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Cancer Discov. 2017 Apr;7(4):400-409. doi: 10.1158/2159-8290.CD-16-1237. Epub 2017 Feb 9.

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).

Author information

1
Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York. drilona@mskcc.org.
2
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
3
Dipartimento di Oncologia e Emato-Oncologia, Università degli Studi di Milano, Milan, Italy.
4
Chao Family Comprehensive Cancer Center, University of California, Irvine, California.
5
Sarah Cannon Research Institute/Florida Cancer Specialists, Sarasota, Florida.
6
Samsung Medical Center, Seoul, Korea.
7
Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, Tennessee.
8
Massachusetts General Hospital, Boston, Massachusetts.
9
The University of Texas MD Anderson Cancer Center, Houston, Texas.
10
Georgetown Lombardi Comprehensive Cancer Center, Washington, DC.
11
University of Colorado Cancer Center, Aurora, Colorado.
12
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
13
Nerviano Medical Sciences s.r.l, Milan, Italy.
14
Ignyta, Inc., San Diego, California.

Abstract

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.

PMID:
28183697
PMCID:
PMC5380583
DOI:
10.1158/2159-8290.CD-16-1237
[Indexed for MEDLINE]
Free PMC Article

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