As a result of the little benefit obtained from standard treatments and the poor prognosis of these patients, the BRAF-V600E mutant MSS aCRC represents an unmet medical need requiring clinical research.
The combination of encorafenib, cetuximab and binimetinib as second- or third-line treatment for mCRC resulted in significantly better outcomes than standard therapy in a phase 3 clinical trial, which also revealed treatment safety and tolerability to be acceptable. Compared to the control group (cetuximab and irinotecan or cetuximab and FOLFIRI), the triplet therapy cohort showed higher median overall survival (9.3 vs. 5.9 months) and response rates (26.8% vs. 1.8%). Grade 3 adverse events occurred in 65.8% and 64.2% of patients for triple-therapy and control groups, respectively.
Based on these results, the investigators speculated that the combination of encorafenib, cetuximab and binimetinib could be used as induction therapy to improve treatment outcomes in BRAF-V600E-mutated MSS aCRC locally advanced initially unresectable but potentially resectable; initially resectable or initially unresectable but potentially resectable oligometastatic disease; and in patients with stage II-IV who have relapsed after chemotherapy (neo and/or adjuvant) or surgery, if the shorter time after resection or from treatment end to relapse is longer than 6 months.
1. Male or female participants age ≥18 years at the time of informed consent. 2. Capable of giving signed informed consent/assent. 3. Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
Locally advanced colorectal cancer with initially unresectable but potentially resectable disease according to the local Multidisciplinary Tumour Board (MTB).
ANC ≥1.5 × 109/L
Platelets ≥100 × 109/L
1. Any medical or psychiatric condition including recent (within the past year) or current suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study.
History of acute myocardial infarction, acute coronary syndromes (including unstable angina, coronary artery bypass graft, coronary angioplasty or stenting) ≤6 months prior to the start of study treatment.
Congestive heart failure requiring treatment (New York Heart Association Grade ≥2).
History or presence of clinically significant cardiac arrhythmias (including uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia).
Single group
EBC
DrugPatients will receive the following per 28-day cycle: * Encorafenib: 300 mg (4 × 75 mg oral capsule) daily (QD) * Binimetinib: 45 mg (3 × 15 mg oral tablet) twice daily (BID) * Cetuximab: 500 mg/m2 every 2 weeks as per standard institutional practice.
Efficacy of cetuximab in combination with encorafenib plus binimetinib as induction therapy for the treatment of BRAF-V600E mutated MSS aCRC to perform radical treatment of the primary and/or metastases
Radical treatment rate, defined as the number of patients radically treated for their primary tumor and/or distant metastases by surgery and/or by any other radical therapeutic procedure with curative intent (i.e. radiofrequency, cryotherapy, laserhyperthermia, stereotactic body radiotherapy or chemoembolization).
Overall response rate (ORR)
Number of patients achieving complete response (CR) or partial response (PR) as best response according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, divided by the total number of patients.
Tumor regression grade (TRG), after any surgical treatment of the primary tumor and/or distant metastases
TRG1, no residual tumor; TRG2, microscopic residual tumor; TRG3, moderate response; TRG4, minor response; and TRG5, no response
Progression-free-survival (PFS)
Time in months from first dose of study treatment to disease progression or death (due to any cause)
Overall survival (OS)
Time in months from first dose of study treatment to death due to any cause
To determine the presence/expression level/levels of serum and tumour tissue biomarkers associated with cell and tumour growth and/or involved in the mechanisms of action of EBC
To be confirmed
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Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD)
Lead sponsor
Merck, S.L., Spain
Collaborator
Pierre Fabre Ibérica, S.A.
Collaborator
