Introduction: Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers in various tumor types. Larotrectinib is a first-in-class, highly selective, central nervous system (CNS)-active TRK inhibitor approved in over 40 countries, including the US, for the treatment of adult and pediatric patients with TRK fusion cancer. Larotrectinib was approved by the FDA in 2018 based on efficacy and safety outcomes in a primary analysis cohort of 55 patients with TRK fusion cancer from 3 clinical trials (Drilon A et al. NEJM. 2018). Here, we report long-term efficacy follow-up for larotrectinib and molecular data on co-occurring mutations in this primary analysis cohort. Methods: Patients with non-primary CNS TRK fusion cancer treated with larotrectinib were identified from 3 clinical trials (NCT02122913, NCT02576431, NCT02637687). NTRK gene status was determined by local molecular testing. Adult and pediatric patients received larotrectinib 100 mg and 100 mg/m2 twice daily, respectively. The primary endpoint was investigator-assessed objective response rate (ORR) (per RECIST v1.1). Next-generation sequencing was performed on pre-treatment tumor samples from a subset of patients with evaluable tumor material (n=31) using the FoundationOne® CDx assay. The data cut-off was July 15, 2019. Results: A total of 55 patients with 17 different tumor types were included in the primary analysis cohort. Median age was 45 years (range 0.3-76 years). Patients had gene fusions involving NTRK1 (45%), NTRK2 (2%), or NTRK3 (53%). For 31 patients the detailed genomic profile, including co-occurring mutations, will be presented. Forty-four (80%) patients had received prior systemic therapy, with a median of 2 prior therapies (range 0-10). ORR with larotrectinib was 80% (95% confidence interval [CI] 67-90%); 13 (24%) patients had a complete response (CR), 31 (56%) patients had a partial response (PR), 5 (9%) patients had stable disease, and 6 (11%) patients had progressive disease. With longer follow-up, best response for 4 patients improved from PR to CR. Median duration of response and progression-free survival were 35.2 months (95% CI 19.8-not estimable [NE]) and 25.8 months (95% CI 9.9-NE), respectively. Median overall survival (OS) was not reached (95% CI 44.4-NE) over a median follow-up of 32.5 months. The 36-month OS rate was 76% (95% CI 63-89%). In an expanded safety population (n=279), larotrectinib-related adverse events were mainly Grade 1-2. Conclusions: Larotrectinib demonstrated a robust response rate with long durability and extended survival benefits in adult and pediatric patients with TRK fusion cancer. These data highlight the importance of identifying NTRK gene fusions in patients with cancer.

Citation Format: Alexander Drilon, Shivaani Kummar, Catherine M. Albert, Ramamoorthy Nagasubramanian, Jaclyn F. Hechtman, John A. Reeves, Georg Beckmann, Marion Rudolph, Justyna A. Wierzbińska, Laura Dima, Nicoletta Brega, Theodore W. Laetsch, David S. Hong. Long-term outcomes of patients with TRK fusion cancer treated with larotrectinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT020.