A phase I study of binimetinib (MEK162) in Japanese patients with advanced solid tumors

Watanabe, Koichiro; Otsu, Satoshi; Hirashima, Yoshinori; Morinaga, Ryotaro; Nishikawa, Kazuo; Hisamatsu, Yasushi; Shimokata, Tomoya; Inada‐Inoue, Megumi; Shibata, Takashi; Takeuchi, Hiromi; Watanabe, Takahiro; Tokushige, Kota; Maacke, Heiko; Shiaro, K.; Ando, Yumiko

doi:10.1007/s00280-016-3019-5

Cited by 26 publications

(19 citation statements)

References 19 publications

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“…Due to its unresponsiveness to cytotoxic chemotherapy, treatment of unresectable LGSOC has been a challenge. Alternative treatment modalities including hormonal therapy and anti-angiogenic agent have been studied ( Oswald and Gourley, 2015 ; Gershenson et al, 2009 ; Schmeler et al, 2008 ; Watanabe et al, 2016 ), however, treatment response to hormonal therapy is suboptimal (9%) and bevacizumab studies showed conflicting findings in terms of response-rate even though it did appear that anti-angiogenic treatment prolonged the duration of response ( Oswald and Gourley, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Binimetinib (MEK162) in recurrent low-grade serous ovarian cancer resistant to chemotherapy and hormonal treatment

Han

Bellone

Zammataro

et al. 2018

Gynecologic Oncology Reports

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BackgroundManagement of advanced/recurrent low-grade serous ovarian carcinoma (LGOSC) is often challenging. Effective treatment options remain limited for hormone and chemotherapy-resistant LGSOC.CASE: A 65-year-old woman with recurrent widespread LGSOC harboring the KRAS-G12 V hotspot mutation experienced a dramatic clinical response to Binimetinib (MEK162), a mitogen-activated protein kinase (MEK) inhibitor, after failing multiple chemotherapy and hormonal treatments. An 81% reduction of target lesions by RECIST 1.1 over 31 months of response duration was confirmed with serial CT scans. Episodes of drug-related toxicity (pneumonitis) easily resolved without sequelae with the use of oral steroids.ConclusionBinimetinib may present a new treatment option for hormone- and chemotherapy-resistant LGSOC harboring KRAS mutations.

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Section: Discussionmentioning

confidence: 99%

Binimetinib (MEK162) in recurrent low-grade serous ovarian cancer resistant to chemotherapy and hormonal treatment

Han

Bellone

Zammataro

et al. 2018

Gynecologic Oncology Reports

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“…However, because of ocular toxicities and the need for dose modifications among the initial patients treated in the expansion phase, the starting dose was reduced to 45 mg BID for the remainder of the expansion phase and is the recommended phase 2 dose for subsequent single-agent clinical studies. The 45 mg BID dose was also identified as the MTD/recommended phase 2 dose in a recent phase I study of binimetinib monotherapy conducted in Japan in patients with advanced solid tumours (Watanabe et al , 2016). Consistent with the known class effects of MEK inhibition (Adjei et al , 2008; Rosen et al , 2011; Infante et al , 2012), common AEs included rash, diarrhoea, nausea, peripheral oedema, vomiting, fatigue, and ocular events.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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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.

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“…Following standard dose-escalation rules, no DLTs were encountered in all binimetinib dosing arms and the MTD of binimetinib in combination with FOLFOX every 2 weeks was 45 mg orally twice daily in either continuous or intermittent dosing schedules. Common DLTs that have been observed in early binimetinib trials include CPK elevation, retinopathy, and skin toxicity, which appear to represent class effects of MEK inhibitors [ 15 – 17 , 19 – 22 ]. Through baseline and every 2-cycle ophthalmologic examinations, we encountered only 1 case of a non-DLT of grade 3 retinopathy observed in a 59-year-old Caucasian male following 8 cycles of study treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the median PFS was 3.5 months (95% CI 1.9- NR) in the MTD cohort of continuous binimetinib + FOLFOX. In phase I trials, single-agent binimetinib produced SD rates as high as 67% in patients with advanced solid tumors [ 15 – 17 ]. The activity noted in RAS and BRAF wild-type patients in our study could be related to possibly enrolling MEK sensitive RAS-WT and BRAF-WT tumors.…”

Section: Discussionmentioning

confidence: 99%

“…In the first dose-escalation phase I study, the maximum tolerated dose (MTD) of single-agent oral binimetinib was 60 mg twice daily in patients with pretreated advanced solid tumors [ 15 ]. Despite a manageable safety profile in other phase I trials in advanced solid tumors, oral binimetinib at 45 mg twice daily became the recommended phase II dose (RP2D) due to recurrent dose-limiting toxicities (DLTs) of retinal events [ 16 , 17 ]. In a phase II trial of binimetinib 45 mg twice daily, grade 1–2 retinal adverse events (AEs) were seen in 18% of patients with NRAS - or BRAF -mutated advanced melanomas [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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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.

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A phase I study of binimetinib (MEK162) in Japanese patients with advanced solid tumors

Abstract: Binimetinib demonstrated efficacy and acceptable safety in Japanese patients with solid tumors, supporting the 45 mg BID dose of binimetinib as the RP2D.

Cited by 26 publications

References 19 publications

Binimetinib (MEK162) in recurrent low-grade serous ovarian cancer resistant to chemotherapy and hormonal treatment

Binimetinib (MEK162) in recurrent low-grade serous ovarian cancer resistant to chemotherapy and hormonal treatment

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

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

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