Abstract 1986
Background
While BRAF mutations occur in 10-15% of metastatic colorectal cancer (mCRC), BRAF Non-V600E mutations was recently reported with ranging 2.2 - 5.2%. We have reported that BRAF Non-V600E could be a negative impact on survival outcome as well as anti-EGFR antibody treatment for pretreated mCRC patients (Shinozaki E, et al. Br J Cancer 2017). In addition, simultaneous inhibitions of MEK, BRAF and EGFR exhibited most potent anti-tumor activities in BRAF Non-V600E mutant cell lines and xenografted models (unpublished data).
Trial design
BIG BANG study is a multicenter phase II study to assess efficacy, safety and proof-of-concept of the triple combinations of binimetinib (BINI) + encorafenib (ENCO) + cetuximab (CETUX) in patients with BRAF Non-V600E mutated mCRC, identified by either tumor tissue-based analysis (primary analysis cohort) or circulating tumor DNA (ctDNA) analysis (liquid biopsy cohort). Key eligibility criteria includes ECOG PS ≤ 1; mCRC with BRAF Non-V600E mutant and RAS wild-type; refractory or intolerant to at least one fluoropyrimidine-based regimen (including irinotecan or oxaliplatin) and no prior history of anti-EGFR antibody and regorafenib. Enrolled patients receive BINI (45 mg, BID), ENCO (300 mg, QD), and CETUX (initially 400 mg/m2, and subsequently 250 mg/m2, QW), which are same recommended doses as the BEACON CRC trial (NCT02928224). In addition, the natural history data of patients with BRAF Non-V600E mutations who do not meet the eligibility criteria are collected as a historical control. The primary endpoint is the objective response rate (ORR) for primary analysis cohort. A sample size of the primary analysis cohort is calculated to be 21 on the hypothesis that the threshold ORR is 6% and expected ORR is 30%, with a significant level of 2.5% (one-sided) and power of 80%. Furthermore, paired tissue and blood samples will be obtained for pharmacodynamics analysis before study treatment, pre-dose of second cycle, and after disease progression. To our best knowledge, this is the first study targeting BRAF Non-V600E mutated mCRC.
Clinical trial identification
UMIN000031857 and 000031860.
Legal entity responsible for the study
Hideaki Bando.
Funding
The Japan Agency for Medical Research and Development.
Editorial Acknowledgement
Disclosure
H. Bando: Research funding: AstraZeneca, Sysmex, Falco biosystemes. T.E. Nakajima: Personal financial interests: Eli Lilly, Sanofi, Chugai, Sawai, Bayer, Bristol, Taiho, Merck, Ono, Takeda, Mochida, MSD; Institutional financial interests: Ono, Taiho, A2 Health Care, JCRO, Daiichi-Sankyo, Mediscience Planning. T. Nishina: Grants, honoraria: Ono, Merck Serono, Yakult, Taiho, Chugai. T. Esaki: Grant: Taiho, Eli Lilly, Eisai, Daiichi-Sankyo, DS Pharma, Merck Serono, Ono, Nihon Kayaku, Novartis, AstraZeneca, Boehringer, MSD, Astellas, Bayer, Pfizer, Yakult; Personal fees: Taiho, Bristol, Eli Lilly, Eisai, Daiichi-Sankyo, Merck Serono, Chugai, Ono, Takeda, Kyowa-Kirin, Nihon Kayaku. S. Nomura: Honoraria: Taiho. T. Yoshino: Grant: MSD, Sanofi, Sumitomo Dainippon Pharma, Chugai, GlaxoSmithKline, Nippon Boehringer Ingelheim; Personal fees: Sanofi, Chugai, Eli Lilly, Merck Serono. All other authors have declared no conflicts of interest.
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