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Treatment Holidays from Tyrosine Kinase Inhibitors in Advanced Renal Cell Carcinoma
Although less frequently used as monotherapy today, tyrosine kinase inhibitors (TKIs) in combination with immune checkpoint inhibitors continue to be a backbone in the initial management of patients with metastatic renal cell carcinoma. Toxicities with TKIs are significant and have a negative impact on quality of life for most patients receiving these agents.
Investigators in the U.K. conducted an open-label, noninferiority, randomized phase 2/3 trial comparing conventional administration schedules of either sunitinib or pazopanib to a drug-free interval strategy. Over a 5-year period, 920 patients initiated conventional administration schedules of their physician-selected TKI for 24 weeks, at which time patients with stable disease or better either continued standard treatment schedules or had their drug held until evidence of progressive disease. The co-primary endpoints for phase 3 of the trial were overall survival (OS), defined as time to death from any cause, and quality-adjusted life-years (QALYs). Of note, the co-primary endpoints were assessed in the intention-to-treat (ITT) population, and noninferiority required the endpoints to be met in both the ITT and per-protocol groups.
At a median follow-up of 58 months, median OS was 27 months in the drug-free interval strategy group and 28 months in the conventional continuation strategy group. Noninferiority of the drug-free interval strategy for OS was demonstrated only in the ITT population, while noninferiority for QALYs was observed in both groups. Treatment-related toxicities were consistent with the known side effect profiles of both drugs.
As noted by the authors, although noninferiority of the drug-free interval strategy for both OS and QALY was not demonstrated, the results of this trial show that patients taking planned treatment breaks are unlikely to have a clinically meaningful reduction in OS. Given that many patients with metastatic renal cancer are now managed with immune checkpoint inhibitor/TKI combinations, these findings may provide impetus to further explore the role of alternative TKI administration strategies in the setting of combination therapy.
Brown JE et al.
Title: 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.
Source: Lancet Oncol 2023 Mar ; [e-pub]. (Abstract/FREE Full Text)