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342 A phase 3 study (COSMIC-313) of cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced renal cell carcinoma of intermediate or poor risk
  1. Toni Choueiri1,
  2. Laurence Albiges2,
  3. Thomas Powles3,
  4. Nehal Mohamed4,
  5. Fong Wang4 and
  6. Robert Motzer5
  1. 1Dana-Farber Cancer Institute, Boston, MA, USA
  2. 2Institute Gustave Roussy, Villejuif, Ile-de-France, France
  3. 3Barts Cancer Institute, London, UK
  4. 4Exelixis, Inc., Alameda, CA, USA
  5. 5Memorial Sloan Kettering Cancer Center, New York, NY, USA


Background Cabozantinib (C) inhibits tyrosine kinases involved in tumor growth, angiogenesis, and immune regulation, including MET, VEGFR, and TAM kinases (Tyro3, AXL, MER), and may promote an immune-permissive tumor environment, resulting in enhanced response to immune checkpoint inhibitors. C has shown preliminary clinical activity and tolerability in combination with the PD-1 inhibitor nivolumab (N) and as part of a triplet combination with N and the CTLA-4 inhibitor ipilimumab (I) in patients (pts) with advanced renal cell carcinoma (aRCC) (Nadal et al. ASCO 2018). C is approved for pts with aRCC, and N+I is approved as a combination therapy in pts with previously untreated aRCC of intermediate or poor risk. We present the study design of a phase 3 trial of C+N+I vs N+I in previously untreated pts with aRCC of IMDC intermediate or poor risk (NCT03937219).

Methods This randomized, double-blind, controlled phase 3 study evaluates the efficacy and safety of C+N+I vs N+I in previously untreated pts with IMDC intermediate or poor risk aRCC. Eligible pts are randomized 1:1 to receive C+N+I or N+I in combination with placebo, stratified by IMDC prognostic score and geographic region. Pts receive C (40 mg oral QD) + N (3 mg/kg IV Q3W) x 4 doses + I (1 mg/kg IV Q3W) x 4 doses, followed by C (40 mg oral QD) + N (480 mg IV flat dose Q4W). Control pts receive C-matched placebo and the same treatment regimen for N+I as the experimental arm. N will be administered for a maximum of 2 years. Eligibility criteria include histologically confirmed metastatic or aRCC with a clear cell component, intermediate or poor risk RCC per IMDC criteria, measurable disease per RECIST 1.1, KPS ≥70%, adequate organ and marrow function and age ≥18 years. Exclusion criteria include prior systemic therapy for aRCC and uncontrolled significant illnesses. The primary endpoint is PFS per RECIST 1.1 by BICR; the secondary endpoint is OS. Additional endpoints include ORR, safety, correlation of biomarkers with outcomes, and pharmacokinetics of C in combination with N+I. The first patient was enrolled in June 2019 and enrollment is ongoing.

Results N/A

Conclusions N/A

Trial Registration NCT03937219

Ethics Approval This study is being conducted in compliance with Good Clinical Practice (GCP), including International Conference on Harmonisation (ICH) Guidelines, the most recent accepted version of the Declaration of Helsinki, and all applicable local laws and regulatory requirements. The appropriate Institutional Review Boards (IRBs) or Ethics Committees (ECs) of participating centers have approved approve the study protocol. All patients have provided written informed consent.

Consent All patients have provided written informed consent.

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

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