Temporary treatment cessation versus continuation of first-line tyrosine kinase inhibitor in patients with advanced clear cell renal cell carcinoma (STAR): an open-label, non-inferiority, randomised, controlled, phase 2/3 trial.

BACKGROUND

Temporary drug treatment cessation might alleviate toxicity without substantially compromising efficacy in patients with cancer. We aimed to determine if a tyrosine kinase inhibitor drug-free interval strategy was non-inferior to a conventional continuation strategy for first-line treatment of advanced clear cell renal cell carcinoma.

METHODS

This open-label, non-inferiority, randomised, controlled, phase 2/3 trial was done at 60 hospital sites in the UK. Eligible patients (aged ≥18 years) had histologically confirmed clear cell renal cell carcinoma, inoperable loco-regional or metastatic disease, no previous systemic therapy for advanced disease, uni-dimensionally assessed Response Evaluation Criteria in Solid Tumours-defined measurable disease, and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) at baseline to a conventional continuation strategy or drug-free interval strategy using a central computer-generated minimisation programme incorporating a random element. Stratification factors were Memorial Sloan Kettering Cancer Center prognostic group risk factor, sex, trial site, age, disease status, tyrosine kinase inhibitor, and previous nephrectomy. All patients received standard dosing schedules of oral sunitinib (50 mg per day) or oral pazopanib (800 mg per day) for 24 weeks before moving into their randomly allocated group. Patients allocated to the drug-free interval strategy group then had a treatment break until disease progression, when treatment was re-instated. Patients in the conventional continuation strategy group continued treatment. Patients, treating clinicians, and the study team were aware of treatment allocation. The co-primary endpoints were overall survival and quality-adjusted life-years (QALYs); non-inferiority was shown if the lower limit of the two-sided 95% CI for the overall survival hazard ratio (HR) was 0·812 or higher and if the lower limit of the two-sided 95% CI of the marginal difference in mean QALYs was -0·156 or higher. The co-primary endpoints were assessed in the intention-to-treat (ITT) population, which included all randomly assigned patients, and the per-protocol population, which excluded patients in the ITT population with major protocol violations and who did not begin their randomisation allocation as per the protocol. Non-inferiority was to be concluded if it was met for both endpoints in both analysis populations. Safety was assessed in all participants who received a tyrosine kinase inhibitor. The trial was registered with ISRCTN, 06473203, and EudraCT, 2011-001098-16.

FINDINGS

Between Jan 13, 2012, and Sept 12, 2017, 2197 patients were screened for eligibility, of whom 920 were randomly assigned to the conventional continuation strategy (n=461) or the drug-free interval strategy (n=459; 668 [73%] male and 251 [27%] female; 885 [96%] White and 23 [3%] non-White). The median follow-up time was 58 months (IQR 46-73 months) in the ITT population and 58 months (46-72) in the per-protocol population. 488 patients continued on the trial after week 24. For overall survival, non-inferiority was demonstrated in the ITT population only (adjusted HR 0·97 [95% CI 0·83 to 1·12] in the ITT population; 0·94 [0·80 to 1·09] in the per-protocol population). Non-inferiority was demonstrated for QALYs in the ITT population (n=919) and per-protocol (n=871) population (marginal effect difference 0·06 [95% CI -0·11 to 0·23] for the ITT population; 0·04 [-0·14 to 0·21] for the per-protocol population). The most common grade 3 or worse adverse events were hypertension (124 [26%] of 485 patients in the conventional continuation strategy group vs 127 [29%] of 431 patients in the drug-free interval strategy group); hepatotoxicity (55 [11%] vs 48 [11%]); and fatigue (39 [8%] vs 63 [15%]). 192 (21%) of 920 participants had a serious adverse reaction. 12 treatment-related deaths were reported (three patients in the conventional continuation strategy group; nine patients in the drug-free interval strategy group) due to vascular (n=3), cardiac (n=3), hepatobiliary (n=3), gastrointestinal (n=1), or nervous system (n=1) disorders, and from infections and infestations (n=1).

INTERPRETATION

Overall, non-inferiority between groups could not be concluded. However, there seemed to be no clinically meaningful reduction in life expectancy between the drug-free interval strategy and conventional continuation strategy groups and treatment breaks might be a feasible and cost-effective option with lifestyle benefits for patients during tyrosine kinase inhibitor therapy in patients with renal cell carcinoma.

