Efficacy and safety of larotrectinib in patients with non-primary central nervous system TRK fusion cancer: An updated analysis.

3148 Background: NTRK gene fusions are oncogenic drivers in various tumor types. Larotrectinib (laro) is the first-in-class, highly selective, central nervous system (CNS)-active TRK inhibitor approved for tumor-agnostic use in patients (pts) with TRK fusion cancer based on a robust and durable objective response rate in pts with various cancers. Here, we report updated long-term efficacy and safety data in adult and pediatric pts with non-primary CNS TRK fusion cancer treated with laro. Methods: Pts with TRK fusion cancer enrolled in 3 laro clinical trials (NCT02637687 [SCOUT], NCT02576431 [NAVIGATE], NCT02122913) were included. Laro was administered at 100 mg twice daily (BID) and 100 mg/m 2 BID in most adult and pediatric pts, respectively. Responses were independent review committee (IRC)-assessed per RECIST v1.1. Pts enrolled in SCOUT were permitted to stop laro in the absence of on-treatment progression (“wait-and-see”). The data cutoff was July 20, 2024. Results: At data cutoff,304 pts were eligible for efficacy assessment by IRC; 25 pts had known CNS metastases at baseline. Median age was 45 years (range 0–90). There were 28 different tumor types, including soft tissue sarcoma (24%), infantile fibrosarcoma (16%), lung (11%), and thyroid (10%). A total of 101 pts (33%) received no prior systemic therapies in the metastatic/unresectable setting; 115 (38%) received 2 or more. NTRK gene fusions were detected by next-generation sequencing (NGS) in 267 (88%) pts. The overall response rate was 65% (95% confidence interval [CI] 59–70): 66 (22%) complete responses (CR), 20 (7%) pathological CR, 112 (37%) partial responses, 56 (18%) stable disease, 32 (11%) progressive disease, and 18 (6%) not evaluable/undefined. Median time to response was 1.8 months (mo; range 0.9–22.9). Median duration of response (DoR), progression-free survival (PFS), and overall survival (OS) were 43 mo (95% CI 34–not estimable), 28 mo (95% CI 22–38), and not reached, respectively, at median follow-ups of 45, 42, and 57 mo. The 4-year rates for DoR, PFS, and OS were 48% (95% CI 40–57), 39% (95% CI 32–46), and 63% (95% CI 57–68), respectively. Median duration of treatment was 19 mo (range 0–100+). Fifty-five of 99 pediatric pts in SCOUT had participated in “wait-and-see”; the median duration of the first “wait-and-see” period was 33 mo (range 1–72). At data cutoff, 83 pts (27%) remained on trial (either on treatment or in “wait-and-see”). Treatment-related adverse events (TRAEs) were mainly Grade 1/2 (n = 189; 62%). Grade 3/4 TRAEs occurred in 71 (23%) pts. Five (2%) pts discontinued due to TRAEs. Conclusions: Laro continues to demonstrate rapid and durable responses, extended survival, clinical benefit, and a favorable safety profile in pts with TRK fusion cancer. This data supports the wider adoption of NGS panels that include NTRK gene fusions to identify pts who may benefit from treatment with TRK inhibitors. Clinical trial information: NCT02637687 , NCT02576431 , NCT02122913 .