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

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

doi:10.1038/bjc.2017.10

Cited by 87 publications

(62 citation statements)

References 39 publications

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“…Common adverse events were mostly grade 1/2 rash, nausea, vomiting, diarrhea, peripheral edema, and fatigue [60]. Target inhibition was observed in serum and skin biopsy samples [60].…”

Section: Colorectal Cancer (Crc)mentioning

confidence: 99%

“…In BRAF inhibitor-pretreated patients, the ORR and mPFS were 22% and 1.9 months, respectively [59]. In trial NCT00959127, the maximum tolerated dose (MTD) was 60 mg twice daily with a subsequent decrease to 45 mg twice daily due to the frequency of treatment-related ocular toxicities [60]. Common adverse events were mostly grade 1/2 rash, nausea, vomiting, diarrhea, peripheral edema, and fatigue [60].…”

Section: Colorectal Cancer (Crc)mentioning

confidence: 99%

“…In trial NCT00959127, the maximum tolerated dose (MTD) was 60 mg twice daily with a subsequent decrease to 45 mg twice daily due to the frequency of treatment-related ocular toxicities [60]. Common adverse events were mostly grade 1/2 rash, nausea, vomiting, diarrhea, peripheral edema, and fatigue [60]. Target inhibition was observed in serum and skin biopsy samples [60].…”

Section: Colorectal Cancer (Crc)mentioning

confidence: 99%

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Current Insights into Combination Therapies with MAPK Inhibitors and Immune Checkpoint Blockade

Shin

Kim

Lim

et al. 2020

IJMS

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The recent development of high-throughput genomics has revolutionized personalized medicine by identifying key pathways and molecular targets controlling tumor progression and survival. Mitogen-activated protein kinase (MAPK) pathways are examples of such targets, and inhibitors against these pathways have shown promising clinical responses in patients with melanoma, non-small-cell lung cancer, colorectal cancer, pancreatic cancer, and thyroid cancer. Although MAPK pathway-targeted therapies have resulted in significant clinical responses in a large proportion of cancer patients, the rate of tumor recurrence is high due to the development of resistance. Conversely, immunotherapies have shown limited clinical responses, but have led to durable tumor regression in patients, and complete responses. Recent evidence indicates that MAPK-targeted therapies may synergize with immune cells, thus providing rationale for the development of combination therapies. Here, we review the current status of ongoing clinical trials investigating MAPK pathway inhibitors, such as BRAF and MAPK/ERK kinase (MEK) inhibitors, in combination with checkpoint inhibitors targeting programmed death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T cell associated antigen-4 (CTLA-4). A better understanding of an individual drug’s mechanism of action, patterns of acquired resistance, and the influence on immune cells will be critical for the development of novel combination therapies.

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“…Common adverse events were mostly grade 1/2 rash, nausea, vomiting, diarrhea, peripheral edema, and fatigue [60]. Target inhibition was observed in serum and skin biopsy samples [60].…”

Section: Colorectal Cancer (Crc)mentioning

confidence: 99%

Section: Colorectal Cancer (Crc)mentioning

confidence: 99%

Section: Colorectal Cancer (Crc)mentioning

confidence: 99%

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Current Insights into Combination Therapies with MAPK Inhibitors and Immune Checkpoint Blockade

Shin

Kim

Lim

et al. 2020

IJMS

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“…An update of this study including two expansion cohorts with biliary and colorectal cancer patients was published very recently [22]. Initially, this group investigated binimetinib at increasing oral doses from 30 to 80 mg twice daily in 19 predominantly male patients with different cancer types (colorectal, pancreatic, cholangiocarcinoma and others) harboring a heterogeneous mutation profile [21].…”

Section: • Phase I and Ii Datamentioning

confidence: 99%

“…Overall, out of 91 evaluable patients in this Phase I study, 3 patients with biliary cancer showed an objective response to binimetinib therapy (1 complete response [CR], 2 PRs). Notably, only one of the tumor samples was tested positive for an NRAS mutation, both other tumors responding to binimetinib treatment were wild-type for BRAF, NRAS and KRAS [22].…”

