Does use of larotrectinib/larlotinib depend on specific genetic mutations?

Larotrectinib/Larotrectinib, as a potent inhibitor of TRKA, TRKB and TRKC, has demonstrated its significant therapeutic effect on TRK fusion-positive cancers in a series of phase I/II clinical trials, and its side effects are controllable. This drug works by blocking the ATP binding site of TRK family receptors. Its 50% inhibition constant in vitro is 5-11nmol/L, showing strong efficacy.

In November 2018, the U.S. Food and Drug Administration (FDA) granted accelerated approval to larotrectinib for the treatment of adult and pediatric patients with solid tumors carrying NTRK gene fusions who do not have known acquired resistance mutations. It is worth noting that there is currently no FDA-approved standard method for detecting NTRK gene fusions.

Although larotrectinib has been approved and granted Breakthrough Therapy Designation by theFDA, its accompanying diagnostic test has not yet been determined. Trial design for larotrectinib and other TRK inhibitors can use next-generation sequencing (NGS) or fluorescence in situ hybridization (FISH) technology according to the protocols of each designated laboratory. Although NGS is more commonly used than other methods, different methods may be used. The main advantage of NGS technology is that it can detect multiple genes simultaneously using limited tissue samples. This feature is particularly important in tumors where NTRK alterations are rare and in other tumors where potential molecular targets may exist (such as non-small cell lung cancer).

However, it should be noted that not allNGS platforms are designed to detect NTRK fusions, which becomes a potential problem. Furthermore, it has been found that DNA-based NGS analysis may occasionally fail to detect certain fusions involving NTRK2 or NTRK3 due to the presence of large intronic regions. Therefore, RNA-based fusion analysis has been proposed as an alternative or complementary approach to DNA-based strategies.