As reported in The Lancet Oncology by Brown et al, the phase II/III STAR trial showed that noninferiority in overall survival and quality-adjusted life-years (QALYs) could not be concluded for temporary treatment cessation vs continuous treatment with first-line tyrosine kinase inhibitor therapy in patients with advanced clear cell renal cell carcinoma.
Study Details
In the open-label multicenter trial, 920 patients (intent-to-treat [ITT]) population) were randomly assigned between January 2012 and September 2017 to the conventional continuation strategy (n = 461) or the drug-free interval strategy (n = 459). All patients received sunitinib at 50 mg per day or pazopanib at 800 mg per day for 24 weeks. Patients in the drug-free interval group then had a treatment break until disease progression, with subsequent reinitiation of treatment; patients in the continuation group continued treatment. The per-protocol population consisted of 453 patients in continuation group and 418 patients in the drug-free interval group.
The coprimary endpoints were overall survival and QALYs; noninferiority was shown if the lower limit of the two-sided 95% confidence interval for the overall survival hazard ratio was 0.812 or higher, and if the lower limit of the two-sided 95% confidence interval of the marginal difference in mean QALYs was –0.156 or higher. Noninferiority had to be met for both endpoints in both the ITT and per-protocol populations for noninferiority of the drug-free interval strategy to be concluded.
Key Findings
Median follow-up was 58 months in both the ITT population and per-protocol population. For overall survival, noninferiority of the drug-free interval group was demonstrated in the ITT population (median = 28 months in continuation group vs 27 months in drug-free interval group; adjusted hazard ratio [HR] = 0.97, 95% confidence interval [CI] = 0.83–1.12). Noninferiority was not met in the per-protocol population (median = 28 vs 27 months; adjusted HR = 0.94, 95% CI = 0.80–1.09). For QALYs, noninferiority of the drug-free interval group was met in both the ITT population (marginal effect difference = 0.06, 95% CI = –0.11 to 0.23) and in the per-protocol population (marginal effect difference = 0.04, 95% CI = –0.14 to 0.21).
Among 485 patients in the continuation group and 431 in the drug-free interval group in the safety population, the most common grade ≥3 adverse events were hypertension (26% vs 29%), hepatotoxicity (11% vs 11%), and fatigue (8% vs 15%). Serious adverse events occurred in 9% vs 12% of patients after continuation and treatment break were instituted. Treatment-related death occurred in three patients in the continuation group vs nine patients in the drug-free interval group.
The investigators stated: “Overall, noninferiority 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.”
Janet E. Brown, MD, FRCP, of the Department of Oncology and Metabolism, University of Sheffield, Weston Park Hospital, Sheffield, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by the UK National Institute for Health and Care Research. For full disclosures of the study authors, visit thelancet.com.
