Phase II trial of encorafenib and binimetinib (E+B) in patients (pts) with BRAF-altered advanced solid tumors: Results of E+B cohort in the BELIEVE trial (NCCH1901)

BackgroundBRAF gene alterations, representing BRAF V600E mutation, are prevalent in melanoma, thyroid cancer, non-small cell lung cancer, and other malignancies to a lesser degree. The BELIEVE trial is a single-arm, open-label Japanese multi-institutional study equivalent to the NCI-MATCH trial, and we report the results of the cohort that assessed the efficacy of E+B in BRAF-altered solid tumors refractory to standard of care.MethodsPts with solid tumors recommended E+B in molecular tumor board based on comprehensive genomic profiling were eligible. Participants received Encorafenib 450 mg once daily and Binimetinib 45 mg twice daily continuously until disease progression or intolerable toxicity occurred. The primary endpoint was the investigator-assessed objective response rate (ORR) according to the RECIST v1.1. The clinical hypothesis was that patients would respond to the genotype-matched drugs. Bayesian analysis using a prior distribution with an expected ORR of 30% [Beta (0.6, 1.4)] was carried out.ResultsForty-nine pts were extracted as a full analysis set with a median age of 65. The primary site of 23 pts was thyroid, central nervous system in 6, and biliary tract in 4. BRAF V600E mutation was detected in 43 pts, other BRAF mutation in 5, and BRAF fusion in 1, respectively. The confirmed ORR was 32.7% (95% CI, 20.0-47.5), which showed expected efficacy. Median PFS and PFS rate at 6 months were 4.8 months (95% CI, 2.2-6.9) and 37.5%. Data regarding overall survival was premature, with a median of 11.7 months at the time of analysis. Furthermore, the median PFS was 2.1 months (95% CI, 0.6 to 10.9 months) for the eight patients without target lesions in the exploratory analysis. Frequently observed adverse events (AEs) in a safety analysis set (58 pts) were ALT increased (8.6%), nausea (6.9%), anemia (6.9%), creatinine increased (6.9%), and CPK increased (6.9%). Grade ≥3 AEs was observed in 34.5%.ConclusionsThis study showed the efficacy of matched drubs with an ORR of 32.7%, and other clinical outcomes also encouraged the efficacy of E+B in BRAF-altered solid tumors.Clinical trial identificationjRCTs031190104.Legal entity responsible for the studyThe authors.FundingJapan Agency of Medical Research and Development (22ck0106622h0003), Japan Grants-in-Aid for Scientific Research (19EA1008, 202307020A).DisclosureY. Honma: Financial Interests, Personal, Advisory Board: Janssen, Rakuten Medical Japan; Financial Interests, Personal and Institutional, Coordinating PI: Taiho Pharmaceutical, Chugai Pharma, MSD, Janssen, Merck Biopharma; Financial Interests, Institutional, Coordinating PI: GSK, Adlai Nortye Biopharma, Maruho, Genmab, Astellas pharma, AstraZeneca; Financial Interests, Institutional, Funding: Rakuten Medical Japan. I. Kinoshita: Financial Interests, Personal, Invited Speaker, Invited Speaker: MSD Pharmaceutical; Financial Interests, Personal, Invited Speaker, Invited Speaker, chairperson of lecture: Bayer; Financial Interests, Personal, Invited Speaker, Invited Speaker: Takeda Pharmaceutical, Konica Minolta Realm; Financial Interests, Personal, Other, chairperson of lecture: Chugai Pharma, Novartis Pharma, Guardant Health Japan; Financial Interests, Personal and Institutional, Local PI, local PI: Daiichi Sankyo; Financial Interests, Personal and Institutional, Research Grant, research grant: Konica Minolta Realm; Financial Interests, Personal and Institutional, Local PI, Local PI: Eisai. C. Ishioka: Financial Interests, Personal, Invited Speaker: m3, Ono, Nihon Kayaku, Merck, Lilly Japan, Incyte, Daiichi Sankyo, Chugai, Bayer, Bristol Myers Squibb, Novartis, Taiho, Takeda, AstraZeneca, MSD, Kyowa-Kirin; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Royalties: Riken Genesis, Hitachi; Financial Interests, Institutional, Research Grant: Taiho, Asahi-Kasei, Chugai, Nihon Kayaku, Kyowa-Kirin, Daiichi Sankyo; Financial Interests, Institutional, Funding: Hitachi. M. Muto: Financial Interests, Personal, Invited Speaker: Chugai, MSD, Ono Pharma, Meiji Seika Pharma, Novartis, Taiho; Non-Financial Interests, Advisory Role: KBBM, PRiME-R. All other authors have declared no conflicts of interest.