The power of three: triplet drug combination slows disease progression in patients with advanced kidney cancer

cristina saurez web 3
  • Published in The New England Journal of Medicine (1) results of the phase 3 COSMIC-313 trial show that the addition of targeted kinase inhibitor cabozantinib to dual checkpoint inhibition with nivolumab and ipilimumab in patients with advanced or metastatic renal cell carcinoma led to a 27% lower risk of disease progression or death compared to those on the standard of care immunotherapy doublet.


  • Led by Toni Choueiri, Director of the Lank Center for Genitourinary Cancer at the Dana-Farber Cancer Institute in Boston, the global and multi-center COSMIC-313 trial included 855 previously untreated patients and is the first study in metastatic renal cell carcinoma to evaluate a three-drug experimental combination using standard of care nivolumab plus ipilimumab as the control arm.


  • Co-authored by Cristina Suarez, Senior Investigator of VHIO’s Genitourinary, Central Nervous System Tumors and Sarcoma Group, and Medical Oncologist at Vall d’Hebron, results of this study were initially selected to first outing during a Presidential Symposium (2) at the 2022 annual Congress of the European Society for Medical Oncology (ESMO) in Paris.


Renal cell carcinoma (RCC), though rare, is the most common form of kidney cancer found in adults and accounts for around 2% of all malignant tumors. Clear cell renal cell carcinoma is the most common subtype of RCC representing between 75-80% of cases. The first-line combination of checkpoint inhibitors nivolumab plus ipilimumab is a contemporary standard of care in previously untreated patients with advanced renal cell carcinoma.

With progression-free survival as the primary endpoint, the global, double-blind, randomized COSMIC-313 study was designed to evaluate the efficacy of adding tyrosine kinase inhibitor cabozantinib to immunotherapy with nivolumab and ipilimumab as a triplet treatment strategy versus nivolumab plus ipilimumab­—a contemporary standard of care —as the control arm.

“Cabozantinib is an inhibitor of tyrosine kinases receptors including MET, VEGFR and TAM kinases, and promotes an immune-permissive environment which could enhance response to immune checkpoint inhibitors. The combination of PD-1 inhibitor nivolumab with ipilimumab, another antibody that binds to the CTLA-4 protein, boosts an immune response to tumor cells and triggers T cells to attack and destroy cancer cells,” explains Cristina Suarez, Senior Investigator of the Vall d’Hebron Institute of Oncology’s (VHIO) Genitourinary, Central Nervous System Tumors and Sarcoma Group, and Medical Oncologist at the Vall d’Hebron University Hospital (HUVH), Vall d’Hebron Barcelona Hospital Campus.

Published in The New England Journal of Medicine (1), results of this study show that patients treated with the triplet combination had a 27% lower risk of disease progression or death compared to those who received the two immunotherapy drugs, and that progression-free survival advantage met the primary endpoint.

“COSMIC-313 is the first phase three study in metastatic renal cell carcinoma to evaluate a triplet treatment strategy against standard of care first-line doublet immunotherapy. Our initial observations demonstrate the efficacy and safety of this first-line three-drug combination and show a significant progression-free benefit in these patients,” adds Cristina Saurez, co-author of this present study.

COSMIC-313 enrolled 855 previously untreated patients with clear cell metastatic or advanced renal cell carcinoma, 428 of whom received the triplet experimental combination, and 427 who were treated with the standard immunotherapy doublet. The overall response rate in the specified intention-to-treat population was 43% with the triplet combination compared to 36% with the standard two-drug immune-oncology combination. More grade 3 or 4 adverse events were observed in those patients receiving the experimental treatment, 79% versus 56% in those treated with nivolumab plus ipilimumab.

 “Despite the increased toxicity, our findings show a clear progression-free survival benefit. Next analysis will show if these initial data translate in improved overall survival to identify those patients who could benefit from this three-drug combination,” concludes Suarez.



  1. Choueiri TK, Powles T, Albiges L, Burotto M, Szczylik C, Zurawski B, Yanez Ruiz E, Maruzzo M, Suarez Zaizar A, Fein LE, Schutz FA, Heng DYC, Wang F, Mataveli F, Chang YL, van Kooten Losio M, Suarez C, Motzer RJ; COSMIC-313 Investigators. Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma. N Engl J Med. 2023 May 11;388(19):1767-1778.


LBA8 – Phase III study of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in previously untreated advanced renal cell carcinoma (aRCC) of IMDC intermediate or poor risk (COSMIC-313). T.K. Choueiri, T.B. Powles, L. Albiges, M. Burotto, C. Szczylik, B. Zurawski, E. Yanez Riuz, M. Maruzzo, A. Suarez Zaizar, L.E. Fein, F.A. Barros Schutz, D.Y.C. Heng, F. Wang, F. Mataveli, Y. Chang,

Related Posts

Privacy Preferences
When you visit our website, it may store information through your browser from specific services, usually in form of cookies. Here you can change your privacy preferences. Please note that blocking some types of cookies may impact your experience on our website and the services we offer.