Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children
Fusions involving the NTRK genes have been reported in a number of different cancers and are driver events when they occur. The fusions lead to a constitutively activated tyrosine kinase that acts through the classically proliferative MAP/ERK and PI3K pathways. The fusions occur rarely in some common cancers but much more frequently in a few rare tumors including Infantile fibrosarcoma, salivary gland carcinoma, and secretory breast carcinoma. This is a phase 1/2 trial of Larotrectinib - a selective inhibitor of TRK proteins.
A phase 1 trial of children and adults and a phase 2 trial of adults are both included in this publication. An ongoing phase 2 trial including children will be reported elsewhere. These single-arm trials gave either liquid or pill forms of Larotrectinib to patients on an ongoing basis until they reached a dose-limiting toxicity or had progression. Primary outcome was overall response rate by RECIST criteria.
55 patients were treated including 12 patients under 15 years of age (all children had infantile fibrosarcoma or other soft tissue sarcomas). Of all patients, the overall response rate was 75% and after a median of 9 months follow up, 86% of responders had undergone definitive surgery or continued to take Larotrectinib. Toxicity profile was limited with no DLTs and the most common grade 3/4 adverse event being increased liver enzymes, anemia, and fever. In a secondary analysis, the authors sequenced the NTRK gene in patients with drug resistance and found mutations that would likely inhibit Larotrectinib binding.
Although this is a phase I/II study, patients were selected for their good performance score, and the excellent results here mean that this drug will receive approval without a phase III study.