No abstract

Focal amplifi cation and activating point mutation of the MET gene are well-characterized oncogenic drivers that confer susceptibility to targeted MET inhibitors. Recurrent somatic splice site alterations at MET exon 14 ( MET ex14) that result in exon skipping and MET activation have been characterized, but their full diversity and prevalence across tumor types are unknown. Here, we report analysis of tumor genomic profi les from 38,028 patients to identify 221 cases with MET ex14 mutations (0.6%), including 126 distinct sequence variants. MET ex14 mutations are detected most frequently in lung adenocarcinoma (3%), but also frequently in other lung neoplasms (2.3%), brain glioma (0.4%), and tumors of unknown primary origin (0.4%). Further in vitro studies demonstrate sensitivity to MET inhibitors in cells harboring MET ex14 alterations. We also report three new patient cases with MET ex14 alterations in lung or histiocytic sarcoma tumors that showed durable response to two different MET-targeted therapies. The diversity of MET ex14 mutations indicates that diagnostic testing via comprehensive genomic profi ling is necessary for detection in a clinical setting. SIGNIFICANCE:Here we report the identifi cation of diverse exon 14 splice site alterations in MET that result in constitutive activity of this receptor and oncogenic transformation in vitro . Patients whose tumors harbored these alterations derived meaningful clinical benefi t from MET inhibitors. Collectively, these data support the role of MET ex14 alterations as drivers of tumorigenesis, and identify a unique subset of patients likely to derive benefi t from MET inhibitors. Cancer Discov; 5(8);

Entrectinib, a potent oral inhibitor of the tyrosine kinases TRKA/B/C, ROS1, and ALK, was evaluated in two Phase 1 studies in patients with advanced or metastatic solid tumors, including patients with active 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 RP2D. Entrectinib was well tolerated, with predominantly Grades 1/2 adverse events that were reversible with dose modification. Responses were observed in NSCLC, colorectal cancer, mammary analog 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.