K Watanabe1,2, S Otsu3, Y Hirashima3, R Morinaga3, K Nishikawa3, Y Hisamatsu3, T Shimokata4, M Inada-Inoue4, T Shibata4, H Takeuchi5, T Watanabe6, K Tokushige7, H Maacke8, K Shiaro3, Y Ando4. 1. Department of Medical Oncology, Kouseiren Tsurumi Hospital, 4333 Ooaza Tsurumi, Beppu, Oita, 879-5593, Japan. kwata@me.com. 2. Department of Medical Oncology and Hematology, Oita University Faculty of Medicine, Oita, Japan. kwata@me.com. 3. Department of Medical Oncology and Hematology, Oita University Faculty of Medicine, Oita, Japan. 4. Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Aichi, Japan. 5. Oncology Early Clinical Trial Management Department, Novartis Pharma KK, Tokyo, Japan. 6. Medical Science Liaison Group, Novartis Pharma KK, Tokyo, Japan. 7. Integrated Science and Operations Department, Novartis Pharma KK, Tokyo, Japan. 8. Translational Clinical Oncology, Novartis Pharma AG, Basel, Switzerland.
Abstract
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.
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.
Authors: 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 Journal: Br J Cancer Date: 2017-02-02 Impact factor: 7.640
Authors: Kevin Blas; Thomas G Wilson; Nathan Tonlaar; Sandra Galoforo; Alaa Hana; Brian Marples; George D Wilson Journal: Clin Transl Radiat Oncol Date: 2018-04-27
Authors: May Cho; Jun Gong; Paul Frankel; Timothy W Synold; Dean Lim; Vincent Chung; Joseph Chao; Daneng Li; Yuan Chen; Stephen Sentovich; Kurt Melstrom; Gagandeep Singh; Eloise Luevanos; Marwan Fakih Journal: Oncotarget Date: 2017-07-18