Cabozantinib (C) is an inhibitor of multiple receptor tyrosine kinases involved in tumor cell proliferation, neovascularization, and immune cell regulation, including MET, VEGFRs, and TAM family of kinases (TYRO3, MER, and AXL). Preclinical/clinical studies suggest that C promotes an immune-permissive environment that may facilitate synergistic effects with checkpoint inhibitors. This Phase 1b study evaluates C in combination with the programmed death ligand (PD-L1) targeting antibody atezolizumab (A) in pts with solid tumors (NCT03170960).
Safety and clinical activity of C (2 dose levels: 40 mg, 60 mg QD) + A (1200 mg Q3W) administered in 3-week cycles were evaluated in a 3 + 3 dose escalation design. Safety data of all pts and criteria for dose limiting toxicity (DLT) determined the recommended dose (RD) for a subsequent expansion stage. Tumor response was assessed by CT/MRI and bone scan (RECIST v 1.1).
12 pts with treatment-naïve advanced RCC (mostly clear-cell subtype) were treated in the dose escalation stage (6 at each dose level). At data cutoff, all pts were actively receiving study treatment (range, 3–12 cycles). There were no DLTs or serious adverse events (AEs) in either C+A dose cohort. Most AEs were Grade 1/2 including immune-related AEs. Grade 3 AEs included 3 events of hypertension, 2 events each of diarrhea and hypophosphatemia, and 1 pulmonary embolism. There were no Grade 4/5 AEs. Among 10 pts investigator-assessed confirmed ORR was 50% (1 CR, 4 PRs); 2 additional pts had unconfirmed PRs with only 1 tumor assessment at data cut-off.
C+A is well tolerated and shows encouraging anti-tumor activity in advanced RCC. C 40 mg QD + A 1200 mg Q3W was selected as the RD for expansion in multiple solid tumor cohorts including RCC.
Clinical trial identification
Legal entity responsible for the study
N. Agarwal: Consulting or advisory role: Pfizer, Novartis, Merck, Genentech, Eisai, Exelixis, Clovis, EMD Serono, BMS, AstraZeneca, Astellas. U. Vaishampayan: Honoraria: Astellas Pharma, Bayer, Bristol-Myers Squibb, Exelixis, Genentech, Janssen, Novartis, Pfizer, Sanofi; Consulting or advisory role: Astellas Pharma, Bayer, Bristol-Myers Squibb, Exelixis, Genentech/Roche, Novartis, Pfizer; Speakers' bureau: Astellas Pharma, Bayer, Bristol-Myers Squibb, Exelixis, Genentech/Roche, Novartis, Pfizer, Sanofi; Research funding: Astellas Pharma, Bristol-Myers Squibb, Exelixis, Novartis, Pfizer. M. Green, F. di Nucci: Employee: Genentech. P-Y. Chang: Employee of Exelixis Inc. C. Scheffold: Employee of and owns stock in Exelixis, Inc. S. Pal: Honoraria: Astellas Pharma, Medivation, Novartis; Consulting or advisory role: Aveo, Bristol-Myers Squibb, Exelixis, Genentech, Myriad Pharmaceuticals, Novartis, Pfizer; Research funding: Medivation.