Rahal, Rami1; Maynard, Michelle1; Hu, Wei1; Brubaker, Jason D.1; Cao, Qiongfang1; Kim, Joseph L.1; Sheets, Michael P.1; Wilson, Douglas P.1; Fleming, Paul1; Wilson, Kevin J.1; DiPietro, Lucian1; Labranche, Tim1; Wolf, Beni1; Guzi, Timothy1; Lengauer, Christoph1; Evans, Erica K.1
1 Blueprint Medicines, Cambridge, MA, USA
Background: RET is an important oncogenic driver in both medullary thyroid cancer (MTC; ~60% with activating point mutations) and papillary thyroid cancer (~10% with RET fusions); however, selective RET inhibitors have not been developed to address RET-driven thyroid cancer.
Methods: We designed a next-generation kinase inhibitor, BLU-667, to specifically target oncogenic RET variants, while sparing closely-related kinases that exhibit dose-limiting toxicity profiles, such as KDR/VEGFR2. BLU-667 is an investigational agent that potently inhibits both wild-type and activating RET mutants (IC50 = 0.4 nM) and demonstrates 80-fold selectivity over KDR/VEGFR2 in enzymatic assays. In several RET-driven thyroid cancer cell lines, including MZ-CRC-1, TT, and TPC-1 cells, BLU?667 inhibited both RET autophosphorylation and cell proliferation in the low nanomolar range.
Results: Oral administration of BLU-667 robustly inhibited growth of diverse RET-driven models in vivo, including a RET(C634W) MTC xenograft. Notably, BLU-667, but not cabozantinib, induced tumor growth inhibition without impacting biomarkers of KDR/VEGFR2 inhibition, confirming BLU-667’s KDR-sparing activity in vivo and providing direct evidence that RET inhibition alone is sufficient for activity in these preclinical models.
Discussion & Conclusion: BLU-667 is a potent and highly selective RET inhibitor with preclinical activity against oncogenic mutants and fusions identified in thyroid cancer. Our preclinical data demonstrate that selective inhibition of RET with BLU-667 led to sustained inactivation of kinase activity in vivo without functionally impacting KDR/VEGFR2. BLU-667 may provide a new opportunity for patients with RET-driven malignancies, and as such, a first-in-human phase 1 trial for BLU-667 has initiated in patients with RET-driven solid tumors, including advanced thyroid cancer (NCT03037385).