TY - JOUR
T1 - Temporary treatment cessation versus continuation of first-line tyrosine kinase inhibitor in patients with advanced clear cell renal cell carcinoma (STAR)
T2 - an open-label, non-inferiority, randomised, controlled, phase 2/3 trial
AU - Brown, Janet E.
AU - Royle, Kara Louise
AU - Gregory, Walter
AU - Ralph, Christy
AU - Maraveyas, Anthony
AU - Din, Omar
AU - Eisen, Timothy
AU - Nathan, Paul
AU - Powles, Tom
AU - Griffiths, Richard
AU - Jones, Robert
AU - Vasudev, Naveen
AU - Wheater, Matthew
AU - Hamid, Abdel
AU - Waddell, Tom
AU - McMenemin, Rhona
AU - Patel, Poulam
AU - Larkin, James
AU - Faust, Guy
AU - Martin, Adam
AU - Swain, Jayne
AU - Bestall, Janine
AU - McCabe, Christopher
AU - Meads, David
AU - Goh, Vicky
AU - Min Wah, Tze
AU - Brown, Julia
AU - Hewison, Jenny
AU - Selby, Peter
AU - Collinson, Fiona
AU - Carser, Judith
AU - Srinivasan, Gopalakrishnan
AU - Thistlewaite, Fiona
AU - Azzabi, Ashraf
AU - Beresford, Mark
AU - Farrugia, David
AU - Decatris, Marios
AU - Thomas, Carys
AU - Gale, Joanna
AU - McAleer, James
AU - Clayton, Alison
AU - Boleti, Ekaterini
AU - Geldart, Thomas
AU - Sundar, Santhanam
AU - Lester, Jason
AU - Palaniappan, Nachi
AU - Hingorani, Mohan
AU - Scott, Angela
AU - Baxter, Mark
AU - Highley, Martin
N1 - Funding Information:
We thank the UK National Institute for Health and Care Research (NIHR) for funding this trial (HTA/09/91/21) and all the patients and site staff who participated, without whom this study would not have been possible. This study/project is funded by the NIHR (Heath and Technology Assessment Programme [09/91/21]). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. We are grateful to the UK National Cancer Research Institute Renal Clinical Studies Group for input into and approval of the study design and the University of Leeds, UK for sponsoring the trial and the University of Leeds Clinical Trials Research Unit for running the study. We are grateful for the support and advice given by the Trial Steering Group and the Data Monitoring and Ethics Committee. We wish to acknowledge the dedication of Pat Hanlon, the patient representative on the Trial Management Group, who died before the trial could be published. We also wish to express appreciation to the following clinicians who assisted with classification of safety events: Kevin Chan, Catherine Handforth, Amy Kwan, Elisavet Theodoulou, Sebastian Trainor, Gustavo Ariaspinilla, Abdulazeez Salawu, and Luis Daverede.
Publisher Copyright:
© 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
PY - 2023/3
Y1 - 2023/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85148343151&partnerID=8YFLogxK
U2 - 10.1016/S1470-2045(22)00793-8
DO - 10.1016/S1470-2045(22)00793-8
M3 - Article
C2 - 36796394
AN - SCOPUS:85148343151
SN - 1470-2045
VL - 24
SP - 213
EP - 227
JO - The Lancet Oncology
JF - The Lancet Oncology
IS - 3
ER -