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Nivolumab/Cabozantinib Combo Shows Promise in GU Cancers

Virginia Powers, PhD
Published: Tuesday, Oct 18, 2016

Andrea B. Apolo, MD

Andrea B. Apolo, MD

Cabozantinib (Cabometyx) plus nivolumab (Opdivo) demonstrated promising activity in the second-line setting and beyond at all dose levels tested in patients with advanced/refractory genitourinary cancers, according to results from a phase I study reported at the 2016 ESMO Congress.1

Among 23 patients with evaluable data, the objective response rate (ORR) was 43%; 1 patient with bladder squamous cell carcinoma (SCC) showed complete response, and partial responses were observed in 9 patients. Among 6 patients with urothelial carcinoma, 4 achieved a response.

“Cabozantinib targets multiple tyrosine kinases, including VEGFR, MET, and AXL, and has also been reported to show immunomodulatory properties leading to a decrease in CD4+ T regulator cells, plus increased PD-1 expression, and decreased CTLA expression in these cells,” said principal investigator Andrea B. Apolo, MD, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute. “We recently reported that cabozantinib has durable clinical activity in heavily pretreated patients with relapsed or refractory metastatic urothelial carcinoma.2

“Cabozantinib has immunomodulary properties that may counteract tumor-induced immunosuppression, providing a rationale for combining it with the PD-1 inhibitor nivolumab,” added Apolo.

Apolo and colleagues conducted this phase I dose-escalation study to evaluate safety, and also to determine the dose-limiting toxicity and recommended phase II dose of cabozantinib plus nivolumab with or without ipilimumab.

The recommended phase II dose for the combination was determined as cabozantinib at 40 mg daily plus nivolumab at 3 mg/kg once every 2 weeks.

The study enrolled 7 patients with metastatic urothelial carcinoma, 4 with urachal bladder cancer, 3 with bladder SCC, 4 with germ cell tumor, 4 with castrate-resistant prostate cancer, 1 with renal cell carcinoma, and 1 with trophoblastic tumor. The median patient age was 55 years (range, 35-75) and 21 (88%) patients were male. Patients had received 1 to 6 (median, 3) prior treatments, with nearly half (n = 10) receiving 4 or more prior regimens. The Karnofsky Performance status was 90%, 80%, and 70% for 9, 12, and 3 patients, respectively.

“It is important to note that rare tumors, such as squamous cell carcinoma of the bladder, urachal adenocarcinoma, and penile cancer, demonstrated responses to the combination of cabozantinib and nivolumab,” Apolo said.

An additional 15 patients have been enrolled in part 2 of this study, which will evaluate the triplet of cabozantinib, nivolumab, and ipilimumab; those findings will be reported at a later date.

A rolling 6 design was used: In part 1, 6 patients received 4 dose levels (DL) of oral cabozantinib daily and nivolumab intravenously every 2 weeks for 28 days: DL1/2 comprised cabozantinib at 40 mg plus nivolumab at 1 mg/kg or 3 mg/kg, and DL3/4 comprised cabozantinib at 60 mg plus nivolumab at 1 mg/kg or 3 mg/kg. Tumors were assessed for ORR by RECIST 1.1 every 8 weeks.

“Activity was seen at all dose levels,” Apolo noted.

One patient left the study for an unrelated reason but 52% of patients remained on study at cutoff. Dose reductions were required for 9 patients. Mild-to-moderate fatigue was reported in 79% of patients, diarrhea in 71%, anorexia in 58%, and hoarseness in 42%.

Laboratory adverse events (AEs) of any grade occurring in >40% of patients included increased alanine aminotransferase in 75% of patients, hypothyroidism in 63%, increased aspartase aminotransferase in 54%, and decreased neutrophil count in 42%. Grade 3 laboratory AEs included decrease neutrophil count in 17% of patients. One grade 4 laboratory AE of increased lipase was reported.

“The cabozantinib and nivolumab combination was well tolerated with no dose-limiting toxicities. Part 2 of this phase I study is ongoing and expansion studies in patients with metastatic urothelial and renal cell carcinoma are planned,” said Apolo.


  1. Apolo AB, Mortazavi A, Stein M, et al. A phase I study of cabozantinib plus nivolumab (CaboNivo) in patients (pts) with refractory metastatic urothelial carcinoma (mUC) and other genitourinary (GU) tumors. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract 774PD.
  2. Apolo AB, Parnes HL, Francis DC, et al. A phase II study of cabozantinib in patients (pts) with relapsed or refractory metastatic urothelial carcinoma (mUC). J Clin Oncol 34, 2016 (suppl; abstr 4534).

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