Authors' objectives: There is interest in using treatment breaks in oncology, to reduce toxicity without compromising efficacy. To determine if a drug-free interval strategy is non-inferior to a conventional continuation strategy in terms of the co-primary outcomes of overall survival and quality-adjusted life-years. There is increasing interest in using treatment breaks in oncology, to reduce toxicity without compromising efficacy. STAR was designed to determine if a tyrosine kinase inhibitor (TKI) drug-free interval strategy (DFIS) was non-inferior to a conventional continuation strategy (CCS) in the first-line treatment of advanced renal cell carcinoma (RCC). The overall primary objective was to determine whether a sunitinib or pazopanib DFIS is non-inferior in terms of overall survival (OS) and quality-adjusted life-year (QALY) compared to a sunitinib or pazopanib CCS in patients with locally advanced and/or metastatic clear cell RCC. Secondary objectives included comparing a DFIS to a CCS in terms of summative progression-free interval, time to strategy failure, time to treatment failure, toxicity (common terminology criteria for adverse events v.4.0), quality of life (QoL) [Functional Assessment of Cancer Therapy – Kidney Symptom Index (FKSI-15), Functional Assessment of Cancer Therapy-G (FACT-G), EuroQol-5 Dimensions (EQ-5DTM) and EQ-Visual Analogue Scale (VASTM)], cost effectiveness, progression-free survival (PFS). Three ancillary studies were also included in the trial. The Patient Preference and Understanding Study was designed to understand the participants’ experiences of taking part in the trial. The dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) substudy was designed to investigate whether early DCE-MRI could predict progressive disease (PD) at 24 weeks. The computerised tomography (CT) substudy was designed to determine CT as a potential biomarker and predictor of PD at 24 weeks.

Authors' results and conclusions: Nine hundred and twenty patients were randomised (461 conventional continuation strategy vs. 459 drug-free interval strategy) from 13 January 2012 to 12 September 2017. Trial treatment and follow-up stopped on 31 December 2020. Four hundred and eighty-eight (53.0%) patients [240 (52.1%) vs. 248 (54.0%)] continued on trial post week 24. The median treatment-break length was 87 days. Nine hundred and nineteen patients were included in the intention-to-treat analysis (461 vs. 458) and 871 patients in the per-protocol analysis (453 vs. 418). For overall survival, non-inferiority was concluded in the intention-to-treat analysis but not in the per-protocol analysis [hazard ratio (95% confidence interval) intention to treat 0.97 (0.83 to 1.12); per-protocol 0.94 (0.80 to 1.09) non-inferiority margin: 95% confidence interval ≥ 0.812, intention to treat: 0.83 > 0.812 non-inferior, per-protocol: 0.80 < 0.812 not non-inferior]. Therefore, a drug-free interval strategy was not concluded to be non-inferior to a conventional continuation strategy in terms of overall survival. For quality-adjusted life-years, non-inferiority was concluded in both the intention-to-treat and per-protocol analyses [marginal effect (95% confidence interval) intention to treat −0.05 (−0.15 to 0.05); per-protocol 0.04 (−0.14 to 0.21) non-inferiority margin: 95% confidence interval ≥ −0.156]. Therefore, a drug-free interval strategy was concluded to be non-inferior to a conventional continuation strategy in terms of quality-adjusted life-years. Non-inferiority was shown for the quality-adjusted life-year end point but not for overall survival as pre-defined. Nevertheless, despite not meeting the primary end point of non-inferiority as per protocol, the study suggested that a treatment-break strategy may not meaningfully reduce life expectancy, does not reduce quality of life and has economic benefits. Although the treating clinicians’ perspectives were not formally collected, the fact that clinicians recruited a large number of patients over a long period suggests support for the study and provides clear evidence that a treatment-break strategy for patients with renal cell carcinoma receiving tyrosine kinase inhibitor therapy is feasible. Participant flow Two thousand one hundred and ninety-seven patients were screened; of these, 920 were randomised (CCS: 461, DFIS: 459). In total, 878 (95.4%) participants ceased trial treatment prior to the end of follow-up. Radiological disease progression was the most frequent reason for treatment discontinuation at 43.7% (CCS: 48.4%, DFIS: 39.0%). Overall, 13,147 (78.6%, n = 16,726) (CCS: 5764/7401, 77.9%; DFIS: 7383/9327, 79.2%) of QoL questionnaire booklets were returned on the trial. The proportions of reasons for missing booklets were similar between the two arms, where the highest reason was ‘missed by site in error’ (overall: 27%, CCS: 28.4%, DFIS: 25.8%). However, the majority of reasons for missing were missing (overall: 52.1%, CCS: 50.6%, DFIS: 53.4%). Overall, 63 participants (6.8%, n = 920) withdrew from some aspect of the trial. This resulted in 21 (2.82%, n = 920) participants being formally lost to follow-up (CCS: 11, 2.4%; DFIS: 10, 2.2%). An additional DFIS participant was lost to follow-up due to the participant moving away. However, all participants were included in the analysis. Implications for health care The STAR trial is an exemplar trial, being one of the first to be powered on a QALY end point. It demonstrated no substantial detriment in terms of OS and QALY from a DFIS compared to a CCS. However, NI between the two arms cannot be concluded due to a lack of statistical power for the analysis of OS, as a result of fewer than expected OS events due to the changing landscape of effective treatments for relapsed advanced RCC during the trial. These results provide evidence-based reassurance for people who received National Institute for Health and Care Excellence (NICE)-approved treatment breaks in this setting during the COVID-19 pandemic. Through compliance with the protocol, treatment breaks within the trial were shown to be acceptable to patients and health professionals.

