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A phase I study of binimetinib (MEK162) in Japanese patients with advanced solid tumors
K Watanabe1,2, S Otsu3, Y Hirashima3
1Department of Medical Oncology, Kouseiren Tsurumi Hospital, 4333 Ooaza Tsurumi, Beppu, Oita, 879-5593, Japan. kwata@me.com.
Purpose:
Binimetinib is a potent, selective MEK1/2 inhibitor with demonstrated efficacy against BRAF- and RAS-mutant tumors. Retinal adverse events associated with MEK inhibitors have been reported in some cases. The aim of this study was to assess single-agent binimetinib, with detailed ophthalmologic monitoring, in Japanese patients with advanced solid tumors.
Methods:
This was an open-label phase I dose-escalation and dose-expansion study (NCT01469130). Adult patients with histologically confirmed, evaluable, advanced solid tumors were enrolled and treated with binimetinib 30 or 45 mg twice daily (BID). The primary objective was to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of single-agent binimetinib in Japanese patients.
Results:
Twenty-one patients were enrolled; 3 and 8 patients had documented BRAF and KRAS mutations, respectively. Two of 6 patients (33 %) receiving binimetinib 45 mg BID in dose-escalation experienced recurrent grade 2 retinal adverse events (AEs) which were reversible, and this dose was declared the MTD and RP2D. All patients experienced ≥1 AE suspected to be treatment related; the most common (>50 %) were blood creatine phosphokinase increase (76 %), retinal detachment and aspartate aminotransferase increase (62 % each), and diarrhea (52 %). There were no complete or partial responses; 14 patients (67 %) had stable disease, which lasted >180 days in 5 patients. Expression of phospho-ERK decreased in the skin following binimetinib treatment at both dose levels, indicating target inhibition.
Conclusions:
Binimetinib demonstrated efficacy and acceptable safety in Japanese patients with solid tumors, supporting the 45 mg BID dose of binimetinib as the RP2D.
Insights
Binimetinib showed efficacy in Japanese patients with advanced solid tumors. The recommended dose was 45 mg twice daily, with acceptable safety and manageable retinal adverse events.
Area of Science:
- Oncology
- Pharmacology
- Ophthalmology
Background:
- Binimetinib is a MEK1/2 inhibitor effective against BRAF/RAS-mutant tumors.
- Retinal adverse events are a known concern with MEK inhibitors.
Purpose of the Study:
- To evaluate single-agent binimetinib in Japanese patients with advanced solid tumors.
- To determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) with ophthalmologic monitoring.
Main Methods:
- An open-label, phase I dose-escalation and expansion study (NCT01469130).
- Adult patients received binimetinib 30 or 45 mg twice daily (BID).
Main Results:
- The MTD and RP2D were established as 45 mg BID.
- Retinal adverse events occurred in 33% of patients at 45 mg BID but were reversible.
- Most common treatment-related adverse events included elevated creatine phosphokinase, retinal detachment, elevated AST, and diarrhea.
Conclusions:
- Binimetinib demonstrated efficacy and acceptable safety in Japanese patients.
- The 45 mg BID dose is supported as the RP2D for further studies.
