Author(s): Prof Janet E Brown, MD FRCP1;Kara-Louise Royle, MSc2;Prof Walter Gregory, PhD2;Christy Ralph, PhD2;Prof Anthony Maraveyas, PhD3;Omar Din, MD4;Prof Timothy Eisen, MBBChir5,6;Prof Paul Nathan, FRCP7;Prof Tom Powles, MD8;Richard Griffiths, FRCP9;Prof Robert Jones, PhD10;Naveen Vasudev, PhD MBChB11;Matthew Wheater, FRCP PhD12;Abdel Hamid, FRCR MSc13;Tom Waddell, MD14;Rhona McMenemin, MSc FRCR15;Prof Poulam Patel, PhD16;Prof James Larkin, FRCP PhD17;Guy Faust, MD18;Adam Martin, PhD19;Jayne Swain, PhD2;Janine Bestall, PhD20;Prof Christopher McCabe, PhD21;David Meads, PhD22;Prof Vicky Goh, MD FRCR23;Prof Tze Min Wah, PhD24;Prof Julia Brown, MSc2;Prof Jenny Hewison, PhD20;Prof Peter Selby, DSc11;Fiona Collinson, MD2
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.
Author Affiliations1Department of Oncology and Metabolism, University of Sheffield, Weston Park Hospital, Sheffield;2Leeds Cancer Research UK Clinical Trials Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK;3Queens Centre for Oncology and Haematology, Faculty of Health Sciences, Hull York Medical School, Hull, UK;4Department of Clinical Oncology, Cancer Centre, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK;5Department of Oncology, University of Cambridge, Cambridge, UK;6Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK;7Mount Vernon Cancer Centre, East and North Hertfordshire NHS Trust, Northwood, UK;8Barts Cancer Institute, Queen Mary University, London, UK;9The Clatterbridge Cancer Centre NHS Foundation Trust, Liverpool, UK;10University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK;11Leeds Institute of Medical Research at St James’s, Leeds Institute for Medical Research, University of Leeds, Leeds, UK;12University Hospital Southampton NHS Foundation Trust, Southampton, UK;13Broomfield Hospital, Mid and South Essex NHS Foundation Trust, Chelmsford, UK;14Christie NHS Foundation Trust, Manchester, UK;15Northern Centre for Cancer Care, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK;16Academic Unit of Translational Medical Sciences, University of Nottingham, Nottingham, UK;17Royal Marsden NHS Foundation Trust, London, UK;18Leicester Royal Infirmary, University Hospitals of Leicester NHS Trust, Leicester, UK;19Academic Unit of Health Economics, Leeds Institute for Medical Research, University of Leeds, Leeds, UK;20Leeds Institute of Health Sciences, Leeds Institute for Medical Research, University of Leeds, Leeds, UK;21Centre for Public Health, Queens University, Belfast, UK;22Academic Unit of Health Economics, Leeds Institute for Medical Research, University of Leeds, Leeds, UK;23School of Biomedical Engineering and Imaging Sciences, King’s College London, London, UK;24Department of Radiology, Leeds Institute for Medical Research, University of Leeds, Leeds, UK