ASCO 2023: Doublet and Triplet Therapy for Metastatic RCC: The Case for Triplet Therapy

( The 2023 ASCO annual meeting included a session on doublet or triplet therapy for metastatic renal cell carcinoma (RCC), featuring a presentation by Dr. Katy Beckermann discussing the case for triplet therapy. Dr. Beckermann started by highlighting that triplet therapy for testicular cancer, BEP chemotherapy, increases cure rates without increasing toxicity.

Additionally, among men with metastatic hormone sensitive prostate cancer, triplet therapy with ADT + novel hormone therapy + chemotherapy increases overall survival compared to doublet therapy. Doublet combinations in RCC have improved overall survival, with 48% of patients alive at 5 years with PD1 + CTLA4 blockade, as well as PD1 + TKI. However, the majority of patients with RCC acquire resistance or are primary refractory to front-line doublet therapy. 

Interestingly, early phase I/II triplet therapy data showed similar if not slightly lower complete response rates, with poorer progression free survival outcomes and more adverse events leading to discontinuation, when compared to IO + TKI doublet therapy:
phase 1 and checkmate 9er table
Subsequently, the COSMIC-313 trial was a phase 3 trial of cabozantinib in combination with ipilimumab + nivolumab versus ipilimumab + nivolumab.1 Patients with advanced clear-cell renal-cell carcinoma who had not previously received treatment and had intermediate or poor prognostic risk were enrolled into COSMIC-313. Patients were randomly assigned to receive cabozantinib daily in addition to nivolumab and ipilimumab or matched placebo in addition to nivolumab and ipilimumab. Patients then received nivolumab maintenance therapy (480 mg once every 4 weeks) for up to 2 years. The trial design for COSMIC-313 is as follows:advanced rcc stratifcation flow
The primary end point was progression-free survival, as determined by blinded independent review according to RECIST, v1.1. The secondary end point was overall survival, assessed in all patients who had undergone randomization. This trial had 855 patients that underwent randomization. Among the first 550 patients that were randomized, the probability of progression-free survival at 12 months was 0.57 in the ipilimumab + nivolumab + cabozantinib group and 0.49 in the ipilimumab + group (HR 0.73, 95% CI 0.57 to 0.94):
 RCC triplet survival
Triplet therapy decreased progressive disease as best response, but without evidence of cure:triplet therapy response
Additionally, more patients on triplet therapy (90%) compared to doublet therapy (75%) had tumor shrinkage:triplet graph
There was an increase in the number of patients achieving a partial response, but no difference (3% each group) for complete response, and fewer patients with a deep response. Thus, no difference in cure rate. Grade 3 or 4 adverse events occurred in 79% of the patients in the experimental group and in 56% in the control group, likely secondary overlapping toxicity in the triplet arm: triplet therapy adverse events
Finally, patients in the triplet arm received lower average daily dosing of cabozantinib, fewer doses of ipilimumab, and required more dose holds. There is a plethora of triplet therapy trials currently ongoing, as evidence by the following table:triplet therapy studies table
Dr. Beckermann concluded her presentation discussing the case for triplet therapy with the following take-home points:

  • Multi-drug regimens provide cure: R-CHOP in non-Hodgkin’s lymphoma and BEP in testicular cancer
  • The goal of triplet therapy is to decrease primary progressive disease and increase cure rates
  • The pro is that ipilimumab + nivolumab + cabozantinib improves median progression free survival and decreased the number of patients with progressive disease as best response, compared to the ipilimumab + nivolumab
  • The con is the toxicity from ipilimumab + nivolumab + cabozantinib was significant, requiring dose reduction and discontinuation of at least one drug in 45% of patients
  • Ongoing trials will seek to balance increased efficacy with manageable toxicity based on the safety profile and novel mechanism

Presented by: Katy Beckermann, MD, PhD, Vanderbilt University Medical Center, Nashville, TN

Written By: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 2 – Tues, June 6, 2023.


  1. Choueiri TK, Powles T, Albiges, et al. Cabozantinib plus Nivolumab and Ipilimumab in Renal Cell Carcinoma. N Engl J Med. 2023 May 11;388(19):1767-1778.