Efficacy and safety of larotrectinib in TRK fusion-positive primary central nervous system tumors

BACKGROUND Larotrectinib is a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor approved to treat adult and pediatric patients with TRK fusion-positive cancer. The aim of this study was to evaluate the efficacy and safety of larotrectinib in patients with TRK fusion-positive primary central nervous system (CNS) tumors. METHODS Patients with TRK fusion-positive primary CNS tumors from two clinical trials (NCT02637687, NCT02576431) were identified. The primary endpoint was investigator-assessed objective response rate (ORR). RESULTS As of July 2020, 33 patients with TRK fusion-positive CNS tumors were identified (median age: 8.9 years; range: 1.3-79.0). The most common histologies were high-grade glioma (HGG; n = 19) and low-grade glioma (LGG; n = 8). ORR was 30% (95% confidence interval [CI]: 16-49) for all patients. In all patients, the 24-week disease control rate was 73% (95% CI: 54-87). Twenty-three of 28 patients (82%) with measurable disease had tumor shrinkage. The 12-month rates for duration of response, progression-free survival, and overall survival were 75% (95% CI: 45-100), 56% (95% CI: 38-74), and 85% (95% CI: 71-99), respectively. Median time to response was 1.9 months (range 1.0-3.8 months). Duration of treatment ranged from 1.2-31.3+ months. Treatment-related adverse events were reported for 20 patients, with Grade 3-4 in 3 patients. No new safety signals were identified. CONCLUSIONS In patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated rapid and durable responses, high disease control rate, and a favorable safety profile

CTNI-74. ON-TRK: A NON-INTERVENTIONAL STUDY OF LAROTRECTINIB IN PATIENTS WITH TROPOMYOSIN RECEPTOR KINASE (TRK) FUSION SOLID TUMORS

Abstract Increasingly, health authorities and the medical community are investing resources into evaluating real-world data (RWD) on precision biomarker-based treatments. Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers in various cancers. Larotrectinib is a highly selective, central nervous system (CNS)-active TRK inhibitor approved for tumor-agnostic use in pediatric and adult patients with various cancers. ON-TRK (NCT04142437) is an ongoing non-interventional post-approval study that is critical in gaining RWD on the treatment of patients with TRK fusion cancer and will contribute to the broader understanding of personalized therapy. This open-label, global, multi-cohort, prospective study will enroll up to 300 pediatric and adult patients with TRK fusion cancer scheduled to receive larotrectinib, including ≥ 30 pediatric patients. Patients with cancer harboring NTRK gene fusions, detected locally, are eligible. Patients who have had prior TRK inhibitor therapy and patients with NTRK genomic alterations other than functional gene fusions are excluded. Decisions on the dose and duration of treatment are at the discretion of the treating physician. The primary endpoint is safety, including specific long-term parameters in pediatric patients. Secondary endpoints include: efficacy (objective response rate, disease control rate, time to response, duration of response, progression-free survival, and overall survival), dosing patterns and long-term effects of larotrectinib in pediatric patients. The effects of larotrectinib on growth and developmental milestones in pediatric patients will be reported, including change in height and weight from baseline, age at adrenarche for males and menarche for females, number and percentage of patients with abnormal Tanner stages, and abnormal neurological assessments. All variables will be analyzed using descriptive statistics. Pediatric and adult patients will be followed for ≥ 5 years and ≥ 2 years, respectively, unless lost to follow-up, withdrawal, or death. Enrollment is ongoing worldwide; 24 patients with primary CNS cancer have been enrolled to date

Efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma

Objective: Larotrectinib is a highly selective tropomyosin receptor kinase (TRK) inhibitor with demonstrated efficacy across various TRK fusion-positive solid tumours. We assessed the efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma (TC). Methods: We pooled data from three phase I/II larotrectinib clinical trials (NCT02576431, NCT02122913, and NCT02637687). The primary endpoint was the investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Data cut-off: July 2020. Results: Twenty-nine patients (median age: 60; range: 6-80) with TRK fusion-positive TC were treated. Tumour histology was papillary (PTC) in 20 (69%) patients, follicular (FTC) in 2 (7%), and anaplastic (ATC) in 7 (24%) patients. Among 28 evaluable patients, ORR was 71% (95% CI: 51-87); best responses were complete response in 2 (7%) patients, partial response in 18 (64%), stable disease in 4 (14%), progressive disease in 3 (11%), and undetermined in 1 (4%) due to clinical progression prior to the first post-baseline assessment. ORR was 86% (95% CI: 64-97) for PTC/FTC and 29% (95% CI 4-71) for ATC. Median time to response was 1.87 months (range 1.64-3.68). The 24-month DoR, PFS, and OS rates were 81, 69, and 76%, respectively. Treatment-related adverse events were mainly grades 1-2. Conclusion: In TRK fusion-positive TC, larotrectinib demonstrates rapid and durable disease control and a favourable safety profile in patients with advanced disease requiring systemic therapy. Significance statement: NTRK gene fusions are known oncogenic drivers and have been identified in various histologies of thyroid carcinoma, most commonly in papillary thyroid carcinoma. This is the first publication specifically studying a TRK inhibitor in a cohort of TRK fusion-positive thyroid carcinoma patients. In the current study, the highly selective TRK inhibitor larotrectinib showed durable antitumour efficacy and a favourable safety profile in patients with TRK fusion-positive thyroid carcinoma. Our findings show that patients with advanced non-medullary thyroid carcinoma who may require systemic therapy could be considered for testing for gene fusions by next-generation sequencing

Efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma

© 2022 The authors.Objective: Larotrectinib is a highly selective tropomyosin receptor kinas e (TRK) inhibitor with demonstrated efficacy across various TRK fusion-positive solid tumours. We assessed t he efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma (TC). Methods: We pooled data from three phase I/II larotrectinib clinical trials (NCT02576431, NCT02122913, and NCT02637687). The primary endpoint was the investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints i ncluded duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Data cut-off: July 2020. Results: Twenty-nine patients (median age: 60; range: 6-80) with TRK fu sion-positive TC were treated. Tumour histology was papillary (PTC) in 20 (69%) patients, follicular (FTC) in 2 (7%), and anaplastic (ATC) in 7 (24%) patients. Among 28 evaluable patients, ORR was 71% (95% CI: 51-87); best responses were complete response in 2 (7%) patients, partial response in 18 (64%), stable disease in 4 (14%), progressive di sease in 3 (11%), and undetermined in 1 (4%) due to clinical progression prior to the first post-baseline assessment . ORR was 86% (95% CI: 64-97) for PTC/FTC and 29% (95% CI 4-71) for ATC. Median time to response was 1.87 months (range 1.64-3.68). The 24-month DoR, PFS, and OS rates were 81, 69, and 76%, respectively. Treatment-related adv erse events were mainly grades 1-2. Conclusion: In TRK fusion-positive TC, larotrectinib demonstrates rapid an d durable disease control and a favourable safety profile in patients with advanced disease requiring syste mic therapy.N