Reference Detail

Ref Type Journal Article
PMID (28183697)
Authors Drilon A, Siena S, Ou SI, Patel M, Ahn MJ, Lee J, Bauer TM, Farago AF, Wheler JJ, Liu SV, Doebele R, Giannetta L, Cerea G, Marrapese G, Schirru M, Amatu A, Bencardino K, Palmeri L, Sartore-Bianchi A, Vanzulli A, Cresta S, Damian S, Duca M, Ardini E, Li G, Christiansen J, Kowalski K, Johnson AD, Patel R, Luo D, Chow-Maneval E, Hornby Z, Multani PS, Shaw AT, De Braud FG
Title Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1).
Journal Cancer discovery
Vol 7
Issue 4
Date 2017 Apr
URL
Abstract Text Entrectinib, a potent oral inhibitor of the tyrosine kinases TRKA/B/C, ROS1, and ALK, was evaluated in two phase I studies in patients with advanced or metastatic solid tumors, including patients with active central nervous system (CNS) disease. Here, we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring NTRK1/2/3, ROS1, or ALK gene fusions, naïve to prior TKI treatment targeting the specific gene, and who were treated at doses that achieved therapeutic exposures consistent with the recommended phase II dose. Entrectinib was well tolerated, with predominantly Grades 1/2 adverse events that were reversible with dose modification. Responses were observed in non-small cell lung cancer, colorectal cancer, mammary analogue secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as >2 years. Notably, a complete CNS response was achieved in a patient with SQSTM1-NTRK1-rearranged lung cancer.Significance: Gene fusions of NTRK1/2/3, ROS1, and ALK (encoding TRKA/B/C, ROS1, and ALK, respectively) lead to constitutive activation of oncogenic pathways. Entrectinib was shown to be well tolerated and active against those gene fusions in solid tumors, including in patients with primary or secondary CNS disease. Cancer Discov; 7(4); 400-9. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 339.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
F1245V missense unknown ALK F1245V lies within the protein kinase domain of the Alk protein (UniProt.org). F1245V has been identified in the scientific literature (PMID: 28183697), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Oct 2018).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ALK rearrange Advanced Solid Tumor sensitive Entrectinib Phase I Actionable In a clinical study analyzing combined results of 2 Phase I trials, Entrectinib (RXDX-101) treatment resulted in an objective response rate of 57% (4/7) in patients with ALK rearranged advanced solid tumors that were treatment-naive, but no response (0/19) in patients received prior Alk inhibitor treatments (PMID: 28183697). 28183697
ALK rearrange Advanced Solid Tumor sensitive Entrectinib Phase I Actionable In a Phase I trial, Entrectinib (RXDX-101) treatment resulted in objective response in 67% (4/6) of patients with advanced solid tumors harboring rearrangement in ALK gene (AACR Apr 2016, Abstract # CT007). detail...
ROS1 rearrange non-small cell lung carcinoma sensitive Entrectinib Phase I Actionable In a clinical study analyzing combined results of 2 Phase I trials, Entrectinib (RXDX-101) treatment resulted in complete response in 2 and partial response in 10 patients with ROS-1 rearranged non-small cell lung carcinoma that were treatment-naive (PMID: 28183697). 28183697
ROS1 rearrange Advanced Solid Tumor sensitive Entrectinib Phase I Actionable In a Phase I trial, Entrectinib (RXDX-101) treatment resulted in complete response in 13% (1/12) and objection response in 75% (6/8) of patients with advanced solid tumors harboring rearrangement in ROS1 gene (AACR Apr 2016, Abstract # CT007). detail...
ROS1 rearrange Advanced Solid Tumor sensitive Entrectinib Phase I Actionable In a clinical study analyzing combined results of 2 Phase I trials, Entrectinib (RXDX-101) treatment resulted in an objective response rate of 86% (12/14) in patients with ROS-1 rearranged advanced solid tumors that were treatment-naive, but no response (0/6) in patients received prior Xalkori (crizotinib) (PMID: 28183697). 28183697
ALK F1245V neuroblastoma sensitive Entrectinib Phase I Actionable In a Phase I trial, Entrectinib (RXDX-101) treatment resulted in partial response that lasted 8.3 months in a patient with neuroblastoma harboring ALK F1245V, who remained on treatment for over 3.5 years due to clinical benefit (PMID: 28183697). 28183697