Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial.

Autor:	Pal SK; Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Albiges L; Department of Cancer Medicine, Institut Gustave Roussy, Villejuif, France., Tomczak P; Department of Oncology, Poznan University of Medical Sciences, Poznan, Poland., Suárez C; Department of Medical Oncology, Vall d'Hebron Institute of Oncology, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain., Voss MH; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., de Velasco G; Medical Oncology Department, University Hospital 12 de Octubre, Madrid, Spain., Chahoud J; Department of Genitourinary Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Mochalova A; Department of Chemotherapy, Clinical Hospital Number 1 MEDSI, Moscow, Russia., Procopio G; Department of Medical Oncology, Fondazione Istituto Nazionale dei Tumori di Milano, Milan, Italy., Mahammedi H; Department of Medical Oncology, Jean Perrin Center, Clermont-Ferrand, France., Zengerling F; Department of Urology and Pediatric Urology, University Hospital Ulm, Ulm, Germany., Kim C; Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, South Korea., Osawa T; Department of Urology, Hokkaido University Hospital, Sapporo, Japan., Angel M; Department of Genitourinary Cancer, Instituto Alexander Fleming, Buenos Aires, Argentina., Gupta S; Genentech, South San Francisco, CA, USA., Khan O; Roche Product, Welwyn Garden City, UK., Bergthold G; F Hoffmann-La Roche, Basel, Switzerland., Liu B; Genentech, South San Francisco, CA, USA., Kalaitzidou M; Roche Product, Welwyn Garden City, UK., Huseni M; Genentech, South San Francisco, CA, USA., Scheffold C; Exelixis, Alameda, CA, USA., Powles T; Barts Cancer Institute, Centre for Experimental Cancer Medicine, Queen Mary University of London, London, UK., Choueiri TK; Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: toni_choueiri@dfci.harvard.edu.
Jazyk:	angličtina
Zdroj:	Lancet (London, England) [Lancet] 2023 Jul 15; Vol. 402 (10397), pp. 185-195. Date of Electronic Publication: 2023 Jun 05.
DOI:	10.1016/S0140-6736(23)00922-4
Abstrakt:	Background: Immune checkpoint inhibitors are the standard of care for first-line treatment of patients with metastatic renal cell carcinoma, yet optimised treatment of patients whose disease progresses after these therapies is unknown. The aim of this study was to determine whether adding atezolizumab to cabozantinib delayed disease progression and prolonged survival in patients with disease progression on or after previous immune checkpoint inhibitor treatment. Methods: CONTACT-03 was a multicentre, randomised, open-label, phase 3 trial, done in 135 study sites in 15 countries in Asia, Europe, North America, and South America. Patients aged 18 years or older with locally advanced or metastatic renal cell carcinoma whose disease had progressed with immune checkpoint inhibitors were randomly assigned (1:1) to receive atezolizumab (1200 mg intravenously every 3 weeks) plus cabozantinib (60 mg orally once daily) or cabozantinib alone. Randomisation was done through an interactive voice-response or web-response system in permuted blocks (block size four) and stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk group, line of previous immune checkpoint inhibitor therapy, and renal cell carcinoma histology. The two primary endpoints were progression-free survival per blinded independent central review and overall survival. The primary endpoints were assessed in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov, NCT04338269, and is closed to further accrual. Findings: From July 28, 2020, to Dec 27, 2021, 692 patients were screened for eligibility, 522 of whom were assigned to receive atezolizumab-cabozantinib (263 patients) or cabozantinib (259 patients). 401 (77%) patients were male and 121 (23%) patients were female. At data cutoff (Jan 3, 2023), median follow-up was 15·2 months (IQR 10·7-19·3). 171 (65%) patients receiving atezolizumab-cabozantinib and 166 (64%) patients receiving cabozantinib had disease progression per central review or died. Median progression-free survival was 10·6 months (95% CI 9·8-12·3) with atezolizumab-cabozantinib and 10·8 months (10·0-12·5) with cabozantinib (hazard ratio [HR] for disease progression or death 1·03 [95% CI 0·83-1·28]; p=0·78). 89 (34%) patients in the atezolizumab-cabozantinib group and 87 (34%) in the cabozantinib group died. Median overall survival was 25·7 months (95% CI 21·5-not evaluable) with atezolizumab-cabozantinib and was not evaluable (21·1-not evaluable) with cabozantinib (HR for death 0·94 [95% CI 0·70-1·27]; p=0·69). Serious adverse events occurred in 126 (48%) of 262 patients treated with atezolizumab-cabozantinib and 84 (33%) of 256 patients treated with cabozantinib; adverse events leading to death occurred in 17 (6%) patients in the atezolizumab-cabozantinib group and nine (4%) in the cabozantinib group. Interpretation: The addition of atezolizumab to cabozantinib did not improve clinical outcomes and led to increased toxicity. These results should discourage sequential use of immune checkpoint inhibitors in patients with renal cell carcinoma outside of