For this study, the phase I cohort had seven dose levels. The recommended phase 2 doses for cabozantinib + nivolumab was cabozantinib 40mg and nivolumab 3mg/kg and for cabozantinib + nivolumab + ipilimumab was cabozantinib 40mg, nivolumab 3mg/kg, and ipilimumab 1mg/kg . In expansion cohorts, the dose regimens and disease sites treated are as follows:
The primary objective was to determine safety and tolerability, while the secondary objectives included objective response rate (ORR) by RECIST vs 1.1, progression-free survival (PFS), and overall survival (OS).
There were 78 patients enrolled in the study, with a median age 59 year of which 83% were male. Forty-nine patients were treated with cabozantinib + nivolumab (metastatic urothelial carcinoma n=26; bladder adenocarcinoma n= 9; germ cell tumor (GCT) n= 5; castrate-resistant prostate cancer (CRPC) n= 4; bladder squamous cell carcinoma n= 2; penile carcinoma n=1; metastatic renal cell carcinoma (mRCC) n= 7). Twenty-nine patients were treated with cabozantinib + nivolumab + ipilimumab (metastatic urothelial carcinoma n=9; penile n=3; CRPC n=7; Sertoli n=1; mRCC n=6; bladder small cell carcinoma n=1; renal medullary carcinoma n=2). Any grade adverse events (AEs) were reported in 96% of patients receiving cabozantinib + nivolumab 96% and 96% of patients receiving cabozantinib + nivolumab + ipilimumab. Grade 3 and 4 AEs were reported in 62% of those treated with cabozantinib + nivolumab and 71% for cabozantinib + nivolumab + ipilimumab. The most common any grade AEs for those treated with cabozantinib + nivolumab was fatigue (70%), diarrhea (60%), AST/ALT elevation (60%), and hypophosphatemia (45%) whereas for those treated with cabozantinib + nivolumab + ipilimumab was fatigue (71%), diarrhea (68%), hypophosphatemia (50%), and AST/ALT elevation (43%). Serious AEs included colitis (2.6%), hepatitis (2.6%), pneumonitis (2.6%), aseptic meningitis (1.3%). For patients with urothelial carcinoma, the ORR for cabozantinib + nivolumab was 50% and for cabozantinib + nivolumab + ipilimumab was 29%; median PFS (regardless of regimen) was 12.8 months (95%CI 1.8-NR); median OS was not reached. In the RCC specific cohort, ORR was 54%, median PFS was 18.4 months (95%CI 5.4-18.4), and median OS was not reached.
Dr. Nadal concluded that updated results from this phase I and expanded cohort study assessing cabozantinib + nivolumab and cabozantinib + nivolumab + ipilimumab confirm initial safety findings and promising antitumor activity for both combinations in metastatic urothelial carcinoma, mRCC, and additional other rare genitourinary malignancies. Furthermore, patients with metastatic urothelial carcinoma and mRCC that achieve complete or partial response on either regimen have a prolonged clinical benefit.
Clinical trial information: NCT02496208
Speaker: Rosa Nadal, National Institutes of Health, Bethesda, MD
Co-Authors: Amir Mortazavi, Mark Stein, Sumanta K. Pal, Nicole N. Davarpanah, Howard L. Parnes, Yang-Min Ning, Lisa M. Cordes, Mohammadhadi H. Bagheri, Liza Lindenberg, Ryan Thompson, Seth M. Steinberg, Tina Moore, Tiffany Lancaster, Milisyaris Velez, Esther Mena, Rene Costello, Donald Bottaro, William L. Dahut, Andrea B. Apolo
Written by: Zachary Klaassen, MD, Clinical Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA
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. ESMO 2017, abstr 846O.