668P Efficacy and safety of larotrectinib in a pooled analysis of patients (Pts) with tropomyosin receptor kinase (TRK) fusion cancer

Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers in a variety of tumour types. Larotrectinib is a highly selective, central nervous system-active TRK inhibitor, approved to treat pts with TRK fusion cancer. We report updated efficacy and safety data in an expanded dataset of pts with longer follow-up. Data were pooled from 3 clinical trials (NCT02576431, NCT02122913, NCT02637687) of pts with TRK fusion cancer treated with larotrectinib. Responses were assessed by independent review committee (IRC) per RECIST v1.1. As of 20 July 2022, a total of 289 pts (median age 44 years [range 0–90]) were included. There were 26 different tumour types, including soft tissue sarcoma (24%), infantile fibrosarcoma (17%), thyroid (10%), and lung (10%). Pts received a median of 1 prior line of systemic therapy, with 124 (43%) pts receiving ≥2. Among 274 IRC-eligible pts, the objective response rate was 66% (95% CI 60–72): 75 (27%) complete response (CR), including 13 (5%) pathological CR (pCR); 107 (39%) partial response (PR); 49 (18%) stable disease; 26 (9%) progressive disease; and 17 (6%) not evaluable. Median duration of response was 43.3 months (mo; 95% CI 31.4–54.7) at a median follow-up of 31.5 mo. Median progression-free survival was 30.8 mo (95% CI 22.5–36.1) at a median follow-up of 31.3 mo. Median overall survival (OS) was not reached; 48-mo OS rate was 65%. Pts were treated for up to 75+ mo. At data cut-off, 108 pts had progressed; 46 continued treatment post-progression for ≥4 weeks due to continued clinical benefit. Treatment-related adverse events (TRAEs) were mainly Grade 1/2; 59 (20%) pts had Grade 3/4 TRAEs. Five (2%) pts discontinued due to TRAEs. In a 5-year long-term follow-up analysis of the original 55 pts from the July 2018 primary data cut-off, 8 pts had an improved best overall response from PR to CR (or pCR), with a total CR rate of 27%. Larotrectinib continued to demonstrate rapid and durable responses, extended survival benefit, and a favourable safety profile. This supports the wider adoption of next-generation sequencing panels that include NTRK gene fusions to identify pts who may benefit from treatment.