A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor

Johanna C Bendell, Milind Javle, Tanios S Bekaii-Saab, Richard S Finn, Zev A Wainberg, Daniel A Laheru, Colin D Weekes, Benjamin R Tan, Gazala N Khan, Mark M Zalupski, Jeffrey R Infante, Suzanne Jones, Kyriakos P Papadopoulos, Anthony W Tolcher, Renae E Chavira, Janna L Christy-Bittel, Emma Barrett, Amita Patnaik, Johanna C Bendell, Milind Javle, Tanios S Bekaii-Saab, Richard S Finn, Zev A Wainberg, Daniel A Laheru, Colin D Weekes, Benjamin R Tan, Gazala N Khan, Mark M Zalupski, Jeffrey R Infante, Suzanne Jones, Kyriakos P Papadopoulos, Anthony W Tolcher, Renae E Chavira, Janna L Christy-Bittel, Emma Barrett, Amita Patnaik

Abstract

Background: Binimetinib (MEK162; ARRY-438162) is a potent and selective oral MEK 1/2 inhibitor. This phase 1 study determined the maximum tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and preliminary anti-tumour activity of binimetinib in patients with advanced solid tumours, with expansion cohorts of patients with biliary cancer or KRAS- or BRAF-mutant colorectal cancer.

Methods: Binimetinib was administered twice daily. Expansion cohorts were enroled after MTD determination following a 3+3 dose-escalation design. Pharmacokinetic properties were determined from plasma samples. Tumour samples were assessed for mutations in RAS, RAF, and other relevant genes. Pharmacodynamic properties were evaluated in serum and skin punch biopsy samples.

Results: Ninety-three patients received binimetinib (dose-escalation phase, 19; expansion, 74). The MTD was 60 mg twice daily, with dose-limiting adverse events (AEs) of dermatitis acneiform and chorioretinopathy. The dose for expansion patients was subsequently decreased to 45 mg twice daily because of the frequency of treatment-related ocular toxicity at the MTD. Common AEs across all dose levels included rash (81%), nausea (56%), vomiting (52%), diarrhoea (51%), peripheral oedema (46%), and fatigue (43%); most were grade 1/2. Dose-proportional increases in binimetinib exposure were observed and target inhibition was demonstrated in serum and skin punch biopsy samples. Three patients with biliary cancer had objective responses (one complete and two partial).

Conclusions: Binimetinib demonstrated a manageable safety profile, target inhibition, and dose-proportional exposure. The 45 mg twice daily dose was identified as the recommended phase 2 dose. The three objective responses in biliary cancer patients are encouraging and support further evaluation in this population.

Conflict of interest statement

JCB, MJ, TSB-S, DAL, CDW, BRT, GNK, MMZ, JRI, SJ, and KPP have nothing to disclose. RSF serves as a consultant for Bayer, Novartis, Pfizer Inc, and Bristol-Myers Squibb. ZAW serves as a consultant for Array BioPharma Inc. AWT has a leadership role in Symphogen; serves in a consulting or advisory role for Akebia Therapeutics, ArQule, Asana BioSciences, Astex Pharmaceuticals, Bayer Schering Pharma, Bind Therapeutics, Blend Therapeutics, Celator Pharmaceuticals, Dicerna Pharmaceuticals, Endocyte Inc., Genmab, Heron Therapeutics, Janssen Pharmaceuticals, Johnson & Johnson, Mersana Therapeutics, Inc., Merus Labs Inc., Nanobiotix, Pharmacyclics, Pierre Fabre Medicament, Proximagen, Ltd., Symphogen, Valent Technologies, Upsher-Smith Laboratories, Inc.; and receives funding for his research institution from AbbVie Inc., Aeglea Biotherapeutics, Agios Pharmaceuticals, ARMO BioSciences, ArQule, Asana BioSciences, Astex Pharmaceuticals, AVEO Pharmaceuticals, Inc., Corvus Pharmaceuticals, Cerulean Pharma Inc., Daiichi Sankyo, Dicerna Pharmaceuticals, Eisai Inc., Eli Lilly and Company, Endocyte Inc., Five Prime Therapeutics, F-star, Gilead Sciences Inc., GlaxoSmithKline, Jiangsu Hengrui Medicine Co., Pharmacyclics, Incyte Corp, Infinity Pharmaceuticals, MacroGenics, MedImmune, Merck & Co., Millennium Pharmaceuticals, Inc., Otsuka Pharmaceutical Co., Ltd., Onyx Pharmaceuticals Inc., Pfizer Inc, Plexxikon, Regeneron Pharmaceuticals, Inc, Rexahn Pharmaceuticals Inc., Sanofi, Santa Maria Biotherapeutics Inc., TaiRx, Inc. REC, JLC-B, and EB are current or former employees of Array BioPharma Inc. EB owns stock in Array BioPharma Inc. AP receives institutional research funding from Array BioPharma Inc.

Figures

Figure 1
Figure 1
Geometric mean (s.d.) plasma binimetinib concentrations on cycle 1 day 15, intensive pharmacokinetic sampling scheme (semi-log scale).
Figure 2
Figure 2
Geometric mean (s.d.) plasma binimetinib concentrations on cycle 1 day 15, limited pharmacokinetic sampling scheme (semi-log scale).

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