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Phase 1b investigation of the MEK inhibitor binimetinib in patients with advanced or metastatic biliary tract cancer

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Summary

Background The MAPK pathway plays a central role in regulation of several cellular processes, and its dysregulation is a hallmark of biliary tract cancer (BTC). Binimetinib (MEK162), a potent, selective oral MEK1/2 inhibitor, was assessed in patients with advanced BTC. Patients and Methods An expansion cohort study in patients who received ≤1 line of therapy for advanced BTC was conducted after determination of the maximum tolerated dose in this Phase 1 trial. Patients received binimetinib 60 mg twice daily. The primary objectives were to characterize the safety profile and pharmacokinetics of binimetinib in advanced BTC. Secondary objectives included assessment of clinical efficacy, changes in weight and lean body mass, and pharmacodynamic effects. Tumor samples were assessed for mutations in relevant genes. Results Twenty-eight patients received binimetinib. Common adverse events (AEs) were mild, with rash (82%) and nausea (54%) being most common. Two patients experienced grade 4 AEs, one generalized edema and the other pulmonary embolism. The pharmacokinetics in this patient population were consistent with those previously reported (Bendell JC et al., Br J Cancer 2017;116:575-583). Twelve patients (43%) experienced stable disease and two had objective responses (1 complete response, 1 partial response) per Response Evaluation Criteria in Solid Tumors and stable metabolic disease by positron emission tomography/computed tomography. Most patients (18/25; 72%) did not have KRAS, BRAF, NRAS, PI3KCA, or PTEN mutations, nor was there correlation between mutation status and response. The average non-fluid weight gain was 1.3% for lean muscle and 4.7% for adipose tissue. Conclusion Binimetinib was well tolerated and showed promising evidence of activity in patients with BTC. Correlative studies suggested the potential for binimetinib to promote muscle gain in patients with BTC.

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Funding

This work was supported by Array BioPharma Inc.

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Author notes

  1. R. S. Finn and D. H. Ahn contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, University of California Los Angeles Medical Center, 2020 Santa Monica Blvd, Santa Monica, CA, 90404, USA

    R. S. Finn

  2. Department of Medicine, Mayo Clinic, 5881 E Mayo Blvd, Phoenix, AZ, 85054, USA

    D. H. Ahn & Tanios S. Bekaii-Saab

  3. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit #426, Houston, TX, 77030, USA

    M. M. Javle

  4. Department of Medicine, Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8056, St. Louis, MO, 63110, USA

    B. R. Tan Jr

  5. Department of Medicine, University of Colorado Cancer Center, 12801 E 17th Ave, Aurora, CO, 80045, USA

    C. D. Weekes

  6. Drug Development Program, Sarah Cannon Research Institute/Tennessee Oncology, 250 25th Ave N, Nashville, TN, 37203, USA

    J. C. Bendell

  7. START - South Texas Accelerated Research Therapeutics, 4383 Medical Dr, San Antonio, TX, 78229, USA

    A. Patnaik

  8. Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI, 48202, USA

    G. N. Khan

  9. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 401 N Broadway, Baltimore, MD, 21287, USA

    D. Laheru

  10. Array BioPharma Inc., 3200 Walnut St, Boulder, CO, 80301, USA

    R. Chavira, J. Christy-Bittel & E. Barrett

  11. Cross Cancer Institute Department of Medical Oncology, University of Alberta, 11560 University Ave, Edmonton, AB, T6G 1Z2, Canada

    M. B. Sawyer

Authors
  1. R. S. Finn
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  2. D. H. Ahn
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  3. M. M. Javle
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  4. B. R. Tan Jr
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  5. C. D. Weekes
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  6. J. C. Bendell
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  7. A. Patnaik
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  8. G. N. Khan
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  11. J. Christy-Bittel
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  12. E. Barrett
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  13. M. B. Sawyer
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  14. Tanios S. Bekaii-Saab
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Corresponding author

Correspondence to Tanios S. Bekaii-Saab.

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Disclosures

Dr. R. S. Finn is a consultant for Bayer, Novartis, Pfizer Inc., Bristol-Myers Squibb. Dr. D. H. Ahn is a consultant for Merrimack. Dr. A. Patnaik receives institutional research funding from Array BioPharma Inc. R. Chavira, J. Christy-Bittel, and Dr. Barrett are current or former employees, and may own stock in, Array BioPharma Inc. All remaining authors have declared no conflicts of interest.

Additional information

Key message: MAPK pathway dysregulation is common in biliary tract cancer and is a key mechanism for tumor proliferation and treatment resistance. Its inhibition represents a novel, relevant treatment strategy in this disease. Binimetinib was well tolerated and showed promising clinical activity. Future studies assessing biomarkers will help determine patients that are likely to benefit from binimetinib.

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Finn, R.S., Ahn, D.H., Javle, M.M. et al. Phase 1b investigation of the MEK inhibitor binimetinib in patients with advanced or metastatic biliary tract cancer. Invest New Drugs 36, 1037–1043 (2018). https://doi.org/10.1007/s10637-018-0600-2

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  • DOI: https://doi.org/10.1007/s10637-018-0600-2

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