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Cancer Discov. 2018 Jul;8(7):836-849. doi: 10.1158/2159-8290.CD-18-0338. Epub 2018 Apr 15.

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

Author information

1
Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2
Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
3
Blueprint Medicines Corporation, Cambridge, Massachusetts.
4
Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas.
5
Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
6
Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, Irvine, California.
7
The Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon.
8
Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
9
Blueprint Medicines Corporation, Cambridge, Massachusetts. eevans@blueprintmedicines.com.
#
Contributed equally

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. 797This article is highlighted in the In This Issue feature, p. 781.

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