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

3145 Background: Larotrectinib (laro) is the first-in-class, highly selective 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 in adult and pediatric pts treated with laro with non-primary central nervous system (CNS) TRK fusion cancer. Methods: Pts from 3 clinical trials (NCT02637687 [SCOUT], NCT02576431 [NAVIGATE], NCT02122913) were included. Laro was administered at 100 mg twice daily (BID) and 100 mg/m 2 (max 100 mg) BID in most adult and pediatric pts, respectively. Responses were independent review committee-assessed (RECIST v1.1). Pts enrolled in SCOUT could stop laro in the absence of on-treatment progression (“wait-and-see”) and remain on trial. If pts were re-treated due to progression, response was assessed by investigators. Data cutoff: July 20, 2025. Results: In total, 304 pts were treated; 25 had baseline CNS metastases. There were 28 tumor types, including soft tissue sarcoma (24%), infantile fibrosarcoma (16%), lung (11%), and thyroid (10%). NTRK gene fusions were detected by next-generation sequencing (NGS) in 266 (88%) pts. Overall response rate was 65% (95% confidence interval [CI] 59–70) with 61 (20%) complete responses (CR), 18 (6%) pathological CR, 118 (39%) partial responses (PR), 55 (18%) stable disease (SD), 32 (11%) progressive disease (PD), and 20 (7%) not evaluable/undefined. Median duration of treatment was 19 months ([mo] range 0–111). At data cutoff, 52 pts (17%) remained on trial (either on treatment or in “wait-and-see”). Median time to response was 1.8 mo (range 0.9–80.3). Median duration of response (DoR), progression-free survival (PFS), and overall survival (OS) were 42 mo (95% CI 31–59), 26 mo (95% CI 19–35), and not reached (95% CI 89–not estimable), respectively, at median follow-ups of 54, 52, and 65 mo. The 5-year rates for DoR, PFS, and OS were 41% (95% CI 33–49), 33% (95% CI 27–40), and 61% (95% CI 55–67), respectively. Fifty-seven pediatric pts entered a first “wait-and-see” period (median duration 24 mo [range 0–75+]). Of these, 38 exited the “wait-and-see” period. By investigator assessment, 20 pts had PD and resumed treatment (with 6 CR, 5 PR [including 2 pending confirmation], 7 SD, 2 unevaluable/undefined). The other 18 pts discontinued laro permanently but were all alive at data cutoff. Treatment-related adverse events (TRAEs) were mainly worst Grade 1/2 (n=189; 62%). Worst Grade 3/4 TRAEs occurred in 72 (24%) 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. These data support the wider adoption of NGS panels that include NTRK gene fusions to identify pts who may benefit from TRK inhibitor therapy. Clinical trial information: NCT02637687 , NCT02576431 , NCT02122913 .