Precision Targeted Therapy with BLU-667 for <i>RET</i>-Driven Cancers

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. <i>In vitro</i>, BLU-667 demonstrated ≥10-fold increased potency over approved MKIs against oncogenic RET variants and resistance mutants. <i>In vivo</i>, BLU-667 potently inhibited growth of NSCLC and thyroid cancer xenografts driven by various <i>RET</i> 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 <i>RET</i>-altered NSCLC and MTC without notable off-target toxicity, providing clinical validation for selective RET targeting.<b>Significance:</b> Patients with <i>RET</i>-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 <i>RET</i> mutations and fusions. BLU-667 attenuated RET signaling and produced durable clinical responses in patients with <i>RET</i>-altered tumors, clinically validating selective RET targeting. <i>Cancer Discov; 8(7); 836-49. ©2018 AACR.</i><i>See related commentary by Iams and Lovly, p. 797</i><i>This article is highlighted in the In This Issue feature, p. 781</i>.