Genomic alterations in RET, encoding the RET (rearranged in transformation) kinase, have been identified as bona fide oncogenic drivers in numerous tumor types. Activating RET point mutations are typically associated with multiple endocrine neoplasia (types A and B) and familial medullary thyroid carcinoma. Although activating RET rearrangements can be found in up to 40% of papillary thyroid cancers, they are only present in up to 2% of non-small cell lung cancers and at lower frequencies in multiple other malignancies. As a result of the relatively low prevalence of molecular alterations in multiple tumor types, diagnostics-driven therapeutic selection strategies are being developed to identify patients with RET alterations. There also remains a clinical need for a potent, selective and safe RET inhibitor that demonstrates robust efficacy in malignancies harboring RET rearrangements and other oncogenic alterations.

RXDX-105 (formerly CEP-32496) is a potent, orally available, small molecule kinase inhibitor that potently binds and antagonizes several known oncogenic driver proteins, including RET, while sparing VEGFR2. RXDX-105 is currently in clinical trial in patients with solid tumors. To evaluate the therapeutic potential of RXDX-105 in malignancies bearing RET alterations, we first assessed the ability of RXDX-105 to antagonize RET activity in vitro. In biochemical and cell based assays, RXDX-105 potently antagonizes the activity of RET-fusion proteins and RET activating point mutations, resulting in a dose dependent inhibition of downstream signaling events and cell proliferation. In vivo, RXDX-105 displays potent and dose dependent anti-tumor activity with significant tumor growth regressions in several patient derived xenograft models harboring RET-rearrangements.

These pre-clinical studies support the inclusion of patients bearing RET alterations in future diagnostics-based clinical trials exploring RXDX-105 efficacy across a variety of tumor types.

Citation Format: James Joseph, Aleksandra Franovic, Anni Schairer, Eric Martin, Ge Wei, Danielle Murphy, Jason Christiansen, Robert Shoemaker, Pratik Multani, Robert Wild, Gang Li. RXDX-105 demonstrates potent RET inhibitory activity with therapeutic potential in multiple preclinical models of RET-rearrangement driven cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A174.