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Research Articles

Precision Targeted Therapy with BLU-667 for RET-Driven Cancers

Vivek Subbiah, Justin F. Gainor, Rami Rahal, Jason D. Brubaker, Joseph L. Kim, Michelle Maynard, Wei Hu, Qiongfang Cao, Michael P. Sheets, Douglas Wilson, Kevin J. Wilson, Lucian DiPietro, Paul Fleming, Michael Palmer, Mimi I. Hu, Lori Wirth, Marcia S. Brose, Sai-Hong Ignatius Ou, Matthew Taylor, Elena Garralda, Stephen Miller, Beni Wolf, Christoph Lengauer, Timothy Guzi and Erica K. Evans
Vivek Subbiah
1Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Justin F. Gainor
2Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
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Rami Rahal
3Blueprint Medicines Corporation, Cambridge, Massachusetts.
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  • ORCID record for Rami Rahal
Jason D. Brubaker
3Blueprint Medicines Corporation, Cambridge, Massachusetts.
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Joseph L. Kim
3Blueprint Medicines Corporation, Cambridge, Massachusetts.
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Michelle Maynard
3Blueprint Medicines Corporation, Cambridge, Massachusetts.
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Wei Hu
3Blueprint Medicines Corporation, Cambridge, Massachusetts.
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Qiongfang Cao
3Blueprint Medicines Corporation, Cambridge, Massachusetts.
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Michael P. Sheets
3Blueprint Medicines Corporation, Cambridge, Massachusetts.
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Douglas Wilson
3Blueprint Medicines Corporation, Cambridge, Massachusetts.
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Kevin J. Wilson
3Blueprint Medicines Corporation, Cambridge, Massachusetts.
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Lucian DiPietro
3Blueprint Medicines Corporation, Cambridge, Massachusetts.
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Paul Fleming
3Blueprint Medicines Corporation, Cambridge, Massachusetts.
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Michael Palmer
3Blueprint Medicines Corporation, Cambridge, Massachusetts.
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Mimi I. Hu
4Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Lori Wirth
2Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
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Marcia S. Brose
5Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
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Sai-Hong Ignatius Ou
6Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, Irvine, California.
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Matthew Taylor
7The Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon.
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Elena Garralda
8Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
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Stephen Miller
3Blueprint Medicines Corporation, Cambridge, Massachusetts.
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Beni Wolf
3Blueprint Medicines Corporation, Cambridge, Massachusetts.
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Christoph Lengauer
3Blueprint Medicines Corporation, Cambridge, Massachusetts.
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Timothy Guzi
3Blueprint Medicines Corporation, Cambridge, Massachusetts.
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Erica K. Evans
3Blueprint Medicines Corporation, Cambridge, Massachusetts.
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  • For correspondence: eevans@blueprintmedicines.com
DOI: 10.1158/2159-8290.CD-18-0338 Published July 2018
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Abstract

The receptor tyrosine kinase rearranged during transfection (RET) is an oncogenic driver activated in multiple cancers, including non–small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), and papillary thyroid cancer. No approved therapies have been designed to target RET; treatment has been limited to multikinase inhibitors (MKI), which can have significant off-target toxicities and limited efficacy. BLU-667 is a highly potent and selective RET inhibitor designed to overcome these limitations. In vitro, BLU-667 demonstrated ≥10-fold increased potency over approved MKIs against oncogenic RET variants and resistance mutants. In vivo, BLU-667 potently inhibited growth of NSCLC and thyroid cancer xenografts driven by various RET mutations and fusions without inhibiting VEGFR2. In first-in-human testing, BLU-667 significantly inhibited RET signaling and induced durable clinical responses in patients with RET-altered NSCLC and MTC without notable off-target toxicity, providing clinical validation for selective RET targeting.

Significance: Patients with RET-driven cancers derive limited benefit from available MKIs. BLU-667 is a potent and selective RET inhibitor that induces tumor regression in cancer models with RET mutations and fusions. BLU-667 attenuated RET signaling and produced durable clinical responses in patients with RET-altered tumors, clinically validating selective RET targeting. Cancer Discov; 8(7); 836–49. ©2018 AACR.

See related commentary by Iams and Lovly, p. 797.

This article is highlighted in the In This Issue feature, p. 781

Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

  • Received March 30, 2018.
  • Revision received April 9, 2018.
  • Accepted April 11, 2018.
  • Published first April 15, 2018.
  • ©2018 American Association for Cancer Research.
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Cancer Discovery: 8 (7)
July 2018
Volume 8, Issue 7
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Precision Targeted Therapy with BLU-667 for RET-Driven Cancers
Vivek Subbiah, Justin F. Gainor, Rami Rahal, Jason D. Brubaker, Joseph L. Kim, Michelle Maynard, Wei Hu, Qiongfang Cao, Michael P. Sheets, Douglas Wilson, Kevin J. Wilson, Lucian DiPietro, Paul Fleming, Michael Palmer, Mimi I. Hu, Lori Wirth, Marcia S. Brose, Sai-Hong Ignatius Ou, Matthew Taylor, Elena Garralda, Stephen Miller, Beni Wolf, Christoph Lengauer, Timothy Guzi and Erica K. Evans
Cancer Discov July 1 2018 (8) (7) 836-849; DOI: 10.1158/2159-8290.CD-18-0338

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Precision Targeted Therapy with BLU-667 for RET-Driven Cancers
Vivek Subbiah, Justin F. Gainor, Rami Rahal, Jason D. Brubaker, Joseph L. Kim, Michelle Maynard, Wei Hu, Qiongfang Cao, Michael P. Sheets, Douglas Wilson, Kevin J. Wilson, Lucian DiPietro, Paul Fleming, Michael Palmer, Mimi I. Hu, Lori Wirth, Marcia S. Brose, Sai-Hong Ignatius Ou, Matthew Taylor, Elena Garralda, Stephen Miller, Beni Wolf, Christoph Lengauer, Timothy Guzi and Erica K. Evans
Cancer Discov July 1 2018 (8) (7) 836-849; DOI: 10.1158/2159-8290.CD-18-0338
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