BRAF V600E mutations are present in 5-10% of metastatic colorectal cancer (mCRC) patients, associated with aggressive biology and limited response to standard chemotherapy, especially in second line and beyond. BRAF V600E mutant CRCs have different patterns of gene expression from the BRAF wild-type, and preclinical evidence suggests that microtubule inhibitors have a potential antitumor effect on xenograft models of BRAF V600E mutant CRC; among them, eribulin has greater growth inhibitory activity than either vinblastine or paclitaxel in vitro. In addition, we have experienced a hint of activity for BRAF V600E mutant CRC patients with tumor shrinkage following eribulin treatment (Masuishi T, et al. Ann Oncol, 2018).
BRAVERY study is a multicenter phase II study to evaluate the efficacy and safety of eribulin in patients with BRAF V600E mutant mCRC detected in either tumor tissue (primary analysis cohort) or circulating tumor DNA (ctDNA) assay (liquid biopsy cohort). Key eligibility criteria are refractory or intolerant to at least one regimen (including irinotecan or oxaliplatin) containing fluoropyrimidine, an age of 20 years or older, and ECOG performance status of 0–1. Eribulin is administered intravenously at a dose of 1.4 mg/m2 on Days 1 and 8, repeated every 21 days. Primary endpoint is confirmed objective response rate (ORR) by investigator’s assessment. A sample size of the primary analysis cohort is calculated 27 using two-stage design with ORR of 25% deemed promising and 5% unacceptable (one-sided α, 0.05; β, 0.1). Secondary endpoints include progression-free survival, time to treatment failure, disease control rate, overall survival and adverse events. Furthermore, pretreated tissue and serial blood samples are collected for biomarker analysis; especially focused on gene expression associated with BRAF mutant-like CRC as a predictive marker, BRAF mutant allele frequency in ctDNA as early detection of efficacy, and acquired gene alteration as resistant mechanism to eribulin. At the end of April 2018, four patients have been enrolled in primary analysis cohort since March 2018. Clinical trial information: UMIN000031221 and 000031552.
Clinical trial identification
UMIN000031221 and 000031552. 26/March/2018.
Legal entity responsible for the study
Japan Agency for Medical Research and Development.
T. Esaki: Grant and personal fees: Eisai. All other authors have declared no conflicts of interest.