CheckMate-9ER Hits Efficacy Targets in Frontline Advanced RCC

The immunotherapy and tyrosine kinase inhibitor combination of nivolumab (Opdivo) and cabozantinib (Cabometyx) improved progression-free survival (PFS) and overall survival (OS), and had a superior overall response rate (ORR) to sunitinib in previously untreated advanced or metastatic renal cell carcinoma (RCC), meeting its primary end points and secondary end points of the phase III CheckMate-9ER trial, Bristol Myers Squibb announced in a press release.¹

Nivolumab plus cabozantinib also demonstrated a consistent safety profile to the known profiles of either drug alone.

“The results from the pivotal CheckMate -9ER trial clearly demonstrate the combination of cabozantinib plus nivolumab provides a clinically meaningful benefit in the key efficacy measures of progression-free survival and overall survival for previously untreated kidney cancer patients,” said Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School. “Preliminary assessment of the data shows the combination of a 40mg dose of cabozantinib plus nivolumab demonstrated a favorable safety profile. If approved, this combination may become an important new first-line option for patients with metastatic renal cell carcinoma. We look forward to presenting detailed results at an upcoming congress.”

CheckMate-9ER is an ongoing randomized, open-label study in which patients are randomized 1:1. The primary end point of the study is PFS, and the secondary end points include OS, ORR, the incidence of adverse events (AEs), and the incidence of serious AEs.

Patients are eligible to enroll in the study with histological confirmation of clear-cell RCC and advanced or metastatic disease. The study excludes patients who have had prior systemic therapy for RCC, active central nervous system brain metastases, known or suspected autoimmune disease, any condition requiring systemic treatment with corticosteroids or immunosuppressive agents, and patients who have received a live/attenuated vaccine within 30 days of first treatment.

“The positive topline results from the Phase 3 CheckMate-9ER trial evaluating Opdivo in combination with Cabometyx build on our understanding of Opdivo-based regimens, and we look forward to working with global health authorities to help bring this new combination regimen to previously untreated patients, a population that despite recent advances, remains in need of additional therapeutic options that extend survival,” said Brian Lamon, PhD, development lead, genitourinary cancers, Bristol Myers Squibb. “We would like to thank the patients who participated in this trial, as well as the investigators and site personnel for their perseverance during the conduct of this study and in delivering this important result for patients in the midst of the COVID-19 pandemic.”

Cabozantinib was granted FDA approval in 2017 as treatment of previously untreated patients with advanced RCC. The approval was based on positive results from the phase II CABOSUN trial (NCT01835158).

According to results presented at the 2019 International Kidney Cancer Symposium, cabozantinib demonstrated an improvement in PFS and ORR in patients with MET-positive disease. There were 61 MET-positive patients included overall, and the PFS was 13.8 months with cabozantinib versus 3.0 months with sunitinib. In the 69 patients with MET-negative disease, the PFS was 6.9 months with cabozantinib versus 6.1 months with sunitinib. The subgroup of patients with MET-positive disease had a higher ORR than patients with MET-negative disease. In addition, cabozantinib showed a higher ORR than sunitinib (34% vs 10%).²

“Given the growing body of data showing that Cabometyx may create a more immune-permissive tumor environment that may enhance response to immune checkpoint inhibitors, we have been eagerly awaiting the results for the combination of cabozantinib and nivolumab in previously untreated renal cell carcinoma,” said Gisela Schwab, MD, president, Product Development and Medical Affairs, and chief medical officer, Exelixis. “We’re delighted that the trial met its primary endpoint of progression-free survival as well as the secondary endpoints of overall survival and objective response rate, demonstrating consistent benefit for the combination in previously untreated renal cell carcinoma patients. We look forward to our continued collaboration with Bristol Myers Squibb as we work toward regulatory filings in the near future.”

Nivolumab has several FDA indications in RCC. The first notable indication is the FDA approval of nivolumab is approved as monotherapy for patients with metastatic RCC. Another notable indication is the recent approval of nivolumab plus ipilimumab in in frontline RCC, which was based on positive results from the phase III CheckMate-214 trial (NCT02231749).

The combination reduced the risk of death by 32% compared with sunitinib in patients with mRCC. The risk reduction was 37% in patients with intermediate- and poor-risk RCC, who constituted about 75% of the intent-to-treat population.

As previously mentioned, detailed results from the CheckMate-9ER trial of nivolumab plus cabozantinib will be presented at an upcoming medical meeting.

_References

1. _{Bristol Myers Squibb and Exelixis announce positive topline results from pivotal phase 3 checkmate -9er trial evaluating opdivo® (nivolumab) in combination with Cabometyx®(cabozantinib) in previously untreated advanced renal cell carcinoma [news release]. Princeton, New Jersey and Amaleda, California.}
2. _{George DJ, Hessel C, Halabi S, et al. Cabozantinib Versus Sunitinib for Untreated Patients with Advanced Renal Cell Carcinoma of Intermediate or Poor Risk: Subgroup Analysis of the Alliance A031203 CABOSUN trial. The Oncologist 2019; 24: 1497-1501 doi:10.1038/nm.4118.}