O-020Activity of larotrectinib in patients with TRK fusion GI malignancies

Introduction: TRK fusions arise from aberrant rearrangements of neurotrophic receptor kinase genes NTRK1-3 with a variety of gene partners; these are constitutively active ligand-independent oncogenic drivers in a broad range of solid tumors. The highly selective TRK inhibitor larotrectinib achieved objective responses of 75% by independent review (80% by investigator assessment) in patients with a wide variety of TRK fusion cancers (Drilon et al., NEJM, 378:731-739, 2018). We report here on the activity and safety of larotrectinib in the treatment of GI malignancies from three separate studies (NCT02122913, NCT02637687, and NCT02576431). Methods: Patients with locally advanced or metastatic solid tumors who had received prior standard therapy or had no treatment alternatives were eligible. Evidence of a NTRK gene fusion as detected by CLIA or equivalently certified laboratory was required. Larotrectinib (100 mg or 150 mg po bid) was administered until disease progression, withdrawal, or unacceptable toxicity. Disease status was assessed by investigators and by independent radiologic review using RECIST version 1.1. Results: As of 17th July 2017, a total of 55 patients across 17 cancer types were enrolled in the overall study and constitute the safety population. A sub-group of 12 patients (age range 32-74 years) had a GI malignancy, including 4 with colorectal cancer, 3 with GIST, 2 with cholangiocarcinoma, and one each with adenocarcinoma of the appendix, pancreas and a peri-rectal soft tissue sarcoma. Nine of those patients had fusions involving NTRK1; all 3 GIST patients had ETV6-NTRK3 gene fusions. Objective responses were documented in 8 of 12 patients (75%; per investigator), including colon cancer, pancreatic carcinoma, cholangiocarcinoma and GIST, with one complete response (GIST) and 7 partial responses. Stable disease noted as best response in 3 patients including a patient with appendiceal cancer, and one patient with cholangiocarcinoma exhibited primary progressive disease. Responses were rapid with maximum time to first response < 2 months. Duration of response ranged from 3.5 months (pancreas) to 22.9 months (GIST; ongoing). Adverse events across all study patients were principally grade 1 or 2. The most common grade 3 events were anemia (11%), increased ALT or AST (7%), increased body weight (7%), or decreased neutrophil count (7%). No patient discontinued larotrectinib due to a drug-related adverse event. Conclusion: TRK inhibition with larotrectinib in patients with TRK fusion GI malignancies was well tolerated and resulted in rapid induction of durable responses