Cabozantinib, Nivolumab Active in Metastatic Urothelial Carcinoma

Cabozantinib and nivolumab with or without ipilimumab show activity in genitourinary tumors, particularly urothelial carcinoma, and have manageable safety profiles.

Cabozantinib (Cabometyx) and nivolumab (Opdivo) with or without ipilimumab (Yervoy) show activity in genitourinary (GU) tumors, particularly urothelial carcinoma, and have manageable safety profiles. The objective response rate (ORR) for all GU tumor types was 33% in 42 patients treated in a phase I trial.1 Final results from the trial were reported by Rosa Nadal, MD, a medical oncologist at the Center for Cancer Research, National Cancer Institute, Bethesda, MD at the 2017 ESMO Congress in Madrid, Spain.

Cabozantinib has shown clinical activity in pretreated patients with refractory metastatic urothelial carcinoma (mUC). In the phase II CheckMate-275 trial, nivolumab demonstrated clinical activity in patients with mUC whose disease has progressed despite prior platinum-containing chemotherapy.2 The combination of nivolumab and ipilimumab also showed manageable toxicity and clinical activity in the phase I/II CheckMate-032 study.3

Cabozantinib has immunomodulatory properties that may counteract tumor-induced immunosuppression, providing the rationale for combining cabozantinib with immunotherapy, explained Nadal. Cabozantinib has been shown to reduce the percentage of regulatory T cells in CD4-positive T cells, and downregulate the T-reg population by acting on T-cell polarization. In patients with mUC, those with a lower percentage of T-reg in CD4-positive T cells at baseline had a better response than those who had a higher percentage at baseline.

The objective of the study presented here was to determine the dose-limiting toxicity (DLT) and a recommended phase II dose for combination cabozantinib and nivolumab and combination cabozantinib, nivolumab, and ipilimumab. Secondary endpoints included ORR, progression-free survival (PFS), and overall survival (OS).

The study included 42 patients with a metastatic GU malignancy who had disease progression on at least 1 standard therapy (or for whom no standard therapy has been shown to prolong survival): 15 with urothelial carcinoma of the bladder and 27 with non-urothelial carcinoma GU malignancies. Two-thirds of patients had ≥2 prior systemic regimens. Fifty-five percent of patients had visceral disease (liver and/or lung metastases).

Seven dose levels of cabozantinib and nivolumab were tested in part 1, and 3 dose levels of the cabozantinib, nivolumab, and ipilimumab combination were tested in part 2.

The ORR in the overall study population was 33%. “Please note that this is a very heterogeneous group of patients with many rare tumor types included,” Nadal said. With a median potential follow-up of 16.8 months, the median duration of response was not reached in patients receiving either regimen. Responses were ongoing at the time of database lock in 6 of 9 responders to cabozantinib and nivolumab, and 3 of 4 responders to cabozantinib, nivolumab, and ipilimumab. Median time to response appears to be about 2 months, said Nadal.

“We were delighted to see responses in rare tumors such as squamous cell carcinoma, sarcomatoid renal cell carcinoma, and penile cancer,” she said. “One patient with castration-resistant prostate cancer and 1 patient with urachal adenocarcinoma achieved partial responses.” The ORRs were 38% with cabozantinib and nivolumab and 22% with cabozantinib, nivolumab, and ipilimumab. Median PFS was 5.9 months, with a probability of PFS at 6 months of 50.0% and a probability at 12 months of 35.7%. Median OS was 20 months, with a 6-month survival of 83.3% and a 12-month survival of 63.6%.

The rate of grade 3 or 4 adverse events (AEs) was 67% with cabozantinib and nivolumab over a median follow-up of 18.4 months and 72% with cabozantinib, nivolumab, and ipilimumab over a median follow-up of 12.8 months. Treatment-related AEs leading to discontinuation occurred in 12% of the group receiving cabozantinib and nivolumab and 11.1% receiving cabozantinib, nivolumab, and ipilimumab. Fifty percent of patients in the cabozantinib, nivolumab, and ipilimumab group and 33% in the cabozantinib, nivolumab, and ipilimumab group required at least 1 dose reduction of cabozantinib.

The most common clinical AEs of any grade with cabozantinib and nivolumab were fatigue (71%), nausea/vomiting (71%), diarrhea (67%), skin disorders (67%), anorexia (62%), and oral mucositis or sore throat (62%). In the cabozantinib, nivolumab, and ipilimumab group, most common AEs were fatigue (83%), diarrhea (83%), skin disorders (78%), nausea/vomiting (67%), and anorexia (55%).

“When we started the protocol, we were concerned about overlapping toxicities such as diarrhea. Our concern was that people would not differentiate diarrhea from cabozantinib versus colitis from nivolumab, but we actually found that people were able to clinically differentiate these 2 toxicities,” said Nadal.

The most common potential immune-related adverse event was pneumonitis, experienced by 11% of patients receiving cabozantinib, nivolumab, and ipilimumab.

An increase in elevations of ALT and AST of grade 3/4 severity was experienced by 11% and 5%, respectively, of patients receiving cabozantinib, nivolumab, and ipilimumab. All increases of AST and ALT were grade 1 or 2 with the cabozantinib and nivolumab combination.

The recommended phase II dose was 40 mg of cabozantinib and 3 mg/kg of nivolumab for the cabozantinib and nivolumab combination, and 40 mg of cabozantinib, 3 mg/kg of nivolumab, and 1 mg/kg of ipilimumab for the cabozantinib, nivolumab, and ipilimumab treatment.


  1. Nadal R, Mortazavi A, Stein M, et al. Final results of a phase I study of cabozantinib (cabo) plus nivolumab (nivo) and cabonivo plus ipilimumab (Ipi) in patients (pts) with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignancies. Abstract presented at: 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract 846O.
  2. Sharma P, Retz M, Siefer-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18(3):312-322. doi: 10.1016/S1470-2045(17)30065-7.
  3. Antonia SJ, López-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016;17(7):883-895. doi: 10.1016/S1470-2045(16)30098-5.