Back to Search Start Over

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

Authors :
Janet E Brown
Kara-Louise Royle
Walter Gregory
Christy Ralph
Anthony Maraveyas
Omar Din
Timothy Eisen
Paul Nathan
Tom Powles
Richard Griffiths
Robert Jones
Naveen Vasudev
Matthew Wheater
Abdel Hamid
Tom Waddell
Rhona McMenemin
Poulam Patel
James Larkin
Guy Faust
Adam Martin
Jayne Swain
Janine Bestall
Christopher McCabe
David Meads
Vicky Goh
Tze Min Wah
Julia Brown
Jenny Hewison
Peter Selby
Fiona Collinson
Judith Carser
Gopalakrishnan Srinivasan
Fiona Thistlewaite
Ashraf Azzabi
Mark Beresford
David Farrugia
Marios Decatris
Carys Thomas
Joanna Gale
James McAleer
Alison Clayton
Ekaterini Boleti
Thomas Geldart
Santhanam Sundar
Jason Lester
Nachi Palaniappan
Mohan Hingorani
Khaliq Rehman
Mohammad Khan
Naveed Sarwar
Janine Graham
Alastair Thomson
Narayanan Srihari
Denise Sheehan
Rajaguru Srinivasan
Omar Khan
Andrew Stockdale Jane Worlding
Stergios Boussios
Nicholas Stuart
Carey MacDonald-Smith
Falalu Danwata
Duncan McLaren
Aravindhan Sundaramurthy
Anna Lydon
Sharon Beesley
Kathryn Lees
Mohini Varughese
Emma Gray
Angela Scott
Mark Baxter
Anna Mullard
Pasquale Innominato
Gaurav Kapur
Anil Kumar
Natalie Charnley
Caroline Manetta
Prabir Chakraborti
Prantik Das
Sarah Rudman
Henry Taylor
Christos Mikropoulos
Martin Highley
Dakshinamoorthy Muthukumar
Anjali Zarkar
Roy Vergis
Seshadri Sriprasad
Patryk Brulinski
Amanda Clarke
Richard Osbourne
Melanie Harvey
Renata Dega
Geoffrey Sparrow
Urmila Barthakur
Erica Beaumont
Agnieszka Michael
Emilio Porfiri
Faisal Azam
Ravi Kodavtiganti
Source :
STAR Investigators, Brown, J E, Royle, K-L, Gregory, W, Ralph, C, Maraveyas, A, Din, O, Eisen, T, Nathan, P, Powles, T, Griffiths, R, Jones, R, Vasudev, N, Wheater, M, Hamid, A, Waddell, T, McMenemin, R, Patel, P, Larkin, J, Faust, G, Martin, A, Swain, J, Bestall, J, McCabe, C, Meads, D, Goh, V, Min Wah, T, Brown, J, Hewison, J, Selby, P & Collinson, F 2023, ' 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 ', Lancet Oncology, vol. 24, no. 3, pp. 213-227 . https://doi.org/10.1016/S1470-2045(22)00793-8
Publication Year :
2023
Publisher :
Elsevier BV, 2023.

Abstract

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. 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. 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). 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. UK National Institute for Health and Care Research.

Details

ISSN :
14702045
Volume :
24
Database :
OpenAIRE
Journal :
The Lancet Oncology
Accession number :
edsair.doi.dedup.....3a633cdaf72543d0ca87f46d23005d79
Full Text :
https://doi.org/10.1016/s1470-2045(22)00793-8