Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients with NTRK Fusion-Positive Solid Tumors

Purpose: Entrectinib potently inhibits TRKA/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 manuscript expands prior reports with additional patients and longer follow-up. Patients and methods: Patients with locally advanced/metastatic NTRK fusion-positive solid tumors and {greater than or equal to}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 {greater than or equal to}1 entrectinib dose. Results: At clinical cutoff (August 31, 2020), the efficacy-evaluable population comprised 121 adults with 14 tumor types and {greater than or equal to}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% CI, 13.0-38.2); median PFS 13.8 months (95% CI, 10.1-19.9). In 11 patients with BICR-assessed measurable CNS disease, intracranial ORR was 63.6% (95% CI, 30.8-89.1); 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. Conclusion: 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.