Clinical Topics   /   Oncology

Cabozantinib May Help Overcome Checkpoint Inhibitor Resistance in GU Cancers

by Annette Boyle
June 1, 2018

BETHESDA, MD — The treatment armamentarium for renal cell carcinoma and other genitourinary cancers continues to expand. The last 10 years has seen strong results from several agents that target the vascular endothelial growth factor (VEGF) pathway and a number of new immunotherapies, primarily using checkpoint inhibitors, have also achieved significant improvements in progression free survival and overall survival.

Still, challenges remain, with high level of resistance dogging many of the most promising treatments based on initial response. A study announced today at the 2018 American Society of Clinical Oncology Annual Meeting in Chicago will explore whether cabozantinib, a tyrosine kinase inhibitor (TKI) that targets VEGF, MET and TAM receptors may provide a path forward as previous studies indicate.1

Rosa Maria Nadal, MD, of the National Cancer Institute presented an earlier study at the 2018 American Society of Clinical Oncology Genitourinary Cancers Symposium that demonstrated that cabozantinib combined with the programmed death-1 (PD-1) inhibitor nivolumab with or without ipilimumab increased antitumor activity in patients with relapsed metastatic RCC and other advanced genitourinary tumors.2 In patients with urothelial carcinoma, the cabozantinib/nivolumab combination achieved an objective response rate of 50%, while cabozantinib/nivolumab/ipilimumab had a 29% response rate. Median progression free survival was 12.8 months for both regimens and median overall survival had not been reached. Patients with renal cell carcinoma had a 54% objective response rate and median progression free survival of 18.4 months; median overall survival had not matured.

The newest research will build on the results of the February study. Federal researchers at the Genitourinary Malignancies Branch of the Center for Cancer Research at the National Cancer Institute and colleagues from leading institutions in the US and abroad are enrolling treatment-naïve adult patients with clear cell RCC and evaluable tumor biopsy (NCT01141177). The phase III study excludes patients with active central nervous metastases or autoimmune disease. Participants will be randomized to receive either nivolumab plus cabozantinib or sunitinib until disease progression or unacceptable toxicity is reached. Nivolumab treatment will not exceed two years.

The researchers will stratify patients based on International Metastatic RCC Database Consortium (IMDC) risk score, expression of PD-1 ligand 1 (PD-L1) in tumors and geographic location. Blinded, independent reviewers will assess progression free survival as a primary endpoint as well as secondary endpoints of overall survival, objective response rate and safety/tolerability of the agents in all patients.


1Choueiri TK, Apolo AB, Powles T, et al. A phase 3 randomized, open-label study of nivolumab combined with cabozantinib vs sunitinib in patients with previously untreated advanced or metastatic renal cell carcinoma. J Clin Oncol 36, 2018 (suppl; abstr TPS4598).

2Nadal RM, Mortazavi A, Stein M, et al. Results of phase I plus expansion cohorts of cabozantinib plus nivolumab and CaboNivo plus ipilimumab in patients with metastatic urothelial carcinoma and other genitourinary malignancies. J Clin Oncol 36, February 20, 2018 (no. 6 suppl; abstr 515).

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