KEYMAKER-U03 sub-study 03A: triplet investigational combinations of immunotherapy and targeted treatments as first-line therapy for advanced renal cell carcinoma
KEYMAKER-U03 is an international, multicenter, open-label, phase I/II umbrella trial evaluating experimental combinations of pembrolizumab-based immunotherapy and targeted treatments for advanced clear cell renal cell carcinoma (ccRCC). First results from sub-study 03A of the main study, were presented by Cristina Suarez, Medical Oncologist at the Vall d’Hebron University Hospital and Head of VHIO’s Genitourinary (non-prostate), Central Nervous System Tumors, and Tumors of Unknown Origin Tumors Group, at ESMO Congress 2025 1 and published simultaneously in Annals of Oncology 2 .
Originating in the lining of the kidney tubules, renal cell carcinoma (RCC) is the most common malignant tumor of the kidney, accounting for up to 95% of all cases of kidney cancer in adults. Among the different types of renal cell tumors, ccRCC is the most common subtype (between 75 and 80% of all kidney cancers). Over recent years, dual immunotherapy-based combinations have been approved as first-line therapy for this type of kidney cancer.
Pembrolizumab-based combinations
“ In recent years, triple combinations with new mechanisms of action including monoclonal antibodies directed against new therapeutic targets have been investigated ,” observed Cristina Suarez. “The randomized sub-study 03A, part of the main KEYMAKER-03 phase I/II umbrella trial, assessed four pembrolizumab-based investigational strategies in combination with other targeted therapies versus standard of care pembrolizumab plus lenvatinib.”
This sub-study enrolled 353 patients with advanced ccRCC who were randomly assigned to receive one of the following four investigational combinations, or standard treatment, as first-line therapy:
Favezelimab-pembrolizumab + lenvatinib; vibostolimab-pembrolizumab + lenvatinib; quavonlimab-pembrolizumab + lenvatinib; pembrolizumab + belzutifan + lenvatinib, or pembrolizumab + lenvatinib.
The pembrolizumab-belzutifan-lenvatinib triplet demonstrated promising antitumor activity with an objective response rate (ORR) of 78% and a median progression-free survival (PFS) of 31.8 months as compared to 20.8 months in the reference arm. The pembrolizumab/quavonlimab plus lenvatinib group showed an ORR of 71%, but median PFS was similar to the control arm. The efficacy of the other two combinations was less favorable.
“ We will have to wait and see if the findings observed in this study are confirmed in the phase III LITESPARK-012 clinical trial, currently pending results. Phase III LITESPARK-012 is assessing the two triplet combinations that previously showed efficacy in phases I and II: pembrolizumab plus belzutifan and lenvatinib, and pembrolizumab/quavonlimab combined with lenvatinib, as first-line therapy in patients with clear cell renal cell carcinoma. These two investigational combinations could provide new therapeutic options to improve the survival and quality of life of these patients,” concluded Suarez.
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References
Corresponding session details:
Proffered Paper session 2: GU tumours, renal & urothelial
Date: Sat, 18.10.2025
Chairs: Wenxin Xu (Boston, United States of America), Sara Elena Rebuzzi (Turin, Italy)
Room: Berlin Auditorium - Hub 27
Session Time: 08:30 - 10:00 (CEST)
Abstract: LBA96 - First-line pembrolizumab-based regimens for advanced clear cell renal cell carcinoma: KEYMAKER-U03 substudy 03A
Authors: Cristina Suarez Rodriguez (Barcelona, Spain), Carlos I. Rojas (Recoleta, Chile), Sang Joon Shin (Seoul, Republic of Korea), Patricio E. Yanez Weber (Temuco, Chile), Laurence Albiges (Villejuif, France), Robert J. Motzer (New York, United States of America, NY), Hans Hammers (Dallas, United States of America, MD), Avivit Peer (Haifa, Israel), Jae-Lyun Lee (Seoul, Republic of Korea), Wilson Miller (Montreal, Canada), Tom S. Waddell (Manchester, United Kingdom), Victoria Neiman (Petah Tikva, Israel), Daniel Kejzman (Tel Aviv, Israel), Ariel Zwenger Kloster (Providencia, Chile), Andrew J. Weickhardt (Heidelberg, Australia, Victoria - VIC), Rafal Dziadziuszko (Gdansk, Poland), Leah Suttner (Rahway, United States of America), Manish Sharma (Lebanon, United States of America), Joe Burgents (North Wales, United States of America), Thomas B. Powles (London, United Kingdom)
Speaker: Cristina Suarez Rodriguez (Barcelona, Spain)
Lecture Time: 08:30 - 08:40 (CEST)
2. Suarez C, Rojas C, Shin SJ, Weber PY, Albiges L, Motzer R, Hammers H,Peer A, Lee JL, Miller WH Jr, Waddell T, Neiman V, Keizman D, Kloster AZ, Weickhardt A, Dziadziuszko, R, Suttner L, Sharma M, Burgents JE, Powles T, Novel pembrolizumab-based treatments as firstline therapy in advanced clear cell renal cell carcinoma: Substudy 03A of the open-label, umbrella platform, phase I/II KEYMAKER-U03 trial, Annals of Oncology (2025), doi: https://doi.org/10.1016/j.annonc.2025.10.010.
Annals of Oncology
Novel pembrolizumab-based treatments as first-line therapy in advanced clear cell renal cell carcinoma: Substudy 03A of the open-label, umbrella platform, phase I/II KEYMAKER-U03 trial
17-Oct-2025