Temporary drug treatment cessation might alleviate toxicity without compromising efficacy in patients with renal cell carcinoma (RCC). The results of the STAR trial, recently published in The Lancet Oncology, suggest that taking treatment breaks during tyrosine kinase inhibitor therapy is unlikely to impact overall survival of these patients. A strategy of planned treatment breaks might, therefore, provide a cost-effective alternative to continuous therapy with potential lifestyle benefits.
Tyrosine kinase inhibitors (TKIs), which are normally administered continuously until disease progression, result in improved survival outcomes for patients with advanced or metastatic renal cell carcinoma (RCC). However, such treatment causes considerable toxicity and reduced quality of life. Therefore, temporary drug treatment cessation might alleviate toxicity without substantially compromising efficacy in these patients. Considering the high cost of cancer medicines, strategies that reduce the costs might also enable greater overall access, for example in low-income and middle-income countries. In this context, the phase 2/3 STAR trial assessed the potential benefits of a treatment break strategy compared with a conventional treatment continuation strategy in patients with RCC receiving TKI therapy.
This phase 2/3 STAR trial enrolled 919 adult patients with inoperable loco-regional or metastatic clear cell (cc) RCC who were randomly assigned (1:1) to a conventional continuation (n=461) or drug-free interval (n=459) strategy. All patients received standard dosing schedules of oral sunitinib or pazopanib for 24 weeks before moving into their randomly allocated group. Afterwards, patients allocated to the drug-free interval group had a treatment break until disease progression, when treatment was re-instated. Patients in the conventional continuation strategy group continued treatment. The co-primary endpoints were overall survival (OS) and quality-adjusted life-years (QALYs) in the intention-to-treat (ITT) and per-protocol population. The pre-protocol population (n=871) excluded patients with major protocol violations and who did not begin their randomisation allocation as per the protocol. Non-inferiority was shown if the lower limit of the 95%CI for the OS hazard ratio (HR) was ≥0.812 and if the lower limit of the 95%CI of the marginal difference in mean QALYs was ≥ -0.156 or higher.
After a median follow-up of 58 months, median OS was 28 vs. 27 months in the conventional continuation and drug-free interval strategy groups, respectively, for both ITT and per protocol populations. However, non-inferiority could only be demonstrated in the ITT population (HR[95%CI]: 0.97 [0.83-1.12]), but not in the per-protocol populations (HR[95%CI]: 0.94 [0.80-1.09]. In contrast, non-inferiority was demonstrated for QALYs in both the ITT (marginal effect difference: 0.06 [95%CI: -0.11-0.23]) and per-protocol (marginal effect difference: 0.04 [95%CI: -0.14-0.21]) populations. The most common grade 3 or worse adverse events were hypertension (26% vs. 29% in the conventional continuation strategy group and drug-free interval strategy group, respectively), hepatotoxicity (11% vs. 11%) and fatigue (8% vs. 15%).
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. Therefore, a strategy of planned treatment breaks might be feasible for patients with rCC who wish to prioritise their quality of life.
Brown JE, Royle K-L, Gregory W, et al. 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 Oncol. 2023;24(3):213-27.