A phase I study of cabozantinib plus nivolumab (CaboNivo) in patients (pts) refractory metastatic urothelial carcinoma (mUC) and other genitourinary (GU) tumors

Abstract

Background Cabo is a multiple receptor tyrosine kinase inhibitor primarily targeting MET and VEGFR2. Correlative studies support the theory that cabozantinib has immunomodulatory properties. Nivo is a monoclonal IgG4 antibody to PD-1. We report the safety and clinical activity of the combination of CaboNivo in pts with mUC and other GU tumors (NCT02496208). Methods This phase I trial used a rolling 6 design. 6 pts were treated at 4 dose levels (DL) for part 1 (CaboNivo) of the study. Pts received Cabo PO daily and Nivo IV q2wks: DL1 Cabo 40mg/Nivo 1mg/kg, DL2 Cabo 40mg/Nivo 3mg/kg, DL3 Cabo 60mg/Nivo1mg/kg, DL4 Cabo 60mg/Nivo 3mg/kg. Tumors were assessed for overall response rate (ORR) q8wks (RECIST 1.1). Adverse events (AEs) were graded (G) by NCI-CTCAE v4.0. Results From 7/22/15-5/11/16, 24pts (mUC N = 6; bladder urachal N = 4; bladder squamous cell carcinoma (SCC) N = 3; germ cell tumor (GCT) N = 5; castrate-resistant prostate cancer (CRPC) N = 4; renal cell carcinoma (RCC) N = 1, and trophoblastic tumor N = 1) were treated. Median age was 55 (range 35-75), 21 (88%) were male. 9 pts required dose reductions (N = 2 DL1; N = 1 DL2; N = 2 DL3; N = 4 DL4), for PPE G2 N = 3 (DL1/2/4)); fatigue G1/2 N = 2 (DL3), diarrhea G2 N = 1 (DL3), lipase/amylase elevation G3 (DL1), weight loss G1 N = 1 (DL4), and anorexia/dehydration G2 N = 2 (DL4). Common treatment-related G1/2 AEs were transaminitis N = 20, diarrhea N = 11, hoarseness N = 7, dysgeusia N = 5, thrombocytopenia N = 5, hyponatremia N = 5. Grade 3 AEs included neutropenia N = 3 (DL1), fatigue N = 2 DL2, mucositis N = 1 (DL4), vomiting N = 1 (DL3). There were no G4/5 toxicities, no immune-related AEs and no DLTs. 18 pts were evaluable for response. ORR was 33% 6/18 (1 CR (bladder SCC); 5 PRs (mUC, RCC, urachal, urethral SCC, CRPC). All responses were ongoing at cutoff. SD 38% 7/18. Conclusions CaboNivo was well tolerated with no DLTs. Cabo 60mg resulted in more dose reductions due to clinically significant AEs. The recommended dose is Cabo40mg/Nivo3mg/kg. Part II of the phase I (triplet with ipilimumab (CaboNivoIpi) is ongoing. Expansion studies in pts with mUC and RCC are planned. Clinical trial identification