The FDA has approved nivolumab (Opdivo®, Bristol Myers Squibb) in combination with cabozantinib (Cabometyx®, Exelixis) for patients with advanced renal cell carcinoma (RCC) receiving their first line of therapy.
"As monotherapies, nivolumab and cabozantinib have demonstrated efficacy and a manageable safety profile in advanced RCC," wrote Toni Choueiri, MD, Director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, and colleagues in their abstract of results from the phase 3 CheckMate 9ER trial (NCT03141177), on which the approval was based. "Cabozantinib has immunomodulatory properties that may counteract tumor-induced immunosuppression, providing a rationale for combining nivolumab and cabozantinib."
CheckMate 9ER enrolled 651 patients with previously untreated advanced RCC, including 22.6% with favorable-risk, 57.6% with intermediate-risk, and 19.7% with poor-risk disease. Patients were randomized in a 1:1 ratio to receive 240 mg nivolumab once every two weeks in combination with 40 mg cabozantinib once daily, or 50 mg sunitinib for the first four weeks of each six-week cycle. The primary end point was progression-free survival, with secondary endpoints of overall survival, objective response rate, and safety.
At a median follow-up of 18.1 months, nivolumab/cabozantinib significantly prolonged median progression-free survival compared with sunitinib (16.6 vs 8.3 months). Nivolumab/cabozantinib produced a higher overall response rate (55.7% vs 27.1%) and a higher complete response rate (8.0% vs 4.6%), as well as a significantly longer median duration of response (20.2 vs 11.5 months). Overall survival was also significantly prolonged with nivolumab/cabozantinib (hazard ratio 0.60), although the median overall survival had not yet been reached in either treatment arm at the time of data cutoff for the first interim analysis. Results were consistent across Intermediate Metastatic RCC Database Consortium (IMDC) risk groups and programmed death ligand 1 (PD-L1) expression subgroups.
Any-grade treatment-related adverse events occurred in a similar proportion of patients receiving nivolumab/cabozantinib compared with sunitinib (96.6% vs 93.1%). The most common adverse events experienced by at least 20% of patients receiving nivolumab/cabozantinib included diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysesthesia, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.
"Nivolumab/cabozantinib demonstrated superior progression-free survival, overall survival, and overall response rate versus sunitinib in first-line advanced RCC," concluded Dr. Choueiri and colleagues in their abstract, which was presented at the European Society for Medical Oncology (ESMO) Virtual Congress in September 2020. "The safety profile of this combination was manageable and consistent with the known single-agent adverse event profiles of nivolumab and cabozantinib. These results support nivolumab/cabozantinib as a new checkpoint inhibitor/tyrosine kinase inhibitor option for advanced RCC patients."
The recommended dose is nivolumab 240 mg once every two weeks or 480 mg once every four weeks, administered as a 30-minute intravenous infusion, in combination with cabozantinib 40 mg orally once daily without food, until disease progression or unacceptable toxicity.
For More Information
Choueiri TK, Powles T, Burotto M, et al (2020). Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: first results from the randomized phase III CheckMate 9ER trial. Ann Oncol (ESMO Virtual Congress Abstracts), 31(suppl_4):S1142-S1215. Abstract 6960_PR. DOI:10.1016/annonc/annonc325
Clinicaltrials.gov (2020). A study of nivolumab combined with cabozantinib compared to sunitinib in previously untreated advanced or metastatic renal cell carcinoma (CheckMate 9ER). NLM identifier: NCT03141177.
US Food & Drug Administration (2021). FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-plus-cabozantinib-advanced-renal-cell-carcinoma
Image credit: Mikael Häggström, M.D. Licensed under CC0 1.0