Long-term control and safety of larotrectinib in a cohort of adult and pediatric patients with tropomyosin receptor kinase (TRK) fusion primary central nervous system (CNS) tumors.
Authors: Perreault Sébastien , Drilon Alexander E. , Lassen Ulrik Niels , Geoerger Birgit , Nysom Karsten , Øra Ingrid , Gavrilovic Igor T. , Norenberg Ricarda , Fellous Marc Mardoche , De La Cuesta Esther A. , Laetsch Theodore Willis , Doz Francois , van Tilburg Cornelis Martinus 
Published: June 2022

2010 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions are known oncogenic drivers in a variety of tumor types. Larotrectinib is a highly selective, CNS-active TRK inhibitor that demonstrated an objective response rate (ORR) of 30% and a 24-week disease control rate (DCR) of 73% across 33 evaluable adult and pediatric patients with TRK fusion primary CNS tumors, as of July 2020 (Doz et al, Neuro Oncol 2021). We report updated data on an expanded dataset of patients. Methods: Patients with TRK fusion primary CNS tumors in two clinical trials (NCT02637687, NCT02576431) were included. Larotrectinib was administered at 100 mg twice daily (BID) in adults and 100 mg/m2 (max 100 mg) BID in pediatric patients. Response was investigator-assessed. Results: As of July 2021, 38 adult and pediatric patients with TRK fusion primary CNS tumors were identified: high-grade glioma (HGG; n =23), low-grade glioma (LGG; n =9), and other (n =6; includes glioneuronal, neuroepithelial, diffuse leptomeningeal, neuroblastoma, recurrent small round blue cell, and not otherwise specified). Median age at enrollment was 10.8 years (range 1.3–79.0; 28 [74%] patients < 18 years old). The gene fusions involved NTRK2 (n = 28), NTRK1 (n = 6), and NTRK3 (n = 4). Sixteen (42%) patients received one prior line of systemic therapy and 16 (42%) received ≥2 prior lines. The ORR for 37 evaluable patients was 30% (95% confidence interval [CI] 16–47): three complete responses, eight partial responses, 21 stable disease (16 patients ≥24 weeks), and five progressive disease. The 24-week DCR was 73% (95% CI 56–86) for all patients, 68% (95% CI 45–86) for patients with HGG, and 89% (95% CI 52–100) for patients with LGG. Twenty-five of 31 patients (81%) with measurable disease at baseline had tumor shrinkage. Median time to response was 1.9 months. Median duration of response (DoR) was not reached; median follow-up was 25.6 months. The 12-month DoR rate was 64%. Median progression-free survival (PFS) was 16.5 months (95% CI 6.7–not estimable); median follow-up was 27.4 months. Median overall survival (OS) was not reached; median follow-up was 26.7 months. The 24-month OS rate was 65%. Treatment duration ranged from 0.1+ to 38.7+ months. Twenty-two patients (58%) progressed on treatment and three continued treatment post-progression for ≥4 weeks. Treatment-related adverse events (TRAEs) were reported in 21 patients (55%); the majority of these patients (18/21 [86%]) reported Grade 1 or 2 TRAEs. No Grade 3 or higher treatment-related neurological adverse events were reported. There were no treatment discontinuations due to TRAEs. Conclusions: Larotrectinib achieved a high DCR, rapid and durable responses, and a manageable safety profile in patients with TRK fusion primary CNS tumors. These results support testing for NTRK gene fusions in patients with CNS tumors. Clinical trial information: NCT02637687, NCT02576431.