clinical trials. Funding: F Hoffmann-La Roche and Exelixis. Competing Interests: Declaration of interests SKP reports their institution received grants from or has contracts with Exelixis, Xencor, Pfizer, Allogene Therapeutics, AstraZeneca, Genentech, and CRISPR Therapeutics; reports payment or honoraria for lectures, presentations, or speakers' bureaus from EMD Serono and Pfizer; and reports meeting or travel support from CRISPR Therapeutics and Roche. LA reports their institution received consulting fees from Astellas, Ipsen, BMS, Janssen, Merck, MSD, Pfizer, Eisai, and Roche; and reports travel support from BMS, MSD, and Ipsen. CSu reports grants from or contracts with AB Science, Aragon Pharmaceuticals, Astellas Pharma, AstraZeneca AB, Bayer, Blueprint Medicines, Boehringer Ingelheim España, BMS, Clovis Oncology, Exelixis, Genentech, GlaxoSmithKline, F Hoffmann-La Roche, Novartis, Pfizer, and Sanofi-Aventis; speakers' bureau fees from Astellas Pharma, BMS, F Hoffmann-La Roche, Ipsen, and Pfizer; participation on a data safety monitoring board or advisory board for Astellas Pharma, Bayer, BMS, Eusa Pharma, F Hoffmann-La Roche, Ipsen, MSD, Novartis, Pfizer, and Sanofi-Aventis. MHV reports grants from or contracts with Pfizer; consulting fees from Aveo, Calithera, Eisai, Exelixis, Pfizer, Genentech, Oncorena, MICURx, and Merck; and participation on a data safety monitoring board or advisory board with AstraZeneca, Affimed, Genentech, and Merck. GdV reports consulting fees from Pfizer, MSD, BMS, Roche, Merck, Bayer, Astellas, AstraZeneca, and Ipsen; reports payment or honoraria for lectures, presentations, or speakers' bureaus from Pfizer, MSD, BMS, Roche, Merck, Astellas, and Ipsen; and reports travel support from MSD, Pfizer, and Roche. JC reports grants from or contracts with Pfizer; and participation on a data safety monitoring board or advisory board with Aveo, Exelixis, and Pfizer; and is a board member with VHL Alliance. GP reports consulting fees from Astellas, Roche, and Pfizer; and reports payment or honoraria for lectures, presentations, or speakers' bureaus from AstraZeneca, Bayer, BMS, Eisai, Ipsen, Janssen, Merck, MSD, Novartis, and Gilead Sciences. FZ reports consulting fees from Apogepha Pharma, Astellas Pharma, AstraZeneca Germany, Bayer Vital, Bristol Myers Squibb, Ipsen, Janssen-Cilag, Merck, Pfizer, and Roche; reports payment or honoraria for lectures, presentations, or speakers' bureaus from Astellas, Bayer Vital, Ipsen, Janssen-Cilag, Merck, Pfizer, and Sanofi-Aventis; and reports travel support from Astellas, Ipsen, Janssen-Cilag, and Pfizer. SG, BL, and MH are employees of Genentech. OK is an employee of F Hoffmann-La Roche. GB and MK are employees of F Hoffmann-La Roche and report stock ownership. CSc is an employee of Exelixis. TP reports grants from or contracts with AstraZeneca, BMS, Exelixis, Ipsen, MSD, Novartis, Pfizer, Seagen, Merck Serono, Astellas, Johnson & Johnson, Eisai, and Roche; reports payment or honoraria for lectures, presentations, or speakers' bureaus from AstraZeneca, BMS, Exelixis, Incyte, Ipsen, MSD, Novartis, Pfizer, Seagen, Merck Serono, Astellas, Johnson & Johnson, Eisai, Roche, and Mash Up; and reports travel support from Roche, Pfizer, MSD, AstraZeneca, and Ipsen. TKC reports support for the present manuscript from Alkermes, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVA, Infiniti, Ipsen, Kanaph, Lilly, Merck, Nikang, Novartis, Nuscan, Pfizer, Roche, Sanofi-Aventis, Surface Oncology, Takeda, Tempest, UpToDate, Peerview, Physicians' Education Resource, MJH Life Sciences, Research to Practice, France Foundation, Springer, WebMed, ASiM Ce, and Caribou Publishing; reports their institution received grants from or has contracts with AstraZeneca, Aveo, Arcus, Bayer, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Lilly, Merck, Nikang, Novartis, Pfizer, Roche, Sanofi-Aventis, and Takeda; reports consulting fees from AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVA, Infiniti, Ipsen, Kanaph, Lilly, Merck, Nikang, Novartis, Nuscan, Pfizer, Roche, Sanofi-Aventis, Surface Oncology, Takeda, Tempest, UpToDate, Peerview, Physicians' Education Resource, MJH Life Sciences, Research to Practice, France Foundation, Springer, WebMed, ASiM Ce, and Caribou Publishing; reports participation on a data safety monitoring board or advisory board with Aravive; reports leadership or role with KidneyCan, American Society of Clinical Oncology, European Society for Medical Oncology, National Comprehensive Cancer Network, and National Cancer Institute; has stock or stock options in Pionyr, Tempest, Precede Bio, Osel, and Curesponse; and declares other financial or non-financial interests in Dana-Farber/Harvard Cancer Center Kidney SPORE (2P50CA101942-16) and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School, the Trust family, Michael Brigham, Pan-Mass Challenge, Hinda L and Arthur Marcus Foundation, and Loker Pinard Funds for Kidney Cancer Research at Dana-Farber Cancer Institute. All other authors declare no competing interests. (Copyright © 2023 Elsevier Ltd. All rights reserved.)
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