Cabozantinib in Platinum-Refractory Metastatic Urothelial Carcinoma

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In a single-center phase II trial reported in The Lancet Oncology, Andrea Apolo, MD, and colleagues found that the multikinase inhibitor cabozantinib showed activity in a cohort of patients with platinum-refractory metastatic urothelial carcinoma.

Andrea Apolo, MD

Andrea Apolo, MD

As noted by the investigators, in addition to inhibiting the MET, VEGFR, AXL, and RET kinases, cabozantinib has an effect on the tumor immune microenvironment by decreasing regulatory T cells and myeloid-derived suppressor cells.

Study Details

The open-label, single-arm, three-cohort phase II trial involved 42 evaluable patients with metastatic platinum-refractory urothelial carcinoma enrolled at the National Cancer Institute between September 2012 and October 2015. Patients received 60 mg of cabozantinib orally once daily in 28-day cycles until disease progression or unacceptable toxicity.

The study also included two exploratory platinum-refractory cohorts: one consisting of 6 patients with bone-only urothelial carcinoma metastases, and the other made up of 13 patients with rare histologies of the genitourinary tract. In the main cohort, 64% of patients had received two or more prior therapies for metastatic disease.


Median follow-up was 61.2 months. In the main cohort, objective response was observed in eight patients (19%), including complete response in one. An additional 19 patients (45%) had stable disease. Median progression-free survival was 3.7 months (95% confidence interval [CI] = 3–6 months), with 6- and 12-month rates of 37% and 10%. Median overall survival was 8.1 months (95% CI = 5.2–10.3 months), with 6- and 12-month rates of 64% and 26%.


  • Objective response was observed in 19% of patients.
  • Stable disease was observed in 45% of patients.

Bone response was observed in three of five evaluable patients in the cohort with bone-only metastatic disease. Among a total of 16 patients with urothelial carcinoma and bone metastases (from the main cohort and the exploratory cohort), median progression-free survival was 3.9 months and median overall survival was 7.2 months.

In biomarker analyses, treatment with cabozantinib reduced myeloid-derived suppressor cell populations, decreased the percentage of regulatory T cells in the CD4-positive T-cell population while increasing the ratio of effector CD8-positive T cells to regulatory T cells, and increased expression of PD-1 on regulatory T cells.

Adverse Events

Among all 68 patients who received cabozantinib, the most commonly reported grade 3 or 4 adverse events were fatigue (in 9% of patients), hypertension (7%), proteinuria (6%), and hypophosphatemia (6%). Serious adverse events included pulmonary embolism and rectovaginal fistula in one patient each.

Adverse events led to discontinuation of treatment in five patients (7%) due to grade 3 platelet decrease in one, grade 3 increase in aspartate aminotransferase in two, grade 3 proteinuria in one, and grade 1 transient ischemic attack (considered unrelated to treatment) in one. No treatment-related deaths were reported.

The investigators concluded, “Cabozantinib has single-agent clinical activity in patients with heavily pretreated, platinum-refractory metastatic urothelial carcinoma with measurable disease and bone metastases and is generally well tolerated. Cabozantinib has innate and adaptive immunomodulatory properties providing a rationale for combining cabozantinib with immunotherapeutic strategies.”

Dr. Apolo, of the Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by the National Cancer Institute Intramural Program and the Cancer Therapy Evaluation Program. For full disclosures of the study authors, visit

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