FUNDING

UK National Institute for Health and Care Research.

Informations de copyright

Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests JEB reports having served as a consultant or adviser for Novartis, Ipsen, Amgen, Merck Sharp & Dohme, Bristol-Myers Squibb, and Bayer; honoraria from Novartis, Ipsen, Amgen, Merck Sharp & Dohme, Bristol-Myers Squibb, and Bayer; research funding paid to their institution from the National Institute for Health and Care Research; and travel expenses from Ipsen. WG reports consulting fees from Janssen and AbbVie. CR reports honoraria from Bristol-Myers Squibb and Wisai. TE reports trusteeship of Kidney Cancer UK and MacMillan Cancer Support. PN reports consulting fees from Novartis, Agensis, Ionctura, Bristol-Myers Squibb, 4SC, Pfizer, Merck Sharp & Dohme, and Merck; honoraria from Novartis and Immunocore; travel, accommodation, and expenses from Immunocore; membership of REFINE Data Safety Monitoring Board; and trusteeship of Melanoma Focus. TP reports consulting fees from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Merck, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Seattle Genetics, and Mashup; honoraria from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Merck, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Seattle Genetics; research funding paid to their institution from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Eisai, Exelixis, Ipsen, Johnson & Johnson, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Seattle Genetics; and travel expenses from AstraZeneca, Ipsen, Merck Sharp & Dohme, Pfizer, and Roche. RJ reports consulting fees from Astellas Pharma, Bayer, Bristol-Myers Squibb, Ipsen, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche; honoraria from Astellas Pharma, Bayer, Bristol- Myers Squibb, Ipsen, Janssen, Merck Serono, Merck Sharp & Dohme, Pfizer, Roche; research funding paid to their institution from Astellas Pharma, Clovis, Exelixis, and Bayer; and participation in a data safety monitoring board for Roche. NV reports consultancy fees from Bristol-Myers Squibb, 4D Pharma, and Merck Serono; honoraria from Bristol-Myers Squibb, EUSA Pharma, Eisai, and Ipsen; and travel expenses from Ipsen. MW reports consultancy fees from Bristol-Myers Squibb and Sciensus; honoraria from Eisai and Ipsen; and travel expenses from Bristol-Myers Squibb. TW reports honoraria from Bristol-Myers Squibb, Pfizer, Eisai, and Ipsen; travel expenses from Bristol-Myers Squibb, EUSA Pharma, and Ipsen; and participation on data safety monitoring boards for Bristol-Myers Squibb, Pfizer, Eisai, Ipsen, and Merck Sharp & Dohme. RM reports travel expenses from Janssen. PP reports research funding paid to their institution from Pfizer. JL reports consultancy fees from iOnctura, Apple Tree, Merck, Bristol-Myers Squibb, Eisai, Debipharm, and Incyte; honoraria from Eisai, Novartis, Incyte, Merck, TouchIME, TouchEXPERTS, Pfizer, Royal College of Physicians, Cambridge Healthcare, Royal College of General Practioners, VJ Oncology, and Agence Unik; research funding paid to their institution from Achilles, Bristol-Myers Squibb, Merck Sharp & Dohme, Nektar, Novartis, Pfizer, Immunocore, Roche, Aveo, and Pharmacyclics; and travel expenses from Pierre Fabre, Roche, and GlaxoSmithKline. GF reports consultancy fees from Bristol-Myers Squibb and Pfizer; honoraria from Bristol-Myers Squibb, Merck, and Pfizer; and travel expenses from Novartis and Bayer. DM reports funding from Otsuka and AbbVie to their institution; being a sub-panel member for the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research; and being a member of a National Institute for Health and Care Excellence Technology Appraisal Committee. VG reports funding from Siemens Healthineers to their institution. TMW reports research funding paid to their institution from Boston Scientific and Angidynamics. JBr reports being Chair of the NIHR Health Technology Assessment General Funding Committee and NIHR Health Technology Assessment funding paid to their institution. JH reports funding to their institution from the NIHR Health Technology Assessment. PS reports funding from an NIHR Senior Fellowship, European Research Council Advanced Awards; travel expenses from the European School of Oncology Training; and several patents on the development of DNA library cancer vaccines. FC reports honoraria from Bayer. All other authors declare no competing interests.