Antitumor activity of RXDX-105 in multiple cancer types with RET rearrangements or mutations Journal Article


Authors: Li, G. G.; Somwar, R.; Joseph, J.; Smith, R. S.; Hayashi, T.; Martin, L.; Franovic, A.; Schairer, A.; Martin, E.; Riely, G. J.; Harris, J.; Yan, S.; Wei, G.; Oliver, J. W.; Patel, R.; Multani, P.; Ladanyi, M.; Drilon, A.
Article Title: Antitumor activity of RXDX-105 in multiple cancer types with RET rearrangements or mutations
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. Antitumor 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. Conclusions: 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. ©2016 AACR.
Journal Title: Clinical Cancer Research
Volume: 23
Issue: 12
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2017-06-01
Start Page: 2981
End Page: 2990
Language: English
DOI: 10.1158/1078-0432.ccr-16-1887
PROVIDER: scopus
PMCID: PMC5477238
PUBMED: 28011461
DOI/URL:
Notes: Article -- Export Date: 3 July 2017 -- Source: Scopus
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MSK Authors
  1. Marc Ladanyi
    863 Ladanyi
  2. Gregory J Riely
    344 Riely
  3. Romel Somwar
    34 Somwar
  4. Alexander Edward Drilon
    136 Drilon
  5. Roger Stephen Smith
    14 Smith