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.
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) / A. Drilon, S. Siena, S.I. Ou, M. Patel, M.J. Ahn, J. Lee, T.M. Bauer, A.F. Farago, J.J. Wheler, S.V. Liu, R. Doebele, L. Giannetta, G. Cerea, G. Marrapese, M. Schirru, A. Amatu, K. Bencardino, L. Palmeri, A. Sartore-Bianchi, A. Vanzulli, S. Cresta, S. Damian, M. Duca, E. Ardini, G. Li, J. Christiansen, K. Kowalski, A.D. Johnson, R. Patel, D. Luo, E. Chow-Maneval, Z. Hornby, P.S. Multani, A.T. Shaw, F.G. De Braud. - In: CANCER DISCOVERY. - ISSN 2159-8274. - 7:4(2017 Apr), pp. 400-409.
|Titolo:||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)|
|Parole Chiave:||Adolescent; Adult; Aged; Aged, 80 and over; Benzamides; Carcinoma, Non-Small-Cell Lung; Colorectal Neoplasms; Dose-Response Relationship, Drug; Female; Humans; Indazoles; Male; Mammary Analogue Secretory Carcinoma; Melanoma; Membrane Glycoproteins; Middle Aged; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Receptor, trkA; Receptor, trkB; Receptor, trkC; Sequestosome-1 Protein; Oncology|
|Settore Scientifico Disciplinare:||Settore MED/06 - Oncologia Medica|
|Data di pubblicazione:||apr-2017|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1158/2159-8290.CD-16-1237|
|Appare nelle tipologie:||01 - Articolo su periodico|
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