CARE1 pragmatic clinical trial: First line randomised study platform to optimize treatment in patients with metastatic renal cell carcinoma

BackgroundSystemic therapy for renal cell carcinoma (RCC) relies on two classes of agents: vascular endothelial growth factor tyrosine kinase inhibitors (VEGFR TKI) and immune checkpoint inhibitors (ICI) targeting either PD1 or CTLA4. ICI based combination therapy is standard-of-care for clear cell RCC with either ICI-ICI or ICI-VEGFR TKI. However, no head-to-head comparison have been performed between the two approaches and patients are treated based on physician decision without biomarker to guide treatment selection. PDL1 staining may help select patient who derive benefit to upfront ICI-ICI strategy.Trial designThe CARE1 study is a pragmatic phase III international multicenter randomized clinical trial funded by the European Union’s Horizon Europe research and innovation program under grant agreement No 101104801, PHRC grant N° K2022-2023 provided by National Cancer Institute in France, Gustave Roussy and CRIS Cancer Foundation Real-Life Trials in Oncology Programme. The main objective of CARE1 is to demonstrate that ICI-ICI improves overall survival over ICI-VEGFR TKI in PDL1 positive patients with metastatic clear-cell renal cell carcinoma in the first line setting, and conversely to demonstrate that ICI-VEGFR TKI improves overall survival over ICI-ICI in PDL1 negative patients. PDL1 positivity is defined locally as ≥1% of stained tumor cells. Patients will be randomized 1:1 to receive ICI-ICI or ICI-TKI. Secondary endpoints are progression-free survival (PFS) – PFS will be a co-primary endpoint specifically in the PDL1 negative population –, objective response rate according to RECIST 1.1, duration of treatment, time-to-treatment discontinuation, treatment-free survival, time to subsequent systemic anticancer therapy, quality of life, safety and cost-effectiveness. A comprehensive translational program including tissue and circulating biomarkers is embedded into the CARE1 study. The trial is currently recruiting and 1200 patients will be enrolled across 8 European countries.Clinical trial identificationEUCT 2023-503317-29-00; NCT0636463.Legal entity responsible for the studyGustave Roussy.FundingEuropean Union’s Horizon Europe research and innovation program under grant agreement No 101104801; National Cancer Institute in France; Gustave Roussy Foundation; Cris Cancer Foundation.DisclosureL. Albiges: Financial Interests, Institutional, Other, Consulting: Astellas, BMS, Eisai, Ipsen, Janssen, MSD, Novartis, Pfizer, Roche, Merck, Amgen; Financial Interests, Personal, Other, Honoraria: Novartis; Non-Financial Interests, Principal Investigator, Clinical trial steering committee: Pfizer, BMS, AVEO, AstraZeneca, MSD; Non-Financial Interests, Principal Investigator: Ipsen; Non-Financial Interests, Other, Clinical trial steering committee: Roche, Exelixis; Non-Financial Interests, Member: ASCO; Non-Financial Interests, Other, Medical Steering Committee: Kidney Cancer Association; Non-Financial Interests, Other, Member of the Renal Cell Carcinoma Guidelines Panel: European Association of Urology (EAU). C. Suarez Rodriguez: Financial Interests, Personal, Invited Speaker: Astellas Pharma, Bristol Myers Sqquib (Inst), Ipsen, Hoffmann-La Roche Ltd, Merck; Financial Interests, Personal, Advisory Board: Bristol Myers Sqquib (Inst), Ipsen, Hoffmann-La Roche Ltd, Merck Sharp and Dohme, Eisai; Financial Interests, Institutional, Funding: Ipsen; Financial Interests, Institutional, Research Grant: Pfizer. G. Procopio: Financial Interests, Personal, Advisory Board, consultant fees: Astellas, AstraZeneca, Amgen, Boehringer, Bayer, Brystol Myers Squibb, Ipsen, Janssen, Eisai, Janssen Cilag, Merck Sharp & Dohme, Merck, Pfizer, Roche, Eli Lilly; Financial Interests, Personal, Other, workgroup: Menarini Group; Financial Interests, Institutional, Research Grant, research funding for no profit clinical trial: Ipsen, Gilead, MSD, Janssen. A. Bex: Financial Interests, Institutional, Advisory Board, Online advisory board: Ipsen; Financial Interests, Institutional, Other, Membership of a DMSB of a Merck led trial (terminated in 2023): Merck; Financial Interests, Institutional, Research Grant, Restricted educational grant for an investigator initiated trial of neoadjuvant therapy in high risk renal cancer: Pfizer; Non-Financial Interests, Principal Investigator, Steering committee member and PI in an adjuvant trial: Roche/Genentech; Non-Financial Interests, Principal