Antitumor Activity of RXDX-105 in Multiple Cancer Types with <i>RET</i> Rearrangements or Mutations.

Abstract

<b>Purpose:</b> While multikinase inhibitors with RET activity are active in <i>RET</i>-rearranged thyroid and lung cancers, objective response rates are relatively low and toxicity can be substantial. The development of novel RET inhibitors with improved potency and/or reduced toxicity is thus an unmet need. RXDX-105 is a small molecule kinase inhibitor that potently inhibits RET. The purpose of the preclinical and clinical studies was to evaluate the potential of RXDX-105 as an effective therapy for cancers driven by <i>RET</i> alterations.<b>Experimental design:</b> The RET-inhibitory activity of RXDX-105 was assessed by biochemical and cellular assays, followed by <i>in vivo</i> tumor growth inhibition studies in cell line- and patient-derived xenograft models. Antitumor activity in patients was assessed by imaging and Response Evaluation Criteria in Solid Tumors (RECIST).<b>Results:</b> Biochemically, RXDX-105 inhibited wild-type RET, CCDC6-RET, NCOA4-RET, PRKAR1A-RET, and RET M918T with low to subnanomolar activity while sparing VEGFR2/KDR and VEGFR1/FLT. RXDX-105 treatment resulted in dose-dependent inhibition of proliferation of <i>CCDC6-RET</i>-rearranged and RET C634W-mutant cell lines and inhibition of downstream signaling pathways. Significant tumor growth inhibition in <i>CCDC6-RET, NCOA4-RET</i>, and <i>KIF5B-RET-</i>containing xenografts was observed, with the concomitant inhibition of p-ERK, p-AKT, and p-PLCγ. Additionally, a patient with advanced <i>RET</i>-rearranged lung cancer had a rapid and sustained response to RXDX-105 in both intracranial and extracranial disease.<b>Conclusions:</b> These data support the inclusion of patients bearing <i>RET</i> alterations in ongoing and future molecularly enriched clinical trials to explore RXDX-105 efficacy across a variety of tumor types. <i>Clin Cancer Res; 23(12); 2981-90. ©2016 AACR</i>.