How selecting best therapy for metastatic NTRK fusion-positive non-small cell lung cancer?

The tropomyosin receptor kinase (TRK) family of receptor tyrosine kinases has become a focus of clinical interest because the NTRK genes (NTRK1-3) encoding them have been identified as oncogenic fusion genes in a wide range of different tumor types, including lung cancer. These NTRK gene fusions usually occur at a low frequency below 1%, in non-small cell lung cancer (NSCLC) in 0.1–0.2% of the cases and have been reported across a wide range of tumor types. The TRK fusion proteins encoded by such gene fusions have constitutively activated tyrosine kinase domains and constitute actionable targets for tyrosine kinase inhibitors (TKIs). The first generation TRK TKIs larotrectinib and entrectinib have been investigated in clinical phase I and II trials in solid tumors both in adult and pediatric patients and results have demonstrated high response rates that are durable and with generally good tolerability. This has led to approval of these TRK inhibitors by regulatory authorities in the USA, Europe and Japan as tumor agnostic treatment of advanced or recurrent NTRK fusion-positive cancers in adult and pediatric patients. With a focus on lung cancer, this review gives a background to NTRK fusion genes, presents clinical data for TRK inhibitors and discuss the issue of acquired resistance to TRK inhibition.