title: Antitumor Activity of RXDX-105 in Multiple Cancer Types withRETRearrangements or Mutations.
abstract: Purpose:While multikinase inhibitors with RET activity are active inRET-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 byRETalterations.Experimental design:The RET-inhibitory activity of RXDX-105 was assessed by biochemical and cellular assays, followed byin vivotumor 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 ofCCDC6-RET-rearranged and RET C634W-mutant cell lines and inhibition of downstream signaling pathways. Significant tumor growth inhibition inCCDC6-RET, NCOA4-RET, andKIF5B-RET-containing xenografts was observed, with the concomitant inhibition of p-ERK, p-AKT, and p-PLCγ. Additionally, a patient with advancedRET-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 bearingRETalterations in ongoing and future molecularly enriched clinical trials to explore RXDX-105 efficacy across a variety of tumor types.Clin Cancer Res; 23(12); 2981-90. ©2016 AACR.
authors.affiliation: Ignyta, Inc., San Diego, California. gli@ignyta.com drilona@mskcc.org.
authors.forename: Gang G
authors.initials: GG
authors.lastname: Li
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Romel
authors.initials: R
authors.lastname: Somwar
authors.affiliation: Ignyta, Inc., San Diego, California.
authors.forename: James
authors.initials: J
authors.lastname: Joseph
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Roger S
authors.initials: RS
authors.lastname: Smith
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Takuo
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: Ignyta, Inc., San Diego, California.
authors.forename: Leenus
authors.initials: L
authors.lastname: Martin
authors.affiliation: Ignyta, Inc., San Diego, California.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Franovic
authors.affiliation: Ignyta, Inc., San Diego, California.
authors.forename: Anni
authors.initials: A
authors.lastname: Schairer
authors.affiliation: Ignyta, Inc., San Diego, California.
authors.forename: Eric
authors.initials: E
authors.lastname: Martin
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riely
authors.affiliation: Ignyta, Inc., San Diego, California.
authors.forename: Jason
authors.initials: J
authors.lastname: Harris
authors.affiliation: Ignyta, Inc., San Diego, California.
authors.forename: Shunqi
authors.initials: S
authors.lastname: Yan
authors.affiliation: Ignyta, Inc., San Diego, California.
authors.forename: Ge
authors.initials: G
authors.lastname: Wei
authors.affiliation: Ignyta, Inc., San Diego, California.
authors.forename: Jennifer W
authors.initials: JW
authors.lastname: Oliver
authors.affiliation: Ignyta, Inc., San Diego, California.
authors.forename: Rupal
authors.initials: R
authors.lastname: Patel
authors.affiliation: Ignyta, Inc., San Diego, California.
authors.forename: Pratik
authors.initials: P
authors.lastname: Multani
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York. gli@ignyta.com drilona@mskcc.org.
authors.forename: Alexander
authors.initials: A
authors.lastname: Drilon
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D015321:Gene Rearrangement / Q000187:drug effects; D006801:Humans; D051379:Mice; D009154:Mutation; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human