Investigator, Steering committee member and local investigator in an adjuvant trial: BMS; Non-Financial Interests, Advisory Role, Medical Steering committee member to advise the patient advocacy group on medical topics and strategy: International Kidney Cancer Coalition, Kidney Cancer Association. V. Gruenwald: Financial Interests, Personal, Invited Speaker: Amgen, Astellas, AstraZeneca, BMS, Eisai, Ipsen, Janssen-Cilag, MSD, Merck Serono, Novartis, Pfizer, Gilead; Financial Interests, Personal, Advisory Board: Apogepha, BMS, Debiopharm, Eisai, MSD, Merck Serono, Oncorena, PCI Biotech, Pfizer, Roche, Cureteq, Synthekine; Financial Interests, Personal, Stocks/Shares: BMS, MSD, AstraZeneca, bicycle; Financial Interests, Institutional, Steering Committee Member: BMS, Novartis; Financial Interests, Institutional, Research Grant: Ipsen, MSD, Pfizer, BMS; Financial Interests, Personal and Institutional, Steering Committee Member: Eisai, Ipsen; Non-Financial Interests, Member: ASCO, German medical Oncology and Hematology Society; Non-Financial Interests, Advisory Role: German Cancer Society; Non-Financial Interests, Leadership Role: Working Group medical oncology; Other, Travel support to ESMO 2022: Pfizer; Other, Travel support for meeting: Merck Serono; Other, Travel Support ASCO GU 2024: Ipsen; Other, Travel Support: Janssen Cilag. M. Schmidinger: Financial Interests, Personal, Advisory Board, advisory boards or lectures: BMS, MSD, Ipsen; Financial Interests, Personal, Advisory Board, Advisory board or lectures: Eisai; Financial Interests, Personal, Advisory Board: Exelixis; Financial Interests, Personal, Other, Travel support: Eusa; Financial Interests, Personal, Advisory Board, Advisor: Pfizer; Financial Interests, Institutional, Other, Research grant: Ipsen; Non-Financial Interests, Principal Investigator, trial investigator: MSD; Non-Financial Interests, Advisory Role, Steering Committee member: Exelixis. B. Melichar: Financial Interests, Personal, Advisory Board: Roche, BMS, MSD, Novartis, Merck Serono, E. Lilly, Pfizer, AstraZeneca. G.A. De Velasco Oria: Financial Interests, Personal, Advisory Board: Pfizer, Astellas, BMS, MSD, Ipsen, Bayer, AstraZeneca, Eisai; Financial Interests, Personal, Invited Speaker: Pfizer, Astellas, BMS, MSD, Roche, Ipsen, Merck, Novartis, Janssen, Bayer; Financial Interests, Institutional, Research Grant: Roche. A.R. Ferreira: Financial Interests, Personal, Advisory Board: Roche, Novartis, Merck Sharp & Dohme, Seagen; Financial Interests, Personal, Invited Speaker: Roche, Novartis, Gilead Sciences; Financial Interests, Personal, Full or part-time Employment: Resilience. N. Rioux-Leclercq: Financial Interests, Personal, Invited Speaker, Paid conferences: Amgen, AstraZeneca, BMS, Ipsen, Janssen, MSD. J. Bonastre: Financial Interests, Personal, Advisory Board, Scientific board: BMS, MSD, Janssen, Roche; Financial Interests, Institutional, Funding, Funding of the MICADO study: BMS. R. Flippot: Financial Interests, Institutional, Invited Speaker: Ipsen, Pfizer; Financial Interests, Institutional, Advisory Board: MSD (Merck Sharp Dohme), Eisai, Astellas, Bayer, Johnson & Johnson, Merck Serono; Financial Interests, Personal, Other, Travel Expenses: Bristol Myers Squibb; Financial Interests, Institutional, Coordinating PI: Bayer. B. Escudier: Financial Interests, Personal, Advisory Board: MSD, Ipsen, Oncorena. S. Foulon: Financial Interests, Institutional, Advisory Board, Participation to the advisory board (statistical advice) of an epidemiological study performed by Gilead on real world data (medico-administrative data): Review and validation of the study protocol, validation of the study population, as well as the review and validation of the results and of the study report: Gilead. T.B. Powles: Financial Interests, Personal, Advisory Board: AstraZeneca, Bristol Myers Squibb, Exelixis, Incyte, Ipsen, Merck, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai, Roche, MSD; Financial Interests, Personal, Other, Travel/Accommodation/Expenses: Roche, Pfizer, MSD, AstraZeneca, Ipsen; Financial Interests, Personal, Other, Sponsorship for Uromigos Podcast: Mashup Ltd; Financial Interests, Institutional, Other, honoraria: Gilead; Financial Interests, Institutional, Research Grant: AstraZeneca, Roche, Bristol Myers Squibb, Exelixis, Ipsen, Merck, MSD, Seattle Genetics, Novartis, Pfizer, Merck Serono, Astellas, Johnson & Johnson, Eisai; Financial Interests, Institutional, Other, Honoraria: Gilead. All other authors have declared no conflicts of interest.