BIG BANG study (EPOC1703): multicentre, proof-of-concept, phase II study evaluating the efficacy and safety of combination therapy with binimetinib, encorafenib and cetuximab in patients with BRAF non-V600E mutated metastatic colorectal cancer.
BACKGROUND
While the BRAF V600E mutation occurs in 5%-15% of metastatic colorectal cancer (mCRC), BRAF non-V600E mutations were recently reported to range from 1.6% to 5.1%. We have previously reported that BRAF non-V600E mutations could have a negative impact on efficacy outcomes as well as BRAF V600E mutation for antiepidermal growth factor receptor (EGFR) antibody treatment for pretreated patients with mCRC. Recently, simultaneous inhibitions of mitogen-activated protein kinase kinase (MEK), BRAF and EGFR exhibited relevant antitumour activities in patients with BRAF V600E mutant and also in BRAF non-V600E mutant but only in the preclinical model.


TRIAL DESIGN
The BIG BANG (study is a multicentre, phase II study to assess the efficacy, safety and proof of concept of the combinations of binimetinib+encorafenib+cetuximab in patients with BRAF non-V600E mutated mCRC, identified by either tumour tissue (tumour tissue group) or blood samples (liquid biopsy group). Key eligibility criteria include Eastern Cooperative Oncology Group Performance Status of ≤1, mCRC with BRAF non-V600E mutant and RAS wild type, refractory or intolerant to at least one fluoropyrimidine-based regimen and no prior history of regorafenib, and no prior history of anti-EGFR antibody treatment (primary analysis cohort and liquid biopsy cohort) or refractory to prior anti-EGFR antibody treatment in patients with class 3 BRAF mutations (anti-EGFR antibody refractory class three cohort). Enrolled patients receive binimetinib (45 mg, two times per day), encorafenib (300 mg, once a day) and cetuximab (initially 400 mg/m2 and subsequently 250 mg/m2, once per week). The primary endpoint is the confirmed objective response rate in the primary analysis cohort.


TRIAL REGISTRATION NUMBERS
UMIN000031857 and 000031860.
['Kotani|Daisuke|D|', 'Bando|Hideaki|H|', 'Taniguchi|Hiroya|H|', 'Masuishi|Toshiki|T|', 'Komatsu|Yoshito|Y|', 'Yamaguchi|Kensei|K|', 'Nakajima|Takako|T|', 'Satoh|Taroh|T|', 'Nishina|Tomohiro|T|', 'Esaki|Taito|T|', 'Nomura|Shogo|S|', 'Takahashi|Koji|K|', 'Iida|Shinobu|S|', 'Matsuda|Seiko|S|', 'Motonaga|Shinya|S|', 'Fuse|Nozomu|N|', 'Sato|Akihiro|A|', 'Fujii|Satoshi|S|', 'Ohtsu|Atsushi|A|', 'Ebi|Hiromichi|H|', 'Yoshino|Takayuki|T|']
D000328:Adult D000971:Antineoplastic Combined Chemotherapy Protocols D001562:Benzimidazoles D002219:Carbamates D000068818:Cetuximab D015179:Colorectal Neoplasms D005260:Female D015658:HIV Infections D006801:Humans D008297:Male D048493:Proto-Oncogene Proteins B-raf D013318:Stroke Volume D013449:Sulfonamides D016277:Ventricular Function, Left D055815:Young Adult
binimetinib encorafenib cetuximab BRAF non-V600E metastatic colorectal cancer