Activating RET fusions have been observed in 1-2% of non-small cell lung adenocarcinomas (NSCLC). These tumors often occur in non-smokers and lack other driver mutations, similar to NSCLC driven by activation of the tyrosine kinases EGFR, ALK or ROS. Multi-kinase inhibitors (mKIs) with in vitro activity against RET, such as cabozantinib and vandetanib, have been tested in RET-rearranged NSCLC, but without the high response rate often seen with targeted therapies in genetically-defined NSCLC, likely a result of off-toxicities that limit the ability to fully inhibit RET kinase activation. BLU-667 is a next-generation kinase inhibitor specifically tailored to target the activated forms of RET, while sparing kinases that contribute to dose-limiting toxicities, such as VEGFR-2. BLU-667 potently inhibited both RET fusion activity (IC50 = 0.4 nM) and demonstrated 88-fold selectivity over VEGFR-2 in enzymatic assays. In a cellular setting, BLU 667 inhibited the most prevalent RET fusion observed in NSCLC, KIF5B-RET, over 20X more potently than the multikinase inhibitors cabozantinib, vandetanib or RXDX-105. KIF5B-RET autophosphorylation and proliferation driven by RET fusions was inhibited with BLU-667 in the low nanomolar range (4 – 15 nM). In vivo oral administration of BLU 667 was well tolerated in mice at all doses and exhibited dose-dependent modulation of oncogenic RET kinase activity in all in vivo models tested, including a KIF5B-RET NSCLC PDX, as well as a KIF5B-RET V804L-driven tumor model with a mutation at the gatekeeper position, a position susceptible to on-target mutation in many oncogenic kinases. Notably, BLU-667, but not cabozantinib, induced tumor growth inhibition without impacting biomarkers of VEGFR-2 inhibition, providing strong evidence that selective inhibition of RET alone is sufficient for antitumor activity in vivo. By sparing off-target kinases with known toxicity profiles, BLU-667 is predicted to robustly inhibit RET at clinically achievable doses. Moreover, with activity against predicted resistance mutations such as those at the gatekeeper position, BLU-667 may prevent or delay the emergence of resistance and therefore provide patients with RET-driven malignancies an opportunity for more durable and effective therapies. As such, BLU-667 is currently in the dose-escalation segment of a first-in-human phase 1 trial for patients with RET-driven solid tumors with activating RET alterations (NCT03037385).

Citation Format: Rami Rahal, Michelle Maynard, Wei Hu, Jason Brubaker, Qiangfang Cao, Joseph L. Kim, Michael P. Sheets, Douglas P. Wilson, Kevin J. Wilson, Lucian DiPietro, Timothy LaBranche, Beni Wolf, Timothy Guzi, Christoph Lengauer, Erica K. Evans. BLU-667: A highly selective RET inhibitor to target RET-driven NSCLC [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B01.