Background: NTRK gene fusions are oncogenic drivers in various tumors. Laro, a highly selective, central nervous system-active TRK inhibitor, is approved for tumor-agnostic use in pts 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 pts with TRK fusion GI cancer treated with laro with longer follow-up. Methods: Pts with TRK fusion GI cancer in the phase II clinical trial NAVIGATE (NCT02576431) were included. Responses were independent review committee (IRC)-assessed (RECIST v1.1). Results: As of July 2022, 42 pts were enrolled. Median age was 67.0 years (range 32–90). Tumor types included colorectal (CRC; n=24), pancreatic (n=7), cholangiocarcinoma (n=4), gastric (n=3), and one each of appendiceal, duodenal, esophageal squamous cell carcinoma, and hepatocarcinoma. Among the pts with CRC, 14 were microsatellite-instability-high (MSI-H), eight were not MSI-H (which includes microsatellite stable), and two had unknown microsatellite status. Five (12%), 11 (26%), 15 (36%) and 11 (26%) patients had received 0, 1, 2, or ≥3 prior lines of systemic therapy, respectively. Four pts with CRC (three MSI-H) received prior immune-oncology (IO) therapy; best response to IO therapy was partial response (PR) in one pt, progressive disease (PD) in two pts, and not evaluable in one pt. Among 34 IRC-eligible pts, ORR was 29% (95% CI 15–47): two complete responses (CR; 6%), eight PR (24%), 17 stable disease (SD; 50%), two PD (6%), and five not evaluable (15%). Median time to response was 1.8 months (mo). Median duration of response (DoR), progression-free survival (PFS), and overall survival (OS) were 27.3 mo (95% CI 5.6–not estimable [NE]), 7.2 mo (95% CI 3.5–12.3), and 14.1 mo (95% CI 6.1–36.5). In the 19 IRC-eligible pts with CRC, ORR was 47% (95% CI 24–71): two CR (11%), seven PR (37%), nine SD (47%), and one not evaluable (5%); five of nine responders were MSI-H. Median DoR, PFS, and OS for all IRC-eligible pts with CRC were 27.3 mo (95% CI 5.6–NE), 29.4 mo (95% CI 5.4–NE), and 29.4 mo (95% CI 6.1–NE). Treatment duration ranged from 0.3 to 44+ mo. At data cutoff, 23 pts were alive. Treatment-related adverse events (TRAEs) were mostly Grade 1/2. Grade 3/4 TRAEs were reported in seven (17%) pts (two each increased alanine aminotransferase and aspartate aminotransferase; one each abnormal hepatic function, hyperesthesia, nausea, anemia, decreased neutrophils, decreased white blood cells, and decreased platelets). No pts discontinued treatment due to TRAEs. Results from the most recent cutoff date, July 2023, will be presented at the congress. Conclusions: Laro continued to demonstrate long-lasting responses, extended survival, and a favorable safety profile in pts with TRK fusion GI cancer, including those with MSI-H CRC. This supports the wider adoption of next-generation sequencing testing for NTRK gene fusions in pts with GI cancer. Clinical trial information: NCT02576431.