Authors' methods: Participants Patients with locally advanced or metastatic renal cell carcinoma, starting tyrosine kinase inhibitor as first-line treatment at United Kingdom National Health Service hospitals. At trial entry, patients were randomised (1 : 1) to a drug-free interval strategy or a conventional continuation strategy. After 24 weeks of treatment with sunitinib/pazopanib, drug-free interval strategy patients took up a treatment break until disease progression with additional breaks dependent on disease response and patient choice. Conventional continuation strategy patients continued on treatment. Both trial strategies continued until treatment intolerance, disease progression on treatment, withdrawal or death. The main limitation of the study is the fewer than expected overall survival events, resulting in lower power for the non-inferiority comparison. STAR was a UK Phase II/III multicentre, open-label, parallel-group, randomised controlled non-inferiority (NI) trial. The trial recruited adults, with histologically confirmed locally advanced or metastatic clear cell, uni-dimensionally measurable, RCC who required but had not received prior systemic therapy. Participants were required to have an Eastern Cooperative Oncology Group performance status of 0–1, meet pre-specified blood parameters prior to randomisation, provide written informed consent, be able and willing to comply with the terms of the protocol and follow approved pregnancy prevention guidelines. Exclusion criteria included pulmonary or mediastinal disease, life expectancy < 6 months, previous treatment with or known contraindications or hypersensitivity to TKIs, untreated brain metastases, concurrent or previous invasive cancers which could confuse diagnosis or end points, use of contraindicated concomitant medication or substances and poorly controlled hypertension. At trial entry, participants were randomised (1 : 1) centrally by Leeds CTRU to a CCS or a DFIS. Randomisation was stratified by Motzer prognostic group (favourable, intermediate, poor), trial site, gender, age (< 60, ≥ 60 years), disease status (metastatic, locally advanced), previous nephrectomy (yes, no), TKI (sunitinib, pazopanib). Both strategies received an initial 4 cycles of trial treatment [sunitinib: 1 cycle of treatment refers to 50 mg (starting dose) on days 1–28, repeated every 42 days; pazopanib: 1 cycle of treatment refers to 800 mg (starting dose) on days 1–42, repeated every 42 days] following which participants in the DFIS arm took up their first treatment break. Following disease progression on a treatment break, DFIS participants restarted their treatment. Additional breaks were permitted following a further 4 cycles of treatment at the treating clinician’s discretion. The trial strategy continued until death, progression while receiving treatment, unacceptable toxicity (clinical withdrawal) or participant withdrawal. Following cessation of the trial strategy, participants were followed up after 6 months and then annually thereafter until death, patient withdrawal or the end of the trial. All trial data were collected on trial-specific case report forms (CRFs). All CRFs, apart from the questionnaires for the patient-reported outcome measures (FSKI-15, FACT-G, EQ-5D and EQ-VAS) were completed by research staff at the site. Overall survival was defined as time from randomisation to death from any cause. For NI to be concluded, a margin of ≤ 7.5% in OS was pre-specified. The survival at 2 years in the CCS arm was assumed to be 48.5%. A 7.5% NI margin led to the survival at 2 years in