In a recent press release, Loxo Oncology announced an update on the status of their TRK (tropomyosin receptor kinase) inhibitor drug, larotrectinib (LOXO-101). Larotrectinib targets the NTRK genes, which encode for the TRK kinases. These kinases can be affected by gene fusions, leading to oncogenic activity.
Gene fusions are hybrid genes formed by previously separate genes. They occur when chromosomes, which carry genetic information, break apart, forming the hybrid gene which can activate a signaling pathway, the way cells communicate with one another. When this occurs, the fused gene plays an important role in oncogenesis (formation of cancer cells). Fusion genes can lead to tumor formation because they carry much more abnormal protein than non-fusion genes.
About 10-15% of gastrointestinal stromal tumors (GIST) lack mutations in KIT, PDGFRa. SDHx, or RAS pathway. Gene fusions or gene rearrangements that activate the NTRK1, NTRK3 or FGFR1 have recently been uncovered in this subset of GIST and are now actionable with TRK inhibitors. Further information on TRK fusions can be found on Loxo Oncology’s website.
As new biomarkers are identified, it will be important for KIT/PDGFRa negative patients to get the latest series of mutation and IHC tests, which should include BRAF/NH1 and many other known GIST related biomarkers including the NTRK fusion. Laboratory tests to see if the GIST tumor has these gene fusions can be performed on a paraffin embedded tumor sample that was previously obtained from surgery or biopsy.
“Since initiating our NAVIGATE Phase 2 trial in October 2015, we have been hard at work identifying TRK fusion patients and engaging with regulators to pursue a rapid path to market for larotrectinib,” said Josh Bilenker, M.D., chief executive officer of Loxo Oncology. “Based on current enrollment and written regulatory correspondence, we are able to provide this exciting update for larotrectinib, and begin planning for a potential commercial launch. We look forward to sharing top-line data for the NDA dataset in concert with worldwide regulatory filings. We are also excited to bring LOXO-292 and LOXO-195 forward into potential proof-of-concept studies in 2017.”
The larotrectinib, LOXO-292, and LOXO-195 updates are summarized in the press release, which can be found here.
Results of the clinical trial for LOXO-101 were shared at the recent ESMO Asia conference. Slides with more detail can be found here.