A phase I clinical trial of binimetinib in combination with FOLFOX in patients with advanced metastatic colorectal cancer who failed prior standard therapy

Abstract

BackgroundThis was a first in-human, open-label, dose-escalation phase I study conducted to evaluate the maximum tolerated dose (MTD), safety, and efficacy of the combination of oral binimetinib and FOLFOX.Materials and MethodsPatients with metastatic colorectal cancer (mCRC) who progressed on prior standard therapies received twice daily binimetinib continuously or intermittently with FOLFOX. Dose-limiting toxicities (DLTs) were assessed in the first 2 cycles of study treatment. Pharmacokinetic (PK) analysis of 5-FU and oxaliplatin was performed at the MTD in an expanded 6 patient cohort.ResultsTwenty-six patients were enrolled and assessed for safety. In the dose-escalation phase, no DLTs were noted in all binimetinib dosing schedules and the MTD of binimetinib in with FOLFOX was 45 mg orally twice daily. There were no significant differences in the PKs of 5-FU or oxaliplatin with or without binimetinib. Continuous dosing of binimetinib produced SD at 2 months in 9 of 13 evaluable patients and a median PFS of 3.5 months. Nine of 10 patients had PD at 2 months on the intermittent arm.ConclusionsOral binimetinib and FOLFOX has a manageable toxicity profile and showed some evidence of antitumor activity in heavily pretreated mCRC patients.

BRAF and MEK Inhibitors: Use and Resistance in BRAF-Mutated Cancers

“…The trial noted dose-limiting adverse events of dermatitis acneiform and ocular toxicity, including chorioretinopathy [53]. Further phase I and II trials have evaluated binimetinib with a variety of targeted and chemotherapy agents; for example, a 2017 study demonstrated the safety of combined binimetinib and FOLFOX in 26 patients with colorectal cancer who previously progressed on standard therapies [54]. Currently, the COLUMBUS (encorafenib in combination with binimetinib in BRAF -mutant melanoma) and BEACON CRC (encorafenib, binimetinib and cetuximab in BRAF -mutant colorectal cancer) are major Phase III trials in progress to evaluate the role of binimetinib in advanced cancers [51].…”

“…The general mechanism is the feedback activation of the MAPK/ERK pathway through EGFR. Studies using a BRAF inhibitor in combination with an antibody or small-molecule inhibitor targeting this growth factor receptor have shown optimal synergism compared to the BRAF inhibitor alone in CRC patients [54]. It is also important to emphasize that CRC patients generally have higher expression levels of EGFR than melanoma patients lending some reasoning for the difference in response to BRAF inhibitors.…”

Translational research of combined anticancer therapies targeting the MAPK pathway

“…(36) Thus, the data suggest that the differences between encorafenib and other BRAF inhibitors in terms of target binding may underlie the observed differences clinically, including efficacy in BRAF V600E-mutated CRC, which in terms of the ability to modulate the MAPK-pathway is inherently less sensitive to BRAF inhibition than melanoma. (40,41) The randomized portion of the BEACON CRC study is ongoing, and if results approximate those from the SLI, the combination of binimetinib, encorafenib, and cetuximab may become a new standard of care for patients with BRAF V600E-mutated CRC. To maximize the potential for benefit to patients, results warrant additional investigation of this regimen in the first-line and potentially in the adjuvant settings.…”

“…(19,(22)(23)(24) Unlike in other tumor histologies with BRAF V600 mutations such as melanoma and nonsmall cell lung cancer, where BRAF inhibition is clinically highly active(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36), BRAF inhibition in BRAF V600E-mutant mCRC produced only marginal clinical activity (35,(37)(38)(39). In vitro studies later demonstrated that in BRAF V600E-mutant colorectal cancer (CRC) cells, BRAF inhibition results in rapid feedback activation of epidermal growth factor receptor (EGFR), permitting sustained MAPK activation and continued cell proliferation; however, combined inhibition of BRAF and EGFR resulted in synergistic inhibition of tumor growth in BRAF V600E-mutant CRC xenograft models (40,41). Subsequent clinical studies of EGFRtargeted monoclonal antibodies combined with BRAF inhibition using the BRAF inhibitors vemurafenib or dabrafenib confirmed that addition of an EGFR-targeted therapy can improve the activity of BRAF-inhibition in BRAF V600E-mutant CRC (42)(43)(44).…”

“…In the randomized trial the favorable disease control rate was 67% for the triplet treatment with vemurafenib, irinotecan and cetuximab versus 22% in the doublet treatment of irinotecan and cetuximab. (30,39) Co-administration of the MEKi binimetinib and chemotherapy, such as 5-fluorpyrimidine/oxaliplatin (FOLFOX), revealed stable disease in 10 patients and manageable toxicity in 23 evaluable patients with BRAFm mCRC in a phase I dose-escalation study (40). Another combination investigated in a phase II trial is dabrafenib and trametinib.…”