Larotinib/larlotinib shows efficacy and tolerability in TRK fusion+ gastrointestinal cancer

Patients with TRK fusion-positive gastrointestinal cancer treated with larotrectinib experienced durable responses, encouraging survival and a favorable safety profile, according to updated data from the Phase 2 NAVIGATE basket trial in 2024 (NCT02576431). Study results include overall response rate (ORR) as assessed by Independent Review Committee (IRC) RECIST v1.1. Larotrectinib is the first highly selective CNS-active TRK inhibitor approved for the tumor-agnostic treatment of adult and pediatric patients with TRK fusion cancer; approval is based on tumor response and durable efficacy.

At the cutoff date of July 20, 2023, 43 patients were IRC eligible; response rate was 28% (95% confidence interval [CI], 15%-44%). In particular, there were 3 patients with complete response (CR; 7%), 9 patients with partial response (PR; 21%), 19 patients with stable disease (SD; 44%), 5 patients with progressive disease (PD; 12%), and 7 patients not evaluable (16%). At 24 weeks, the disease control rate among all patients was 47% (95% CI, 31%-62%). In this patient population, the median duration of response (range 1.7-11.1), median duration of response (DoR), progression-free survival (PFS), and overall Survival times (OS) were 27.3 months (95% CI, 5.6-not estimable [NE]), 6.1 months (95% CI, 4.8-9.2), and 12.5 months (95% CI, 6.8-29.4), respectively.

Among the 25 patients with colorectal cancer who met the IRC criteria, the ORR was 44% (95%CI, 24%-63%); 3 cases were CR (12%), 8 cases were PR (32%), 11 cases were SD (44%), 1 case was PD (4%), and 2 cases were not evaluable (8%). The 24-week disease control rate in these patients was 56% (95% CI, 35%-76%). The median DoR, PFS, and OS of all CRC patients meeting IRC criteria were 27.3 months (95% CI, 5.6-NE), 7.4 months (95% CI, 5.5-NE), and 29.4 months (95% CI, 6.8-NE), respectively. Treatment duration ranges from 0 to 56 months or longer.

At data cutoff,Twenty-eight (64%) [all] patients progressed on treatment, of whom 8 (18%) continued treatment after progression based on investigator assessment. Forty-four patients were included in the analysis; next-generation sequencing determined that all patients had NTRK gene fusions. The average age was 67.0 years (32-90 years). Tumor types included colorectal cancer (n=26), pancreatic cancer (n=7), cholangiocarcinoma (n=4), gastric cancer (n=3), and 1 case each of appendix, duodenum, esophageal squamous cell carcinoma, and liver cancer. Among colorectal cancer patients, 15 had microsatellite instability-high (MSI-H), 9 had undetectable MSI-H (including microsatellite stable), and 2 had unknown microsatellite status.

Thirty-eight patients (86%) had received systemic therapy, 37 patients (84%) had undergone surgery, and 4 patients (9%) had received radiation therapy. The average number of previous systemic treatment regimens was 2 (range 0-4); 6 patients (14%) had 0 previous lines of systemic treatment, 13 patients (30%) had 1 previous line, 16 patients (36%) had 2 previous lines, and 9 patients (20%) had 3 or more previous lines. In best response to prior systemic therapy, 1 patient (2%) had CR, 2 patients (5%) had PR, 11 patients (25%) had SD, and 10 patients (23%) had PD.

At the time of data cutoff,the incidence of adverse events (AEs) in patients with TRK fusion gastrointestinal cancer was ≥15%, and treatment-related adverse events (TRAEs) were "predominantly grade 1 or 2." Grade 3 or 4 TRAEs were reported in 7 (16%) patients, with the 2 most common AEs being increases in alanine aminotransferase and aspartate aminotransferase. Other AEs included nausea, vomiting, anemia, diarrhea, neutropenia, leukopenia, fatigue, weight loss, dizziness, and constipation. No patient discontinued treatment due to TRAEs.

These data support broader adoption of next-generation sequencing panels, includingNTRK gene fusions, to identify patients with gastrointestinal cancers who may benefit from treatment.