ASCO 2020: COSMIC-313 Phase III Study of Cabozantinib in Combination with Nivolumab and Ipilimumab in Patients with Previously Untreated Advanced Renal Cell Carcinoma of Intermediate or Poor-Risk

( Tyrosine kinase inhibitors and immune checkpoint inhibitors have become standard of care for patients with advanced renal cell carcinoma (RCC). Cabozantinib 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.

Based on the CABOSUN trial cabozantinib is approved for patients with advanced RCC,1 and nivolumab + ipilimumab is approved as a combination therapy in patients with previously untreated advanced RCC of intermediate or poor risk based on the CheckMate-214 trial.2  Cabozantinib has shown preliminary clinical activity and tolerability in combination with the PD-1 inhibitor nivolumab and as part of a triplet combination with nivolumab and the CTLA-4 inhibitor ipilimumab in patients with advanced RCC.3 Furthermore, as was recently reported in a press release, in the phase 3 CheckMate 9ER study, the combination of cabozantinib and nivolumab significantly improved progression-free survival, overall survival, and objective response rate versus sunitinib in the first-line setting for advanced RCC. At the virtual ASCO 2020 annual meeting, Dr. Toni Choueiri and colleagues presented the study design of COSMIC-313, a phase 3 trial of cabozantinib + nivolumab + ipilimumab vs nivolumab + ipilimumab in previously untreated patients with advanced RCC of IMDC intermediate or poor risk.

COSMIC-313 is a randomized, double-blind, controlled phase 3 study evaluating the efficacy and safety of cabozantinib + nivolumab + ipilimumab vs nivolumab + ipilimumab in previously untreated patients with IMDC intermediate or poor-risk advanced RCC. Eligible patients are randomized 1:1 to receive cabozantinib + nivolumab + ipilimumab or nivolumab + ipilimumab in combination with placebo, stratified by IMDC prognostic score and geographic region. Patients receive cabozantinib (40 mg oral QD) + nivolumab (3 mg/kg IV Q3W) x 4 doses + ipilimumab (1 mg/kg IV Q3W) x 4 doses, followed by cabozantinib (40 mg oral QD) + nivolumab (480 mg IV flat dose Q4W). Control patients receive a cabozantinib-matched placebo and the same treatment regimen for nivolumab + ipilimumab as the experimental arm. Nivolumab will be administered for a maximum of two years. The trial design for COSMIC-313 is as follows:


Eligibility criteria include histologically confirmed metastatic or advanced RCC with a clear cell component, intermediate or poor risk RCC per IMDC criteria, measurable disease per RECIST 1.1, a Karnofsky performance status of ≥70%, adequate organ and marrow function, and age ≥18 years. Exclusion criteria include prior systemic therapy for advanced RCC and uncontrolled significant illnesses. The primary endpoint is PFS per RECIST 1.1 by blinded independent radiology committee, and the secondary endpoint is OS. Additional endpoints include:

  • Overall Response Rate
  • Correlation of biomarkers with outcomes
  • Pharmacokinetics of cabozantinib in combination with nivolumab + ipilimumab
  • Immunogenicity of nivolumab and ipilimumab
  • Health-related quality of life and health care resource utilization
  • Safety, including immune-related adverse events

Tumor response will be assessed by CT chest/abdomen/pelvis or CT of the chest and MRI of the abdomen/pelvis at baseline, week 10, and then every eight weeks through week 50, and then every 12 weeks thereafter until radiographic disease progression. The study is designed to provide adequate power for both PFS (primary endpoint) and OS (secondary endpoint) with a sample size of 676 patients. The primary analysis of PFS will be conducted in the first 440 randomized patients, defined as the PFS intent to treat population, with 90% power using a 2-sided log-rank test. The secondary endpoint of OS will be evaluated in all 676 randomized patients, with 90% power using a 2-sided log-rank test.

The first patient was enrolled in June 2019 and enrollment is ongoing. COSMIC-313 is open for enrollment in North America, Europe, Asia-Pacific region, and South America:


Clinical trial information: NCT03937219


Presented by: Toni K. Choueiri, MD, Director of the Lank Center for Genitourinary (GU) Oncology at Dana-Farber Cancer Institute/Brigham and Women’s Hospital and the Jerome and Nancy Kohlberg Chair and Professor of Medicine at Harvard Medical School

Co-Authors: Laurence Albiges, Thomas Powles, Christian Scheffold, Fong Wang, Robert J. Motzer; Gustave Roussy, Villejuif, France; Barts Cancer Institute, Queen Mary University of London, London, United Kingdom; Exelixis, Inc., Alameda, CA; Memorial Sloan Kettering Cancer Center, New York, NY

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md at the 2020 American Society of Clinical Oncology Virtual Annual Meeting (#ASCO20), May 29th-May 31st, 2020

1. Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus Sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: The Alliance A031203 CABOSUN Trial. J Clin Oncol 2017;35(6):591-597.
2. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carinoma. N Engl J Med 2018;378(14):1277-1290.
3. Nadal RM, et al. J Clin Oncol 2018;36(suppl 6): Abstract 515.

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