translating to a 40% reduction in the risk of death with nivolumab/cabozantinib (HR, 0.60; P = .0010).

Moreover, the ORR with nivolumab/cabozantinib in this setting was 55.7% versus 27.1% with sunitinib (P <.0001). In the investigational arm, the complete response (CR) rate was 8.0%, the partial response (PR) rate was 47.7%, and the stable disease (SD) rate was 32.2%. Also, 5.6% of patients experienced disease progression, while 6.5% were not evaluable or not assessed. In the control arm, the CR, PR, and SD rates were 4.6%, 22.6%, and 42.1%, respectively. Additionally, 13.7% experienced progressive disease and 17.1% were not evaluable or not assessed.

With regard to safety, any-grade and high-grade treatment-related adverse effects (TRAEs) proved to be comparable between the 2 arms. More than half of the participants on the combination arm needed dose reductions of cabozantinib because of toxicities. Additionally, 15.3% of those who received the combination experienced TRAEs that led to treatment discontinuation; 8.8% of those who received sunitinib discontinued treatment due to TRAEs.

Moreover, 3.1% of participants discontinued both nivolumab and cabozantinib because of toxicities, 5.6% discontinued nivolumab only, and 6.6% discontinued cabozantinib only.

The rate of serious toxicities was also comparable between the 2 arms, although liver toxicity was found to be more frequently reported with the combination. Nineteen percent of participants on nivolumab/cabozantinib needed treatment with corticosteroids because of immune-associated AEs; of these patients, 4% required corticosteroids for at least 30 days.

Additionally, nivolumab/cabozantinib was found to improve HRQoL versus sunitinib. HRQoL was maintained over time with the combination compared with 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.

“With their complementary mechanisms of action and evidence that [cabozantinib] may promote a more immune-permissive environment, we believe there is opportunity for additive or synergistic effects with this potential combination regimen,” said Gisela Schwab, MD, president of product development and medical affairs and chief medical officer of Exelixis.¹ “Based on strong supporting data from CheckMate-9ER, the acceptance of our application is important progress in our efforts to make [cabozantinib] in combination with [nivolumab] available to patients with advanced kidney cancer who need additional treatment options. We look forward to working with the FDA throughout the ongoing review process.

Nivolumab and cabozantinib are currently approved in separate indications in RCC. In April 2018, the FDA gave the green light to nivolumab/ipilimumab (Yervoy) as a first-line treatment for intermediate- and poor-risk patients with advanced RCC. Prior to that, in 2015, the PD-1 inhibitor received regulatory approval for use as a monotherapy in the treatment of patients with metastatic RCC after previous antiangiogenic therapy.

In 2017, cabozantinib received approval by 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.

References

1. 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 19, 2020. https://bit.ly/3o5OvY9​
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(4). Abstract 696O.