RXDX-105 demonstrates anti-tumor efficacy in multiple preclinical cancer models driven by molecular alterations in RET or BRAF oncogenes

Molecular alterations in RET, including rearrangements and activating point mutations, have been identified as oncogenic drivers. Point mutations in RET are typically detected in multiple endocrine neoplasia (types A and B), as well as familial medullary thyroid carcinoma. RET gene rearrangements have been identified in a significant portion of papillary thyroid cancer (FTC), up to 2% of non-small cell lung cancers (NSCLC) and at lower frequencies in multiple other malignancies. Although small molecule RET inhibitors have shown preclinical and clinical activity, there remains a need for better tolerated, more effective RET inhibitors for the treatment of patients with relevant molecutar alterations-Molecular alterations in BRAF are commonly identified in 10% to 15% of colorectal cancers, and 1% to 2% of NSCLC. Although notable clinical activity has been achieved with single-agent vemurafenib and dabrafenib in treating melanoma harboring the BRAF V600E mutation, their clinical efficacy in colorectal cancer (CRC) and NSCLC has not been satisfactory. RXDX-105 is a clinical stage multikinase inhibitor (MKI) that has demonstrated potent inhibition of RET and BRAF In biochemical assays, RXDX-1O5 potently antagonized constitutively active, rearranged and point- mutated RET proteins. In cell based assays, RXDX-1 05 demonstrated a dose-dependent inhibition of RET and downstream signaling events, resulting in inhibition of cellular proliferation. In vivo, RXDX-105 achieved dose-dependent anti-tumor activity, including tumor regression at clinically achievable exposures in several patient derived xenograft (PDX) models harboring RET rearrangements. Similarly, RXDX-1 05 demonstrated signif- icant antitumor activity in a panel of CRC PDX models harboring BRAF mutations, including V600E and non-V600E variants. In addition to RET and BRAF, RXDX-105 is believed to potentially drive additional anti-tumor activity, durability and/or therapeutic potential from its MKI properties, such as anti-angiogenesis and immune-modulatory activities. In conclusion, the potent anti-RET and BRAF activity of RXDX-105 in molecularly defined preclinical models, supplemented with its MKI activities, provides a strong rationale for clinical development of RXDX-105, as a single agent or in combination with standard of care agents in a variety of tumor types.