A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion–Positive Solid Tumors

Abstract

Larotrectinib, a selective TRK tyrosine kinase inhibitor (TKI), has demonstrated histology-agnostic efficacy in patients with TRK fusion-positive cancers. While responses to TRK inhibition can be dramatic and durable, duration of response may eventually be limited by acquired resistance. LOXO-195 is a novel, selective TRK TKI designed to overcome acquired resistance mediated by recurrent kinase domain (solvent front and xDFG) mutations identified in multiple patients who have developed resistance to TRK TKIs. Activity against these acquired mutations was confirmed in enzyme and cell-based assays and in vivo tumor models. As clinical proof of concept, the first two patients with TRK fusion-positive cancers that developed acquired resistance mutations on larotrectinib were treated with LOXO-195 on a first-in-human basis, utilizing rapid dose titration guided by pharmacokinetic assessments. This approach led to rapid tumor responses and extended the overall duration of disease control achieved with TRK inhibition in both patients.

Efficacy of Larotrectinib inTRKFusion–Positive Cancers in Adults and Children

“…13 The NTRK3 G623R mutation and its NTRK1 G595R paralogue are termed “solvent front” mutations because they alter a hydrophilic solvent–exposed portion of the nucleotide-binding loop of the kinase domain, sterically interfere with larotrectinib binding, and reduce the inhibitory potency of larotrectinib. 14 Tumor-derivative material was available for three of the five remaining patients for central analysis. In all three patients, central pan-TRK immunohistochemical testing did not confirm the presence of an expressed TRK fusion, which raises the possibility that the test performed at the local laboratory was a false positive or that the molecularly identified fusion was not expressed at the protein level; this finding potentially explains the lack of response in these patients (see the Supplementary Appendix).…”

“…This finding is of immediate therapeutic relevance, given the early evidence of clinical activity that has been described with the next-generation TRK inhibitor LOXO-195. 14 Specifically designed to address acquired kinase domain mutations such as solvent front substitutions, LOXO-195 is currently being evaluated in a phase 1–2 study involving children and adults (ClinicalTrials.gov number, NCT03215511).…”

Foretinib Overcomes Entrectinib Resistance Associated with the NTRK1 G667C Mutation in NTRK1 Fusion–Positive Tumor Cells in a Brain Metastasis Model

“…TRK-C-G623R in 2 patients (33). However, the effect of LOXO195 against TRK-A-G667C is weaker than that against TRK-A-G595R.…”

Novel TLE4‐NTRK2 fusion in a ganglioglioma identified by array‐CGH and confirmed by NGS: Potential for a gene targeted therapy

“…These histological findings led to a diagnosis of ganglioglioma with atypical features, consistent with WHO grade I according to the most recent classification. 21 Regarding prognosis, a 5-year survival is possible in up to 73% of cases and a 3-year disease-free follow-up in 53% of cases of posterior fossa gangliogliomas. 17 A myriad of genetic targets and targeted therapies have emerged in the last several years, heralding an exciting era for potentially rapid progress.…”