Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Chappell WH, Steelman LS, Long JM, Kempf RC, Abrams SL, Franklin RA, Basecke J, Stivala F, Donia M, Fagone P, Malaponte G, Mazzarino MC, Nicoletti F, Libra M, Maksimovic-Ivanic D, Mijatovic S, Montalto G, Cervello M, Laidler P, Milella M, Tafuri A, Bonati A, Evangelisti C, Cocco L, Martelli AM, McCubrey JA (2011) Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health. Oncotarget 2:135–164

    Article  PubMed  PubMed Central  Google Scholar 

  2. Fremin C, Meloche S (2010) From basic research to clinical development of MEK1/2 inhibitors for cancer therapy. J Hematol Oncol 3:8-8722-3-8

    Article  Google Scholar 

  3. Pratilas CA, Solit DB (2010) Targeting the mitogen-activated protein kinase pathway: physiological feedback and drug response. Clin Cancer Res 16:3329–3334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, Mohr P, Dummer R, Trefzer U, Larkin JM, Utikal J, Dreno B, Nyakas M, Middleton MR, Becker JC, Casey M, Sherman LJ, Wu FS, Ouellet D, Martin AM, Patel K, Schadendorf D, the METRIC Study Group (2012) Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 367:107–114

    Article  CAS  PubMed  Google Scholar 

  5. Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ, Chiarion Sileni V, Lebbe C, Mandalà M, Millward M, Arance A, Bondarenko I, Haanen JBAG, Hansson J, Utikal J, Ferraresi V, Kovalenko N, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, DeMarini DJ, Irani JG, Casey M, Ouellet D, Martin A, Le N, Patel K, Flaherty K (2014) Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 371:1877–1888

    Article  PubMed  Google Scholar 

  6. Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ, Chiarion-Sileni V, Lebbe C, Mandala M, Millward M, Arance A, Bondarenko I, Haanen JB, Hansson J, Utikal J, Ferraresi V, Kovalenko N, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, DeMarini DJ, Irani JG, Swann S, Legos JJ, Jin F, Mookerjee B, Flaherty K (2015) Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet 386:444–451

  7. Lee PA, Wallace E, Marlow A, Yeh T, Marsh V, Anderson D, Woessner R, Hurley B, Lyssikatos J, Poch G, Gross S, Rana S, Winski S, Koch K (2010) Abstract 2515: preclinical development of ARRY-162, a potent and selective MEK 1/2 inhibitor. Cancer Res 70:2515

    Article  Google Scholar 

  8. Winski S, Anderson D, Bouhana K, Impastato R, Woessner R, Zuzack J, Tunquist B, Garrus J, Pheneger T, Lee P (2010) 162 MEK162 (ARRY-162), a novel MEK 1/2 inhibitor, inhibits tumor growth regardless of KRas/Raf pathway mutations. Eur J Cancer Suppl 8:56

    Article  Google Scholar 

  9. Bendell JC, Papadopoulos K, Jones SF, Barrett E, Guthrie K, Kass CL, Litwiler KS, Napier C, Patnaik A (2011) Abstract B243: a phase I dose-escalation study of MEK inhibitor MEK162 (ARRY-438162) in patients with advanced solid tumors. Mol Cancer Ther 10:B243

    Article  Google Scholar 

  10. Ascierto PA, Schadendorf D, Berking C, Agarwala SS, van Herpen CM, Queirolo P, Blank CU, Hauschild A, Beck JT, St-Pierre A, Niazi F, Wandel S, Peters M, Zubel A, Dummer R (2013) MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol 14:249–256

    Article  CAS  PubMed  Google Scholar 

  11. Liew G, Quin G, Gillies M, Fraser-Bell S (2013) Central serous chorioretinopathy: a review of epidemiology and pathophysiology. Clin Exp Ophthalmol 41:201–214

    Article  Google Scholar 

  12. Neuenschwander B, Branson M, Gsponer T (2008) Critical aspects of the Bayesian approach to phase I cancer trials. Stat Med 27:2420–2439

    Article  PubMed  Google Scholar 

  13. LoRusso PM, Krishnamurthi SS, Rinehart JJ, Nabell LM, Malburg L, Chapman PB, DePrimo SE, Bentivegna S, Wilner KD, Tan W, Ricart AD (2010) Phase I pharmacokinetic and pharmacodynamic study of the oral MAPK/ERK kinase inhibitor PD-0325901 in patients with advanced cancers. Clin Cancer Res 16:1924–1937

    Article  CAS  PubMed  Google Scholar 

  14. Infante JR, Fecher LA, Falchook GS, Nallapareddy S, Gordon MS, Becerra C, DeMarini DJ, Cox DS, Xu Y, Morris SR, Peddareddigari VG, Le NT, Hart L, Bendell JC, Eckhardt G, Kurzrock R, Flaherty K, Burris HA III, Messersmith WA (2012) Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol 13:773–781