Section: • Phase I and Ii Datamentioning

confidence: 99%

A review of binimetinib for the treatment of mutant cutaneous melanoma

2017

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UTUREAlthough significant progress has been made in the treatment of unresectable or metastatic melanoma, at least half of all advanced melanoma patients eventually progress and pass away due to their disease. Especially patients with NRAS-mutated melanoma still face limited therapeutic options, with immunotherapy being the current treatment type of choice. Binimetinib is a selective inhibitor of MEK, a central kinase in the tumor-promoting MAPK pathway. The results of a recent Phase III trial rendered binimetinib the first targeted therapy agent to significantly improve progression-free survival in NRAS-mutated melanoma. This review will summarize the development and clinical data of binimetinib in melanoma in general and also explore the potential future role of this substance as single agent or combination therapy. Recently, the advent of targeted therapies and immunotherapy in metastatic melanoma has significantly changed the therapeutic landscape of this devastating disease with impressive tumor responses seen after kinase inhibitor treatment along with a small proportion of patients even achieving long-term survival of 10 years or more after immunotherapy with CTLA-4 antibodies [1][2][3][4][5][6][7]. Despite the availability and effectiveness of these novel treatments, the majority of patients with advanced melanoma still eventually face fatal progression of their disease, thus maintaining an unmet need for the development of further therapeutic agents.While immunotherapy with anti-CTLA-4 or anti-PD1-antibodies in melanoma utilizes a rather universal approach harnessing the patients' own immune system, in other words, T cells to attack and kill aberrant melanocytic tumor cells, targeted therapies, such as BRAF-or MEK-inhibitors aim to reverse the effects of distinct oncogenic mutations that confer proliferation and survival of melanoma cells. Increasing insight into the mutational landscape of cutaneous melanoma by large-scale genomic studies -published by The Cancer Genome Atlas Network and others -has led to the definition of four distinct mutational profiles based on genetic alterations impacting the MAPK pathway in cutaneous melanoma [8,9]. Being the most frequent, BRAF-mutations (predominantly the V600E hotspot mutation) occur in 40-50% of all melanomas, while NRAS-and NF1 mutations are less common, found in approximately 20 and 15% of melanomas, respectively [8][9][10][11]. Of note, BRAF and NRAS mutations are considered to be mutually exclusive despite the recent demonstration of their co-occurrence in melanoma cells, whereas loss-of-function mutations in the tumor suppressor gene NF1 can infrequently be detected both in BRAF-and NRAS-mutated melanomas, albeit being most common in BRAF Wt /NRAS Wt tumors [9,12]. Last, melanomas belonging to the so-called triple

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LC‐ESI‐MS/MS method validation for simultaneous quantification of FDA‐approved anticancer agents futibatinib and binimetinib in rat plasma: Insights from preclinical pharmacokinetics

Dadge,

Yadav,

Rathaur

et al. 2024

Biomedical Chromatography

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This study investigates the combination of FGFR inhibitor futibatinib (FTB) and MEK inhibitor binimetinib (BTB) for KRASmt NSCLC therapy. An analytical method was developed and validated for measuring FTB and BTB concentrations in rat plasma, adhering to USFDA guidelines. Using liquid–liquid extraction on 45‐μL plasma samples, a 6.5‐min run time was achieved. The linear calibration curve ranged from 2 to 100 ng/mL. Intra‐day and inter‐day accuracy ranged between 92.06% and 100.08%. Four blank injections post high‐concentration samples resolved significant carryover. Extraction recoveries averaged 92.06% to 102.37% across concentrations. No significant endogenous interference was detected in blank plasma. The LLOQ for both drugs was 2.0 ng/mL. Selectivity, matrix effects, stability, and dilution integrity met the acceptance criteria. The method assessed FTB and BTB interaction potential in combination therapy at 5 mg/kg. The findings provide essential pharmacokinetics insights for future clinical trials.

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

Cited by 87 publications

References 39 publications

Current Insights into Combination Therapies with MAPK Inhibitors and Immune Checkpoint Blockade

Current Insights into Combination Therapies with MAPK Inhibitors and Immune Checkpoint Blockade

A review of binimetinib for the treatment of mutant cutaneous melanoma

LC‐ESI‐MS/MS method validation for simultaneous quantification of FDA‐approved anticancer agents futibatinib and binimetinib in rat plasma: Insights from preclinical pharmacokinetics

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