Cabozantinib Regimens Active Across Multiple Advanced GU Malignancies

Published: Monday, Feb 20, 2017

Andrea Apolo, MD

Andrea Apolo, MD

The combination of cabozantinib and nivolumab, with or without ipilimumab, proved safe and active in advanced genitourinary cancers, particularly urothelial cancer, a preliminary clinical study showed.

Almost a third of 43 patients responded to the combination therapy, including 3 complete responses. More than half of the patients had stable disease, as only 7 patients had progressive disease as a best response.

The study population included patients with rare cancers for no standard therapy currently exists, and they also benefited from treatment with combination treatments with 2 or 3 drugs, as reported at the 2017 Genitourinary Cancers Symposium in Orlando, FL.

“Both combinations are safe and well tolerated,” Andrea Apolo, MD, head of the bladder cancer section at the Center for Cancer Research of the National Cancer Institute, and coinvestigators concluded in a poster session. “Larger cohorts of metastatic urothelial carcinoma and rare genitourinary tumors are ongoing.”

Cabozantinib primarily inhibits the VEGFR2 and MET pathways. At the 2017 ASCO meeting, Apolo and her colleagues reported that cabozantinib demonstrated activity in refractory metastatic urothelial carcinoma. In a previous study, the investigators showed that cabozantinib treatment of urothelial carcinoma led to a decrease in T-regulatory cells (T-regs) among CD4-positive T-cells, increased PD-1 expression in T-regs, and decreased CTLA-4 expression in T-regs.

The anti-PD-1 agent nivolumab received FDA approval February 2, 2017, for treatment of metastatic urothelial carcinoma. Combining checkpoint inhibitors, such as nivolumab and ipilimumab, with other active agents that enhance the immune system might improve response in urothelial and other genitourinary cancers.

“We hypothesized that cabozantinib has immunomodulatory properties that may counteract tumor-induced immunosuppression, providing a rational for combining cabozantinib with nivolumab,” the investigators stated.

To test the hypothesis, investigators enrolled patients with metastatic genitourinary cancers that had not responded to one or more prior lines of therapy. A total of 30 patients received cabozantinib and nivolumab, a clinical experience that identified 40 mg cabozantinib and 3 mg/kg nivolumab as the phase II dose, which will be evaluated in an expansion cohort of patients with urothelial and renal cell carcinoma (RCC).

An additional 18 patients received cabozantinib, nivolumab, and ipilimumab at 3 dose levels. All 48 patients were evaluable for toxicity, and 43 were evaluable for response.

The study population comprised 19 patients with urothelial carcinoma; 9 with castration-resistant prostate cancer (CRPC); 4 each with urachal adenocarcinoma, germ-cell tumor, and penile cancer; 2 each with squamous cell carcinoma of the bladder or urethra, clear-cell RCC, and sarcomatoid RCC; and 1 each with trophoblastic disease and Sertoli cell carcinoma.

The 43 evaluable patients (26 treated with 2 drugs, 17 with 3 drugs) had an objective response rate (ORR) of 30%, as 3 patients achieved complete responses and 10 achieved partial responses. More than half of the 43 patients had some degree of tumor shrinkage with the combination regimens.

Two of the complete responses occurred in patients with urothelial cancer and the third in a patient with squamous cell carcinoma of the bladder. Partial responses were observed in 4 patients with urothelial cancer, 2 with penile cancer, and 1 each with squamous cell carcinoma of the bladder, CRPC, and sarcomatoid RCC.

The response summary showed that 10 of 26 (38%) patients treated with cabozantinib and nivolumab had ORRs and 3 out of 17 treated with ipilimumab combination. Additionally, 12 patients treated with each combination had stable disease.

The most common adverse events (AEs; any grade) with cabozantinib and nivolumab were fatigue (19 patients); diarrhea (18); hypothyroidism (17); elevated liver enzyme (AST, 15); anorexia (14); hoarseness, mucositis, and hypocalcemia (12 each); and hyponatremia, hypophosphatemia, hand-foot syndrome, and thrombocytopenia (11 each). The most common grade 3/4 AEs were hypophosphatemia (4 patients) and neutropenia (5).

The most common AEs with the ipilimumab regimen were fatigue (13 patients), diarrhea (11), and anorexia (11). The most common grade 3/4 AEs were hypophosphatemia and hypertension (3 patients each); and fatigue, hyponatremia, and elevated lipase (2 each).



Apolo AB, Mortazavi A, Stein MN, et al. A phase I study of cabozantinib plus nivolumab (CaboNivo) and ipilimumab (CaboNivolpi) in patients (pts) with refractory metastatic urothelial carcinoma (mUC) and other genitourinary (GU) tumors. Poster presented at: 2017 Genitourinary Cancers Symposium; February 16-18, 2017; Orlando, FL. Abstract 293.
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