Investigational New Drugs

, Volume 34, Issue 5, pp 604–613 | Cite as

A first-in-human phase I study to evaluate the MEK1/2 inhibitor, cobimetinib, administered daily in patients with advanced solid tumors

  • Lee S. Rosen
  • Patricia LoRusso
  • Wen Wee Ma
  • Jonathan W. Goldman
  • Amy Weise
  • A. Dimitrios Colevas
  • Alex Adjei
  • Salim Yazji
  • Angela Shen
  • Stuart Johnston
  • Hsin-Ju Hsieh
  • Iris T. Chan
  • Branimir I. Sikic


Objective Cobimetinib, a MEK1/2 inhibitor, was administered to patients with advanced solid tumors to assess safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity. Methods For dose-escalation, a 3 + 3 design was used. Oral cobimetinib was administered once daily on a 21-day on/7-day off (21/7) or a 14-day on/14-day off (14/14) schedule. Serial plasma samples were collected for pharmacokinetic (PK) analysis on Day 1 and at steady state. In expansion stages, patients with RAS or RAF mutant tumors were treated at the maximum tolerated dose (MTD) of the 21/7 or 14/14 schedule. Results Ninety-seven patients received cobimetinib. In the 21/7 dose escalation, 36 patients enrolled in 8 cohorts (0.05 mg/kg–80 mg). Dose-limiting toxicities (DLTs) were Grade 4 hepatic encephalopathy, Grade 3 diarrhea, and Grade 3 rash. In the 14/14 dose escalation, 20 patients enrolled in 4 cohorts (60–125 mg). DLTs were Grade 3 rash and Grade 3 blurred vision associated with presence of reversible subretinal fluid. The MTD was 60 mg on 21/7 schedule and 100 mg on 14/14 schedule. Cobimetinib PK showed dose-proportional increases in exposure. The most frequent adverse events attributed to cobimetinib were diarrhea, rash, fatigue, edema, nausea, and vomiting. In patients treated at the 60-mg (21/7) or 100-mg (14/14) dose, one unconfirmed complete response and 6 confirmed partial responses were observed. All responses occurred in melanoma patients; 6 harbored the BRAFV600E mutation. Conclusions Cobimetinib is generally well tolerated and durable responses were observed in BRAFV600E mutant melanoma patients. Evaluation of cobimetinib in combination with other therapies is ongoing.


Cobimetinib Phase I MEK inhibitor BRAF Melanoma 



The authors thank the patients and their families. This study was funded by Genentech, Inc. All authors participated in manuscript writing and approved the final version of the manuscript. We also acknowledge the contributions of Luna Musib, Steve Eppler, Alex de Crespigny, Jill Fredrickson, Mary Gates, and Yibing Yang. Editing and writing assistance was provided by Bryan Hains and Deborah Solymar (Genentech, Inc.) and was funded by Genentech, Inc.

Compliance with ethical standards

Conflict of interest

Lee S. Rosen, Patricia LoRusso, and Jonathan W. Goldman have received research funding from Genentech, Inc. Salim Yazji is a prior employee and current shareholder of Exelixis and is a current employee of Baxalta. Angela Shen is a prior employee of Exelixis and a current employee of Arvinas. Stuart Johnston is a shareholder and prior employee of Exelixis and a current employee of Nektar Therapeutics. Hsin-Ju Hsieh and Iris T. Chan are employees and shareholders of Roche. Branimir I. Sikic has received research funding from Exelixis, Genentech, Inc., Novartis, and Sanofi, and is a consultant for Novartis and Threshold Pharmaceuticals. Wen Wee Ma, Amy Weise, A. Dimitrios Colevas, and Alex Adjei declare that they have no potential conflicts of interest.

Research involving human participants

All procedures performed involving human participants in the protocol were approved by Institutional Review Boards prior to patient recruitment and conducted in accordance International Conference on Harmonization E6 Guidelines for Good Clinical Practice.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

10637_2016_374_MOESM1_ESM.pdf (629 kb)
ESM 1 (PDF 628 kb)


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Lee S. Rosen
    • 1
  • Patricia LoRusso
    • 2
  • Wen Wee Ma
    • 3
  • Jonathan W. Goldman
    • 1
  • Amy Weise
    • 4
  • A. Dimitrios Colevas
    • 5
  • Alex Adjei
    • 3
  • Salim Yazji
    • 6
    • 7
  • Angela Shen
    • 6
    • 8
  • Stuart Johnston
    • 6
    • 9
  • Hsin-Ju Hsieh
    • 10
  • Iris T. Chan
    • 10
  • Branimir I. Sikic
    • 5
  1. 1.David Geffen School of MedicineUCLASanta MonicaUSA
  2. 2.Yale UniversityNew HavenUSA
  3. 3.Roswell Park Cancer InstituteBuffaloUSA
  4. 4.Karmanos Cancer InstituteDetroitUSA
  5. 5.Stanford UniversityStanfordUSA
  6. 6.Exelixis, Inc.South San FranciscoUSA
  7. 7.BaxaltaCambridgeUSA
  8. 8.ArvinasNew HavenUSA
  9. 9.Nektar TherapeuticsSan FranciscoUSA
  10. 10.Genentech, Inc.South San FranciscoUSA

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