In the phase 3 CheckMate-914 clinical trial, the combination of nivolumab and ipilimumab did not achieve its primary end point of improvement in disease-free survival compared with the placebo control.
The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) did not demonstrate improvement in disease-free survival (DFS) as adjuvant treatment of patients with localized renal cell carcinoma (RCC) who have undergone full or partial removal of the kidney and who are at moderate or high risk of relapse.1
The result, announced in a press release by Bristol Meyers, shows that the phase 3 CheckMate-914 trial (NCT03138512) failed to meet its primary end point. The safety profile of nivolumab/ipilimumab in the study was consistent with prior studies of the combination in patients with solid tumors. A full evaluation of the available part A data from CheckMate-914 trial will be conducted, and full results will be presented at a later date.
“Even with notable progress in the treatment of metastatic renal cell carcinoma, there are still limited treatment options available for patients with localized disease,” said Dana Walker, MD, MSCE, vice president, development program lead, genitourinary cancers, Bristol Myers Squibb., in the press release. “Opdivo and Opdivo-based combinations have shown survival benefits in several earlier-stage and advanced cancers, including genitourinary tumors, and we are disappointed that the final analysis of CheckMate-914 part A did not show this same benefit for the post-surgical treatment of patients with localized RCC. Nonetheless, we are dedicated to continuing research and advancing cancer care for all patients with RCC.”
CheckMate-914 is a randomized, double-blind study in which approximately 1641 patients with RCC are treated with either nivolumab monotherapy or nivolumab plus ipilimumab vs placebo. In addition to DFS, the study investigated overall survival, the incidence of adverse events, and DFS in specific treatment arms as secondary end points.2
Patients were eligible to enroll if they had a kidney tumor that had been completely resected; had pathologic tumor, node, and metastasis; and an ECOG performance score of 0 or 1. The post-nephrectomy tumor in patients must have shown RCC with a predominantly clear cell histology, including participants with sarcomatoid features. Moreover, the patients must have had no clinical or radiological evidence of macroscopic residual disease or distant metastases after nephrectomy.
The study excluded patients with active known or suspected autoimmune disease, known history of positive test for human immunodeficiency virus, or known acquired immunodeficiency syndrome. In addition, patients with severe or serious, acute, or chronic medical or psychiatric condition; laboratory abnormality, allergy or hypersensitivity to the drugs used in the study; or a condition requiring systemic treatment with corticosteroids were excluded from the study. In terms of prior treatment, patients were ineligible if they received an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways. Patients could also not have received a live/attenuated vaccine within 30 days of first treatment in the study.
Despite the CheckMate-914 trial missing its primary end point, the combination has previously shown promise in multiple RCC studies, including the CheckMate-214 trial (NCT02231749) as frontline treatment of patients with previously untreated, intermediate- and poor-risk RCC; and CheckMate-025 (NCT01668784) as second-line treatment of patients with previously treated advanced or metastatic RCC. In 2 clinical trials (CheckMate-9ER [NCT03141177] and COSMIC-313 [NCT03937219]), the combination of nivolumab and ipilimumab combined with a tyrosine kinase inhibitor also showed a positive result in patients with previously untreated advanced RCC who were treated in the first-line setting. Studies of nivolumab/ipilimumab in combination with novel agents are also ongoing in the RCC space.1
1. Bristol Myers Squibb provides update on CheckMate -914 trial evaluating Opdivo (nivolumab) plus Yervoy (ipilimumab) as adjuvant treatment of localized renal cell carcinoma. News release. Bristol Myers Squibb. July 29, 2022. Accessed July 29, 2022. https://bit.ly/3bfBAkN
2. A study comparing nivolumab, nivolumab in combination with ipilimumab and placebo in participants with localized kidney cancer who underwent surgery to remove part of a kidney (CheckMate 914). Clinicaltrials.gov. Updated July 20, 2022. Accessed July 29. 2022. https://clinicaltrials.gov/ct2/show/NCT03138512?term=CheckMate-914&draw=2&rank=1