Abstract CT060: STARTRK-2: A global phase 2, open-label, basket study of entrectinib in patients with locally advanced or metastatic solid tumors harboring TRK, ROS1, or ALK gene fusions

Background: Entrectinib is a potent, CNS-penetrant, oral inhibitor of the tyrosine kinases TRKA/B/C (encoded by the genes NTRK1/2/3, respectively), ROS1, and ALK with IC50s < 2 nM (biochemical kinase assay). Two Phase 1 studies ALKA-372-001 and STARTRK-1 have enrolled more than 130 patients with advanced or metastatic solid tumors harboring TRKA/B/C, ROS1, or ALK molecular alterations, with or without CNS disease. Previously, we reported an objective response rate of 79% in 24 tyrosine kinase inhibitor-naïve patients with TRK, ROS1, or ALK gene fusions who were treated at doses that achieved therapeutic exposures consistent with the Recommended Phase 2 Dose (RP2D) (Drilon et al, AACR 2016). Entrectinib was well tolerated, with predominantly Grades 1 or 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. Methods: STARTRK (Studies of Tumor Alterations Responsive to Targeting Receptor Kinases)-2 is a potentially registration-enabling Phase 2 basket study of entrectinib for the treatment of patients with advanced solid tumors that harbor a TRK, ROS1, or ALK gene fusion. In order to determine enrollment eligibility and assignment to a specific tumor type basket, patients are screened for gene fusions either locally, including by ctDNA, or centrally at Ignyta’s CLIA/CAP diagnostic laboratory using next generation sequencing. The study’s eligibility criteria were designed to maximize enrollment of these rare patients by allowing CNS disease, Eastern Cooperative Oncology Group (ECOG) performance status 2, and any prior line of therapy, with the exception of TRK, ROS1, or ALK inhibitors. Patients with ALK- or ROS1-rearranged NSCLC who had previously been treated with crizotinib and experienced CNS-only progression are also eligible. In addition, a “non-evaluable” basket allows enrollment of patients confirmed to have gene fusions who do not meet all the inclusion or exclusion criteria. Entrectinib is administered orally on a continuous daily dosing regimen, at a dose of 600 mg once-daily in repeated 4-week cycles. Safety is assessed by monitoring of adverse events, laboratory tests, and clinic visits. Tumor assessments (computed tomography (CT) or magnetic