In a phase I trial reported in the Journal of Clinical Oncology, Andrea B. Apolo, MD, and colleagues found that the combination of cabozantinib and nivolumab, as well as the combination of cabozantinib/nivolumab plus ipilimumab, produced durable responses in patients with metastatic urothelial carcinoma and other genitourinary malignancies.

Study Details

In the trial, 54 patients—including 15 with metastatic urothelial cancer and 39 with other genitourinary malignancies—received escalating doses (eight dose levels) of cabozantinib/nivolumab (n = 24) and cabozantinib/nivolumab/ipilimumab (n = 30). 

Andrea B. Apolo, MD

Toxicity

No dose-limiting toxicities were observed. The recommended phase II doses were cabozantinib at 40 mg/d plus nivolumab at 3 mg/kg for the doublet arm, and cabozantinib at 40 mg/d, nivolumab at 3 mg/kg, and ipilimumab at 1 mg/kg for the triplet arm.

Grade 3 or 4 treatment-related events occurred in 75% of patients in the cabozantinib/nivolumab group and 87% of the cabozantinib/nivolumab/ipilimumab group, including hypertension in 21% and 10%, fatigue in 17% and 10%, and diarrhea in 4% and 7%, respectively. Treatment-related adverse events resulted in discontinuation of treatment in 17% and 23% of patients, respectively. Grade 3 or 4 immune-related adverse events included hepatitis (0% and 13%) and colitis (0% and 7%).

Responses

Median follow-up was 44.6 months. Among the total of 49 patients evaluable for tumor response, an objective response was observed in 15 (30.6%, 95% confidence interval [CI] = 18.3%–45.4%), with a complete response in 4 (8.2%). The disease control rate was 77.6%. The median duration of response was 21.0 months (95% CI = 5.4–24.1 months). An objective response was observed in 9 of 23 patients (39.1%) receiving cabozantinib/nivolumab and in 6 of 26 (23.1%) receiving cabozantinib/nivolumab/ipilimumab. Among all 54 patients, median progression-free survival was 5.1 months (95% CI = 3.5–6.9 months), and median overall survival was 12.6 months (95% CI = 6.9–18.8 months).

Among 13 evaluable patients with metastatic urothelial carcinoma, an objective response was observed in 5 (38.5%, 95% CI = 13.9%–68.4%), with a complete response in 3 (23.1%). The median duration of response was not reached at the time of analysis, with the 24-month duration of response probability being 80%.

Among all 15 patients with metastatic urothelial carcinoma, median progression-free survival was 12.8 months (95% CI = 1.8–24.1 months), and median overall survival was 25.4 months (95% CI = 5.7–41.6 months).

The investigators concluded: “Cabozantinib/nivolumab and cabozantinib/nivolumab/ipilimumab demonstrated manageable toxicities with durable responses and encouraging survival in patients with metastatic urothelial carcinoma and other genitourinary tumors. Multiple phase II and III trials are ongoing for these combinations.”

Dr. Apolo, of the Genitourinary Malignancies Branch, National Cancer Institute, is the corresponding author of the Journal of Clinical Oncology article.

Disclosure: The trial was supported by the National Cancer Institute’s Intramural Research Program, Cancer Therapy Evaluation Program of the National Institutes of Health, and the Experimental Therapeutics Clinical Trials Network. For full disclosures of the study authors, visit ascopubs.org.