OBJECTIVES: Precision oncology has given rise to tumour-agnostic treatments, frequently evaluated in “basket” trials. Here, patients are enrolled based on the underlying gene mutation, irrespective of tumour type. However, authorities could request conducting tumour-specific randomized controlled trials (RCTs) in this setting. The feasibility of conducting tumour-specific RCTs was assessed based on disease features and mutation prevalence.

METHODS: The decision model considered 12 tumours observed in the clinical trial program for entrectinib in NTRK fusion-positive tumors. Required sample size was estimated for each tumour assuming progression-free survival (PFS) reported for relevant standard-of-care therapies, and a clinically-meaningful difference of 30% reduction in PFS hazard (1:1 allocation; alpha=0.05; beta=0.2). The number needed to test to reach the target sample size was based on the NTRK-positivity rate at the tumour level. Recruitment rate was a function of the recruitment rate in the overall clinical trial programs of NTRK mutations (STARTRK-2 and NAVIGATE; 2pts/month) and the overall NTRK positivity (0.32%); impact of varying both parameters was tested in sensitivity analysis (SA). The time required to recruit patients into each tumour-specific RCT was estimated based on the tumour-specific recruitment rate and the estimated sample size. The minimum required study duration for the conduct of the trial program was estimated as the maximum study duration across all tumour-specific RCTs.

RESULTS: Across all tumours, sample sizes ranged from 206-227 (trial program N=2,322). The number needed to test ranged from 64,375-70,938. Under base case assumptions, the minimum study duration for the conduct of the entire trial program was 2,696 months. In SAs this changed to 1,351 when assuming recruitment of 4pts/month, and 580 when assuming an overall NTRK positivity of 1.5%.

CONCLUSIONS: Conducting tumour-specific RCTs is infeasible for targeted therapies aimed at low prevalence mutations. Tumour-agnostic basket trials represent the best available evidence to evaluate these therapies.