Long-term efficacy and safety of larotrectinib in patients with tropomyosin receptor kinase (TRK) fusion gastrointestinal (GI) cancer: An updated analysis

Neurotrophic tyrosine receptor kinase ( NTRK ) gene fusions are oncogenic drivers in various tumour types. Larotrectinib is a first-in-class, highly selective, central nervous system-active TRK inhibitor. Larotrectinib is approved for tumour-agnostic use in adult and paediatric patients with TRK fusion cancer, based on a rapid, robust and durable objective response rate (ORR) in various cancers. We report data on a subset of patients with TRK fusion GI cancer treated with larotrectinib with longer follow-up. Patients with TRK fusion GI cancer enrolled in the phase II larotrectinib clinical trial NAVIGATE (NCT02576431) were included. Responses were assessed per independent review committee (IRC) using RECIST v1.1. As of July 2022, 42 patients with TRK fusion GI cancer were enrolled. Median age was 67.0 years (range 32–90). The tumour types included were almost exclusively adenocarcinoma, including colorectal (CRC; n=24; 57%), pancreatic (n=7; 17%), cholangiocarcinoma (n=4; 10%), gastric (n=3; 7%), appendiceal (n=1; 2%) and duodenal (n=1; 2%) as well as hepatocarcinoma (n=1; 2%) and oesophageal squamous cell carcinoma (n=1; 2%). Among the patients with CRC, 14 were microsatellite-instability-high (MSI-H), eight were not MSI-H (including microsatellite stable) and two were microsatellite unknown. Overall, five (12%), 11 (26%), 15 (36%) and 11 (26%) patients had received 0, 1, 2 or ≥3 prior lines of systemic therapy, respectively. Among 34 patients eligible for IRC assessment (excludes eight patients who were on treatment for ≤4 months), ORR was 29% (95% CI 15–47): two complete responses (CR; 6%), eight partial responses (PR; 24%), 17 stable disease (SD; 50%), two progressive disease (6%) and five not evaluable (15%). Median time to response was 1.8 months. Median duration of response (DoR), progression-free survival (PFS) and overall survival (OS) was 27.3 months (95% CI 5.6–not estimable [NE]), 7.2 months (95% CI 3.5–12.3) and 14.1 months (95% CI 6.1–36.5); median follow-ups were 7.5, 11.1 and 13.3 months, respectively. In the 19 patients with CRC eligible for IRC assessment, ORR was 47% (95% CI 24–71): two CR (11%), seven PR (37%), nine SD (47%) and one not evaluable (5%). Of the nine responders, five were MSI-H. Median DoR, PFS and OS for all IRC-eligible patients with CRC was 27.3 months (95% CI 5.6–NE), 29.4 months (95% CI 5.4–NE) and 29.4 months (95% CI 6.1–NE); median follow-ups were 7.5, 10.7 and 13.9 months, respectively. Treatment duration for all GI patients ranged from 0.3 to 44+ months. At data cut-off, 23 patients were alive. Treatment-related adverse events (TRAEs) were predominantly Grade 1/2. Grade 3/4 TRAEs occurred in seven (17%) patients (two increased transaminases; one each abnormal hepatic function, anaemia, hyperaesthesia, leukopenia, nausea, neutropenia and thrombopenia). No patients discontinued treatment due to TRAEs. With longer follow-up, larotrectinib continued to demonstrate long-lasting responses, extended survival and a favourable safety profile in patients with TRK fusion GI cancer, particularly in those with MSI-H CRC. These results support the wider adoption of next-generation sequencing panels, which include NTRK gene fusions, in patients with GI cancer.