Efficacy and safety of larotrectinib in pediatric patients with tropomyosin receptor kinase (TRK) fusion-positive cancer: An expanded dataset.
Authors: Mascarenhas Leo , van Tilburg Cornelis Martinus , Doz Francois , Zwaan C. Michel , Albert Catherine M. , Blattman Claudia , Geoerger Birgit , DuBois Steven G. , Federman Noah , Nagasubramanian Ramamoorthy , Pappo Alberto S. , Watt Tanya Carens , Norenberg Ricarda , Fellous Marc Mardoche , De La Cuesta Esther A. , Laetsch Theodore Willis , Xu Rui-hua 
Published: June 2022

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Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions are oncogenic drivers in various tumor types across all ages. Larotrectinib is a first-in-class, central nervous system (CNS)-active, highly selective tropomyosin receptor kinase (TRK) inhibitor approved for pediatric and adult patients (pts) with TRK fusion-positive cancer, demonstrating an objective response rate (ORR) of 88% across 78 pediatric pts with non-CNS cancers (van Tilburg et al, SIOP 2021). We report an analysis of the efficacy and safety of larotrectinib in an expanded dataset of pediatric pts with TRK fusion-positive cancer. Methods: Pediatric pts (< 18 years) with non-CNS TRK fusion-positive cancer in larotrectinib clinical trials (NCT02637687, NCT02576431) were included and ORR (RECIST v1.1) was investigator (INV)-assessed. Data cut-off was July 20, 2021. Results: A total of 94 pts were included in this analysis. Tumor types included infantile fibrosarcoma (52%), other soft tissue sarcoma (40%), congenital mesoblastic nephroma (2%), thyroid cancer (2%), bone sarcoma (1%), breast cancer (1%), and melanoma (1%). Pts had gene fusions involving NTRK1 (43%), NTRK2 (3%), or NTRK3 (54%). Median age was 2.2 years (range 0–18 years). Of the 62 (66%) pts who received prior systemic therapy, 32 (52%) received ≥2 lines. The INV-assessed best ORR for the 93 evaluable pts was 84% (95% confidence interval [CI] 75–91): 35 (38%) complete response (CR; including two pending confirmation and 10 pathological CR), 43 (46%) partial response (two pending confirmation), 11 (12%) stable disease, two (2%) progressive disease, and two (2%) not determined. The median time to response was 1.8 months. Overall, median duration of response was 43.3 months (95% CI 23.4–NE); median follow-up was 26.0 months. Median progression-free survival and overall survival (OS) were 37.4 months (95% CI 22–NE) and not reached, respectively; median follow-up was 21.2 and 30.3 months, respectively. The 36-month OS rate was 93% (95% CI 86–99). Treatment duration ranged from 1+ to 63+ months. At data cut-off, 31 pts had progressed; 18 continued treatment post-progression for ≥4 weeks. There were no treatment-related deaths. Treatment-related adverse events (TRAEs) occurred in 81% of pts (23% were Grade [G] 1, 28% G2, 25% G3, and 5% G4). The most common TRAE was increased aspartate aminotransferase (31 pts [33%]). Four pts (4%) discontinued treatment due to TRAEs. Neurological TRAEs occurred in 12% of pts (5% were G1, 4% G2, and 2% G3). The most common neurological TRAE was headache (5 pts [5%]). Conclusions: In this expanded dataset, larotrectinib continues to demonstrate rapid and durable tumor-agnostic efficacy, extended survival, and a favorable safety profile in pediatric pts with TRK fusion-positive cancer. These results highlight the importance of identifying NTRK gene fusions in pediatric solid tumors. Clinical trial information: NCT02576431, NCT02637687.