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

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

Clin Cancer Res. 2016 Dec 23;:

Authors: Li GG, Somwar R, Joseph J, Smith RS, Hayashi T, Martin L, Franovic A, Schairer A, Martin ES, Riely GJ, Harris J, Yan S, Wei G, Oliver J, Patel R, Multani P, Ladanyi M, Drilon A

Abstract
PURPOSE: While multikinase inhibitors with RET activity are active in RET-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 RET alterations.
EXPERIMENTAL DESIGN: The RET-inhibitory activity of RXDX-105 was assessed by biochemical and cellular assays, followed by in vivo tumor growth inhibition studies in cell line- and patient-derived xenograft models. Anti-tumor activity in patients was assessed by imaging and Response Evaluation Criteria in Solid Tumors (RECIST).
RESULTS: 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 CCDC6-RET rearranged and RET C634W mutant cell lines and inhibition of downstream signaling pathways. Significant tumor growth inhibition in CCDC6-RET, NCOA4-RET and KIF5B-RET-containing xenografts was observed, with the concomitant inhibition of p-ERK, p-AKT, and p-PLCγ. Additionally, a patient with advanced RET-rearranged lung cancer had a rapid and sustained response to RXDX-105 in both intracranial and extracranial disease.
CONCLUSION: These data support the inclusion of patients bearing RET alterations in ongoing and future molecularly-enriched clinical trials to explore RXDX-105 efficacy across a variety of tumor types.

PMID: 28011461 [PubMed - as supplied by publisher]

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