    Article  CAS  PubMed  Google Scholar 

  15. Adjei AA, Cohen RB, Franklin W, Morris C, Wilson D, Molina JR, Hanson LJ, Gore L, Chow L, Leong S, Maloney L, Gordon G, Simmons H, Marlow A, Litwiler K, Brown S, Poch G, Kane K, Haney J, Eckhardt SG (2008) Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol 26:2139–2146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Huang W, Yang AH, Matsumoto D, Collette W, Marroquin L, Ko M, Aguirre S, Younis HS (2009) PD0325901, a mitogen-activated protein kinase kinase inhibitor, produces ocular toxicity in a rabbit animal model of retinal vein occlusion. J Ocul Pharmacol Ther 25:519–530

    Article  CAS  PubMed  Google Scholar 

  17. Urner-Bloch U, Urner M, Stieger P, Galliker N, Winterton N, Zubel A, Moutouh-de Parseval L, Dummer R, Goldinger SM (2014) Transient MEK inhibitor-associated retinopathy in metastatic melanoma. Ann Oncol 25:1437–1441

    Article  CAS  PubMed  Google Scholar 

  18. Falchook GS, Lewis KD, Infante JR, Gordon MS, Vogelzang NJ, DeMarini DJ, Sun P, Moy C, Szabo SA, Roadcap LT, Peddareddigari VG, Lebowitz PF, Le NT, Burris HA III, Messersmith WA, O’Dwyer PJ, Kim KB, Flaherty K, Bendell JC, Gonzalez R, Fecher LA (2012) Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol 13:782–789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sullivan RJ, Weber JS, Patel SP, Dummer R, Miller WH, Cosgrove D, Carlino MS, Tan DS, Lebbe C, Cipani T, Elez E, Maacke H, Nikolopoulos P, Aout M, De Parseval LA, Ascierto PA (2015) A phase Ib/II study of BRAF inhibitor (BRAFi) encorafenib (ENCO) plus MEK inhibitor (MEKi) binimetinib (BINI) in cutaneous melanoma patients naive to BRAFi treatment. ASCO Meeting Abstracts 33:9007

Download references

Acknowledgments

The authors thank the patients and their families and the staff of each site participating in this study. We would like to also thank Dr Ken-ichi Kimoto in the Department of Ophthalmology and Dr Yutaka Hatano in the Department of Dermatology at Oita University for medical advice. Editorial assistance was provided by Maria Alfaradhi, PhD, of ArticulateScience and was funded by Novartis Pharmaceuticals.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Kouseiren Tsurumi Hospital, 4333 Ooaza Tsurumi, Beppu, Oita, 879-5593, Japan

    K. Watanabe

  2. Department of Medical Oncology and Hematology, Oita University Faculty of Medicine, Oita, Japan

    K. Watanabe, S. Otsu, Y. Hirashima, R. Morinaga, K. Nishikawa, Y. Hisamatsu & K. Shiaro

  3. Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Aichi, Japan

    T. Shimokata, M. Inada-Inoue, T. Shibata & Y. Ando

  4. Oncology Early Clinical Trial Management Department, Novartis Pharma KK, Tokyo, Japan

    H. Takeuchi

  5. Medical Science Liaison Group, Novartis Pharma KK, Tokyo, Japan

    T. Watanabe

  6. Integrated Science and Operations Department, Novartis Pharma KK, Tokyo, Japan

    K. Tokushige

  7. Translational Clinical Oncology, Novartis Pharma AG, Basel, Switzerland

    H. Maacke

Authors
  1. K. Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Otsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y. Hirashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. Morinaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K. Nishikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y. Hisamatsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T. Shimokata
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M. Inada-Inoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. T. Shibata
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. H. Takeuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. T. Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. K. Tokushige
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. H. Maacke
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. K. Shiaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Y. Ando
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K. Watanabe.

Ethics declarations

Conflict of interest

YA received grants from Sanofi, Torii Pharmaceutical, Mitsubishi Tanabe Pharma, and Mochida Pharmaceutical; grants and personal fees from Chugai Pharmaceutical, Takeda Pharmaceutical, Daiichi Sankyo, Kyowa Hakko Kirin, Eisai, Taiho Pharmaceutical, Nippon Kayaku, YakultHonsya, Merck Serono, and Hisamitsu Pharmaceutical; and personal fees from Ono Pharmaceutical, Eli Lilly Japan KK, Pfizer, Novartis Pharma KK, Janssen Pharmaceutical KK, AstraZeneca KK, GlaxoSmithKline, ASKA Pharmaceutical, Terumo Corp, Bayel Holding, Meiji Seika Pharma, Arkray Marketing, CBC Radio, Igaku-shoin, Vigorous-Med, Nakayama Shoten, Nanzando Co, Benesse Style Care, Tokyo Kagaku Dojin, Kowa Pharmaceutical, Boehringer Ingelheim, and Bristol-Myers Squibb; outside the submitted work. HT, TW, KT, and HM are employees of Novartis Pharmaceuticals. All remaining authors have declared no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 107 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Watanabe, K., Otsu, S., Hirashima, Y. et al. A phase I study of binimetinib (MEK162) in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol 77, 1157–1164 (2016). https://doi.org/10.1007/s00280-016-3019-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-016-3019-5

Keywords

Search

Navigation