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	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	7	4	2017 Apr	400-409	Cancer Discov

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	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
ALK rearrange	Advanced Solid Tumor	predicted - sensitive	Entrectinib	Clinical Study	Actionable	In a combined analysis of 2 Phase I trials (ALKA-372-001, STARTRK-1), Rozlytrek (entrectinib) 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 who received prior Alk inhibitor treatments (PMID: 28183697; NCT02097810).	28183697
ROS1 rearrange	Advanced Solid Tumor	predicted - sensitive	Entrectinib	Clinical Study	Actionable	In a combined analysis of 2 Phase I trials (ALKA-372-001, STARTRK-1), Rozlytrek (entrectinib) 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 who received prior Xalkori (crizotinib) (PMID: 28183697; NCT02097810).	28183697
ROS1 rearrange	lung non-small cell carcinoma	sensitive	Entrectinib	Clinical Study	Actionable	In a combined analysis of 2 Phase I trials (ALKA-372-001, STARTRK-1), Rozlytrek (entrectinib) treatment resulted in a complete response in 15% (2/13) and partial response in 77% (10/13) patients with ROS-1 rearranged non-small cell lung carcinoma that were treatment-naive (PMID: 28183697; NCT02097810).	28183697
ALK F1245V	neuroblastoma	predicted - sensitive	Entrectinib	Case Reports/Case Series	Actionable	In a combined analysis of 2 Phase I trials (ALKA-372-001, STARTRK-1), Rozlytrek (entrectinib) treatment resulted in a 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; NCT02097810).	28183697