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.
Subject(s)
Benzamides/administration & dosage , Carcinoma, Non-Small-Cell Lung/drug therapy , Colorectal Neoplasms/drug therapy , Indazoles/administration & dosage , Mammary Analogue Secretory Carcinoma/drug therapy , Melanoma/drug therapy , Oncogene Proteins, Fusion/antagonists & inhibitors , Adolescent , Adult , Aged , Aged, 80 and over , Anaplastic Lymphoma Kinase , Benzamides/adverse effects , Benzamides/pharmacokinetics , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Crizotinib , Dose-Response Relationship, Drug , Female , Humans , Indazoles/adverse effects , Indazoles/pharmacokinetics , Male , Mammary Analogue Secretory Carcinoma/genetics , Melanoma/genetics , Melanoma/pathology , Membrane Glycoproteins/antagonists & inhibitors , Membrane Glycoproteins/genetics , Middle Aged , Oncogene Proteins, Fusion/genetics , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacokinetics , Protein-Tyrosine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Pyrazoles/administration & dosage , Pyridines/administration & dosage , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Receptor Protein-Tyrosine Kinases/genetics , Receptor, trkA/antagonists & inhibitors , Receptor, trkA/genetics , Receptor, trkB/antagonists & inhibitors , Receptor, trkB/genetics , Receptor, trkC/antagonists & inhibitors , Receptor, trkC/genetics , Sequestosome-1 Protein/geneticsABSTRACT
Trichomoniasis is a common sexually transmitted disease associated with preterm birth, low birth weight, and increased susceptibility to infection with other pathogenic sexually transmitted microorganisms. Nucleic acid amplification tests for Trichomonas vaginalis have improved sensitivity for detecting infected individuals compared to existing culture-based methods. This prospective, multicenter U.S. clinical trial evaluated the performance of the automated Aptima T. vaginalis assay for detecting T. vaginalis in 1,025 asymptomatic and symptomatic women. Vaginal swab, endocervical swab, ThinPrep PreservCyt, and urine specimens were collected. Subject infection status was determined by wet-mount microscopy and culture. Aptima T. vaginalis assay performance was determined for each specimen type by comparison to subject infection status. Of 933 subjects analyzed, 59.9% were symptomatic. Aptima T. vaginalis clinical sensitivity and specificity were, respectively, 100% and 99.0% for vaginal swabs, 100% and 99.4% for endocervical swabs, 100% and 99.6% in ThinPrep samples, and 95.2% and 98.9% in urine specimens. Aptima T. vaginalis performance levels were similar in asymptomatic and symptomatic subjects. This study validates the clinical performance of the Aptima T. vaginalis assay for screening asymptomatic and symptomatic women for T. vaginalis infection.
