<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Purpose:</jats:title> <jats:p>Entrectinib potently inhibits tropomyosin receptor kinases (TRKAs)/B/C and ROS1, and previously induced deep [objective response rate (ORR) 57.4%] and durable [median duration of response (DoR) 10.4 months] responses in adults with NTRK fusion-positive solid tumors from three phase I/II trials. This article expands prior reports with additional patients and longer follow-up.</jats:p> </jats:sec> <jats:sec> <jats:title>Patients and Methods:</jats:title> <jats:p>Patients with locally advanced/metastatic NTRK fusion-positive solid tumors and ≥12 months' follow-up were included. Primary endpoints were ORR and DoR by blinded independent central review (BICR); secondary endpoints included progression-free survival (PFS), intracranial efficacy, and safety. The safety-evaluable populations included all patients who had received ≥1 entrectinib dose.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>At clinical cut-off (August 31, 2020), the efficacy-evaluable population comprised 121 adults with 14 tumor types and ≥30 histologies. Median follow-up was 25.8 months; 61.2% of patients had a complete (n = 19) or partial response (n = 55). Median DoR was 20.0 months [95% confidence interval (CI), 13.0–38.2]; median PFS was 13.8 months (95% CI, 10.1–19.9). In 11 patients with BICR-assessed measurable central nervous system (CNS) disease, intracranial ORR was 63.6% (95% CI, 30.8–89.1) and median intracranial DoR was 22.1 (95% CI, 7.4–not estimable) months. The safety profile of entrectinib in adults and pediatric patients was aligned with previous reports. Most treatment-related adverse events (TRAEs) were grade 1/2 and manageable/reversible with dose modifications. TRAE-related discontinuations occurred in 8.3% of patients.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>With additional clinical experience, entrectinib continues to demonstrate durable systemic and intracranial responses and can address the unmet need of a CNS-active treatment in patients with NTRK fusion-positive solid tumors.</jats:p> </jats:sec>