645P - A phase Ib dose escalation study of binimetinib plus mFOLFIRI in patients with metastatic RAS mutated colorectal cancer

Background

MEK inhibition (MEKi) may act synergistically when combined with cytotoxics in RAS mutated (mt) metastatic colorectal tumours (mCRC). We investigated the safety and clinical activity of MEKi, binimetinib, and mFOLFIRI in patients (pts) with RAS mt mCRC.

Methods

Eligibility criteria: Pts >18 years with RAS mt mCRC, ECOG 0-1, acceptable organ function, measurable disease, and progression or ineligibility to oxaliplatin. Pts received binimetinib plus mFOLFIRI, in a dose-escalated standard 3+3 design, to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). A 6-day lead-in period with binimetinib alone was required prior to combination therapy. Two levels of binimetinib were evaluated - 30mg BID and 45mg BID - and given on days 1-12/14-day cycle po with mFOLFIRI every 14 days iv. An additional 12 patients enrolled in the dose expansion phase to assess preliminary efficacy. The study completed accrual and herein we report the updated results.

Results

13 pts enrolled in the dose escalation phase (7 pts on the first binimetinib dose level and 6 on the second) and 12 pts in the expansion phase. Median age was 49 yrs (35-71), and 13 were male. All pts in expansion and 9 in escalation, had received irinotecan prior. All pts in the expansion cohort had irinotecan refractory disease. The MTD of binimetinib was 45mg BID. The most common grade 1-2 adverse effects (AEs) (%) were diarrhoea (64), fatigue (64), nausea (48), vomiting (44), rash (24). Grade 3-4 AEs included fatigue (12), rash (4), heart failure (4), and pneumonitis (4). 1 pt with pre-existing heart disease had a DLT of decreased cardiac ejection fraction on dose level 1. 17 pts discontinued therapy due to progression, 5 due to AEs and 3 for other reasons. The mean number of FOLFIRI and MEK cycles received was 6.7 (0-29) and 7.5 (1-30), respectively. Of the 25 pts, 24 were evaluable for response. Best response included 1 PR and 12 SD (all had received prior irinotecan and 10 had progressed on it). 4 pts remained on study for >6 months (7-15). The median PFS was 3.35 months (95% CI 2-8.61) and the median OS was 8.41 months (95% CI 4.7-12.8).

Conclusions

MEKi plus mFOLFIRI has acceptable toxicity and showed activity even in patients with prior progression on irinotecan.

Clinical trial identification

NCT02613650.

Editorial acknowledgement

Legal entity responsible for the study

Huntsman Cancer Institute.

Funding

Huntsman Cancer Institute, Pfizer.

Disclosure

V. Florou: Financial Interests, Personal, Advisory Role: Deciphera, Incyte. H.P. Soares: Financial Interests, Personal, Advisory Board: TerSera, Ipsen, AstraZeneca, Novartis, ITM. I. Garrido-Laguna: Financial Interests, Personal, Advisory Role: SOTIO, Kanaph, Jazz, OncXerna. All other authors have declared no conflicts of interest.