TKI Treatment Breaks May Not Impact Outcomes in Renal Cell Carcinoma

Although non-inferiority could not be determined following planned treatment cessation vs conventional continuation with a first-line tyrosine kinase inhibitor, patients with advanced clear cell renal cell carcinoma did not experience a clinically meaningful decrease in survival outcomes, according to data from the phase 2/3 STAR trial.

In the phase 2/3 STAR trial's intent-to-treat population, the median overall survival was higher in the conventional continuation group vs the drug-free interval group.

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The median overall survival (OS) was 28 months (95% CI, 24-32) in the conventional strategy group vs 27 months (95% CI, 23-31) for the drug-free interval group in the per protocol population. For the intent-to-treat (ITT) population, the median OS was 28 months (95% CI, 24-32) in the conventional continuation group vs 27 months (95% CI, 23-33) in the drug-free interval group.

Investigators also noted that there was noninferiority with regard to quality-adjusted life years (QALYs) in the ITT group (marginal effect difference 0.06; 95% CI, ­–0.11 to 0.23) and the per-protocol population (marginal effect difference 0.04; 95% CI, –0.14 to 0.21).

A total of 920 patients were randomly assigned to either the conventional continuation group (n = 461) or the drug-free interval group (n = 459). The median follow-up for both groups was 58 months. Patients received 50 mg of oral sunitinib (Sutent) a day or 800 mg of oral pazopanib (Votrient) a day.

The ITT population included 919 patients and the per-protocol group included 871. Overall, 73% of patients were male and 96% were White.

Treatment discontinuation was necessary in 47% of patients before beginning randomization at week 24. Reasons for discontinuation included radiological disease progression (58% vs 54%), and toxicity (31% vs 32%) in the continuation and drug-free groups, respectively.

Patients received a median of 4 treatment cycles; before week 24, the median number of treatment cycles was identical between the 2 groups. A dose reduction was necessary in 45% of patients in the conventional group vs 46% in the drug-free interval group.

A total of 54% of patients in the drug-free interval group continued the trial past 24 weeks, of whom 85% started their first treatment break via protocol at week 24. Among the remaining patients (n = 38), 15 did not take a break and continued treatment at week 24 due to error, then withdrew from treatment or had radiological progression.

Additionally, 12 patients took their first break at week 36, 6 patients at week 48, 2 patients at week 60, and 3 at other time points. In the conventional continuation group, 52% continued treatment after week 24.

The median number of breaks was 1and the maximum number of breaks was 9. The median length of all treatment breaks was 87 days. Three percent of patients in the drug-free interval group withdrew to receive continuous treatment.

A total of 74% of patients in the per-protocol group died.

Investigators also reported a hazard ratio of 0.75 (95% CI, 0.66-0.86; P <.0001) for time to strategy failure, 0.77 (95% CI, 0.67-0.89; P = .00037) for summative progression-free interval, 0.75 (95% CI, 0.65-0.86; P <.0001) for time to treatment failure, and 1.37 (95% CI, 1.19-1.57; P <.0001) for progression-free survival.

The most common grade 3 or higher adverse effects (AEs) included hypertension (26% vs 29%), hepatotoxicity (11% vs 11%), and fatigue (8% vs 15%) in the conventional continuation strategy group vs the drug-free interval group.

The most common serious AEs included gastrointestinal disorders (34% vs 16%); infections and infestations (8% vs 13%); and respiratory, thoracic, and mediastinal disorders (8% vs 9%) in the conventional continuation group vs the drug-free interval group, respectively.

Death due to serious AEs occurred in 12 patients and included 3 patients from the conventional continuation group and 9 from the drug-free group. Causes of death included 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).

A post-hoc analysis looked at a clinical response in patients who had not progressed at 24 weeks; investigators noted that the depth of response was similar between the conventional continuation and drug-free interval groups.

Initial treatment response was observed in 245 patients in the conventional continuation group with less than 1% having a complete response (CR), 26% having a partial response (PR), and 74% having stable disease. Among 250 patients in the drug-free interval group who responded to initial treatment, the CR rate was 1%, PR rate was 23%, and stable disease rate was 76%.

Reference

Brown JE, Royle KL, 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):123-227. doi:10.1016/S1470-2045(22)00793-8