Umbrella review of basket trials testing a drug in tumors with actionable genetic biomarkers

Abstract

Background The utilization of basket trials in oncology has gained popularity because of the drive for precision medicine and the increasing ease of genetically profiling tumors. However, it is unknown if this has translated into patient benefit, either through higher response rates because of precision treatment or because of increasing options for less-common tumor types that are less represented in oncology drug trials. We sought to characterize basket studies for oncology drugs targeting a genetic biomarker, determine the responses for various tumor types and genetic biomarkers, and test for correlation between the number of participants in each tumor basket and the incidence of the respective tumor. Methods We conducted a retrospective cross-sectional review of oncology basket trials on Embase or clinicaltrials.gov with published data. We included studies that reported on oncology drugs that target a genetic biomarker. We examined the response for basket trial participants, stratified by tumor type and genetic biomarker and the correlation between the number of participants in each tumor basket and the incidence of the respective tumor. Results The overall response rate for all 25 included trials was 23%. The response for each genetic biomarker ranged from 0 to 69%, and for half of the genetic biomarkers, the response rate ranged from 0 to 100%, depending on tumor type. There is low correlation between the number of participants in each tumor basket and the incidence of the respective tumor (66.41 + -0.20x, R2 = 0.003, p = 0.75). Conclusion While there has been an increase in the number of published basket trials and individuals included in these trials, the response rate is low, but varies widely, depending on tumor type and genetic biomarker.

Basket trials in oncology: a systematic review of practices and methods, comparative analysis of innovative methods, and an appraisal of a missed opportunity

“…( 11 ) and Haslam et al. ( 12 ), all phase Ib or phase II basket trials identified in this review were single-arm non-randomized open label studies, and 91% (133/146) of the trials had objective response rate as either a primary or secondary endpoint. Further information about the review of basket trials in practice and the risk of bias are presented in the Supplementary File 1 .…”

“…A more recent systematic review by Haslam et al. ( 12 ) focused on basket trials in oncology with published results in which they characterized the correlation between the size of a basket and the incidence of the respective tumor. Another recent review by Haslam et al.…”

“…A recent systematic review of basket trial master protocols identified a large increase in the number of basket trials in the past 14 years, from 1 basket trial in 2009 to 49 trials in 2019 ( 11 ). However, it remains a question whether increasing adoption of basket trials has translated into patient benefit, either through higher response rates because of precision treatment or because of increasing options for rare tumor types that are less represented in oncology drug development ( 12 ). There are also challenges on how to evaluate treatment efficacy in basket trials, arising from the disconnect between the implied homogeneity of responses (based on the expectation of a tumor-agnostic effect based on one common molecular alteration) and the heterogeneity observed between different tumor types included in basket trials.…”

Bayesian Hierarchical Models of Basket Trials in the Context of Economic Evaluation

“…However, despite similarities among the different cohorts, there is an expectation that the treatment effect might differ. 4 To facilitate the evaluation of these therapies, basket trial protocols have been used to assess the combination of several molecular markers and targeted therapies across multiple subgroups. 1,3 In this setting, a basket trial typically involves evaluating a single therapy targeting a group of patients who share a common clinical or genetic feature or biomarker, regardless of their histology type (Figure 1).…”

“…The nature of basket trials, in which eligible patients with a common biomarker are recruited independently of tumour type, suggests there may be heterogeneity within tumour histology. 4 One way to account for heterogeneity is to analyze each tumour type separately. However, sample sizes vary among cohorts, and studies for some cancer types -particularly rare ones -may suffer from poor recruitment and limited information on response rates.…”