Preclinical Characterization of Entrectinib

Activated ALK and ROS1 tyrosine kinases, resulting from chromosomal rearrangements, occur in a subset of non-small cell lung cancers (NSCLC) as well as other tumor types and their oncogenic relevance as actionable targets has been demonstrated by the efficacy of selective kinase inhibitors such as crizotinib, ceritinib and alectinib. More recently, low frequency rearrangements of TRK kinases have been described in NSCLC, colorectal carcinoma (CRC), glioblastoma and Spitzoid melanoma. Entrectinib, whose discovery and preclinical characterization are reported herein, is a novel, potent inhibitor of ALK, ROS1 and importantly, of TRK family kinases which shows promise for therapy of tumors bearing oncogenic forms of these proteins. Proliferation profiling against over 200 human tumor cell lines revealed that entrectinib is exquisitely potent in vitro against lines that are dependent on the drug's pharmacological targets. Oral administration of entrectinib to tumor-bearing mice induced regression in relevant human xenograft tumors, including the TRKA-dependent colorectal carcinoma KM12, ROS1-driven tumors and several ALK-dependent models of different tissue origins including a model of brain-localized lung cancer metastasis. Entrectinib is currently showing great promise in Phase I/II clinical trials, including the first documented objective responses to a TRK inhibitor in CRC and in NSCLC. The drug is thus potentially suited to the therapy of several molecularly defined cancer settings, especially that of TRK-dependent tumors, for which no approved drugs are currently available.

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