the DFIS arm assumed to be at least 41%, leading to a hazard ratio (HR) of 0.812. This along with a one-sided 2.5% significance level, 5% dropout rate and 80% power required 920 participants. Where 80% power would be attained when 720 events were observed. Quality-adjusted life-years were defined as the time spent in each health state over trial and follow-up, calculated as the utility index of the EQ-5D questionnaire, which was collected frequently (6-weekly for 24 weeks, 2-weekly for 24 weeks, 6-weekly while on study, 6 months post end of trial strategy and annually thereafter). For NI to be concluded a margin of ≤ 10% in mean QALYs was pre-specified. The power for the QALY comparison was derived using simulations. Under the assumptions of a 0.9 HR in favour of CCS, a sample size of 920, 5.83 years of recruitment and 3.25 years of follow-up a CCS QALY estimate of 1.56 was derived along with a power of 69.94%. The CCS QALY estimate of 1.56 in conjunction with the 10% margin equates to a NI boundary of −0.156 for the difference in mean QALYs. It was pre-specified that NI was required in both intention-to-treat (ITT) and per-protocol (PP) analyses, in both end points, to be concluded overall. An in-depth qualitative inductive study of 11 patients on the DFIS arm was conducted to better understand their acceptability of extended treatment breaks. A thematic analysis using a comparative and contrastive approach was employed. An economic evaluation was also conducted which estimated the cost effectiveness of DFIS versus CCS at 2 years (within-trial analysis) and over the patients’ lifetime (decision modelling analysis). Two thousand one hundred and ninety-seven patients were screened; of these, 920 were randomised (CCS: 461, DFIS: 459). In total, 878 (95.4%) participants ceased trial treatment prior to the end of follow-up. Radiological disease progression was the most frequent reason for treatment discontinuation at 43.7% (CCS: 48.4%, DFIS: 39.0%). Overall, 13,147 (78.6%, n = 16,726) (CCS: 5764/7401, 77.9%; DFIS: 7383/9327, 79.2%) of QoL questionnaire booklets were returned on the trial. The proportions of reasons for missing booklets were similar between the two arms, where the highest reason was ‘missed by site in error’ (overall: 27%, CCS: 28.4%, DFIS: 25.8%). However, the majority of reasons for missing were missing (overall: 52.1%, CCS: 50.6%, DFIS: 53.4%). Overall, 63 participants (6.8%, n = 920) withdrew from some aspect of the trial. This resulted in 21 (2.82%, n = 920) participants being formally lost to follow-up (CCS: 11, 2.4%; DFIS: 10, 2.2%). An additional DFIS participant was lost to follow-up due to the participant moving away. However, all participants were included in the analysis.

Authors' identified further research: Further discussion is required with patient and public involvement (PPI) and NICE regarding the implications of these results after the NHS interim treatment options following the COVID-19 pandemic end. The STAR trial has provided significant learning regarding the development, design and delivery of intermittent therapy trials.

Project Status: Completed

URL for project: https://www.journalslibrary.nihr.ac.uk/programmes/hta/09/91/21

Year Published: 2024

URL for published report: https://www.journalslibrary.nihr.ac.uk/hta/JWTR4127

URL for additional information: English

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: United Kingdom

DOI: 10.3310/JWTR4127

Organisation Name: NIHR Health and Social Care Delivery Program

Contact Name: Rhiannon Miller

Contact Email: rhiannon.m@prepress-projects.co.uk