Combination Regimen Benefits Genitourinary Cancers

Genitourinary cancers — particularly urothelial cancer – saw activity with the combination of Cabometyx (cabozantinib) and Opdivo (nivolumab), with or without Yervoy (ipilimumab), according to a preliminary clinical study.

Almost a third of 43 patients responded to the combination therapy, including three complete responses. More than half of the patients had stable disease, as only seven 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 two or three drugs, as reported at the 2017 Genitourinary Cancers Symposium in Orlando, FL.

“Both combinations are safe and well tolerated,” Andrea Apolo, M.D., 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.”

Cabometyx primarily inhibits the VEGFR2 and MET pathways. At the 2017 ASCO meeting, Apolo and her colleagues reported that Cabometyx demonstrated activity in refractory metastatic urothelial carcinoma. In a previous study, the investigators showed that Cabometyx 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 Opdivo received FDA approval February. 2, 2017 for treatment of metastatic urothelial carcinoma. Combining checkpoint inhibitors, such as Opdivo and Yervoy, 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 Cabometyx and Opdivo, a clinical experience that identified 40 mg Cabometyx and 3 mg/kg Opdivo as the phase 2 dose, which will be evaluated in an expansion cohort of patients with urothelial and renal cell carcinoma (RCC).

An additional 18 patients received Cabometyx, Opdivo and Yervoy at three dose levels. All 48 patients were evaluable for toxicity, and 43 were evaluable for response.

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

The 43 evaluable patients (26 treated with two drugs, 17 with three drugs) had an objective response rate (ORR) of 30 percent, as three 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 four patients with urothelial cancer, two with penile cancer and one each with squamous cell carcinoma of the bladder, CRPC and sarcomatoid RCC.

The response summary showed that 10 of 26 (38 percent) patients treated with Cabometyx and Opdivo had ORRs and three out of 17 treated with Yervoy combination. Additionally, 12 patients treated with each combination had stable disease.

The most common adverse events (AEs; any grade) with Cabometyx and Opdivo 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 (four patients) and neutropenia (five patients).

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