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Biomarker-driven phase 2 study of MK-2206 and selumetinib (AZD6244, ARRY-142886) in patients with colorectal cancer

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Summary

Purpose PI3K/AKT/mTOR and RAS/RAF/MEK pathways are frequently dysregulated in colorectal cancer (CRC). We conducted a biomarker-driven trial of the combination of MK-2206, an allosteric AKT 1/2/3 inhibitor, and selumetinib, a MEK 1/2 inhibitor, in patients with CRC to evaluate inhibition of phosphorylated ERK (pERK) and AKT (pAKT) in paired tumor biopsies. Patients and Methods Adult patients with advanced CRC were enrolled in successive cohorts stratified by KRAS mutation status. Initially, 12 patients received oral MK-2206 90 mg weekly with oral selumetinib 75 mg daily in 28-day cycles. Following an interim analysis, the doses of MK-2206 and selumetinib were increased to 135 mg weekly and 100 mg daily, respectively. Paired tumor biopsies were evaluated for target modulation. Results Common toxicities were gastrointestinal, hepatic, dermatologic, and hematologic. Of 21 patients enrolled, there were no objective responses. Target modulation did not achieve the pre-specified criteria of dual 70 % inhibition of pERK and pAKT levels in paired tumor biopsies. Conclusion Despite strong scientific rationale and preclinical data, clinical activity was not observed. The desired level of target inhibition was not achieved. Overlapping toxicities limited the ability to dose escalate to achieve exposures likely needed for clinical activity, highlighting the challenges in developing optimal combinations of targeted agents.

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Acknowledgments

The authors thank the patients and their families for their contributions to this study. Additionally, we thank Dr. Andrea Regier Voth, Leidos Biomedical Research, Inc., for medical writing support, and Dr. Kate Ferry-Galow, Leidos Biomedical Research, Inc., for quality assurance auditing of the pharmacodynamic data presented in this manuscript.

This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contracts No. HHSN261200800001E and N01-CM-2011-00032. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. MK-2206 and selumetinib were generously provided by Merck and AstraZeneca, respectively, under a collaborative agreement with the Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH.

Conflict of interest

Michael H. Lam is an employee of Merck and Company. No potential conflicts of interest were disclosed by the other authors.

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    Authors and Affiliations

    1. Division of Cancer Treatment and Diagnosis, National Cancer Institute, 31 Center Drive, Bldg 31, Rm 3A44, Bethesda, MD, 20892, USA

      Khanh Do, Giovanna Speranza, Larry Rubinstein, Michelle Eugeni, L. Austin Doyle, James H. Doroshow & Shivaani Kummar

    2. National Eye Institute, Bethesda, USA

      Rachel Bishop & Manuel Datiles

    3. Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, USA

      Sonny Khin & Robert J. Kinders

    4. Merck Research Laboratories – Oncology, Boston, USA

      Michael H. Lam

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    1. Khanh Do
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    Correspondence to Shivaani Kummar.

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    Khanh Do and Giovanna Speranza contributed equally to this work.

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    Do, K., Speranza, G., Bishop, R. et al. Biomarker-driven phase 2 study of MK-2206 and selumetinib (AZD6244, ARRY-142886) in patients with colorectal cancer. Invest New Drugs 33, 720–728 (2015). https://doi.org/10.1007/s10637-015-0212-z

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