Outcome of Larotrectinib
In ½ phase clinical trial studying the use of Larotrectinib in pediatric
NTRK fusion-positive solid tumors, out of the fifteen patients who were
evaluated, fourteen showed a positive response according to the
investigator’s assessment. 26.6% of the cases showed a complete
response, a partial response in 66.6% of the cases, and stable disease
in 6.6% of the cases after an initial partial response.(23) Another
clinical trial investigated the effectiveness of Larotrectinib in NTRK
fusion-positive solid tumors and found that the drug demonstrated rapid,
potent, and long-lasting antitumor activity in both children and adults.
The trial reported a complete response in 13% of the patients, a
partial response in 62%, stable disease in 13%, progressive disease in
9%, and 4% of the cases were unable to be evaluated due to early
withdrawal from the study.(10) Additionally, Larotrectinib shows a
median time of response of 1.8 months in solid tumors of adults and
children.
In phase 1–2 clinical trial, two children with locally advanced tumors
showed enough tumor shrinkage during Larotrectinib treatment, and both
remained progression-free after 4.8 and 6.0 months of follow-up,
respectively. In addition to a study, a median of six cycles of
Larotrectinib was given to five children with locally advanced TRK
fusion sarcomas, and all patients achieved partial response prior to
surgical resection.(11,21,28)
Regarding a study that was conducted in the Children’s Hospital of
Philadelphia, University of Pennsylvania they mentioned their own
outcomes. Larotrectinib and Entrectinib have shown antitumor effects for
both primary CNS tumors and solid tumors reporting a case of
SPECC1L:NTRK3 fusion that achieved complete tumor regression.(11) In
another study of nine patients with primary CNS tumors treated with NTRK
inhibitors, disease control was observed in all evaluable patients with
stable disease in seven patients.(23) Also, a case report of pediatric
low-grade glioma with GKAP1-NTRK2 fusion reveals a significant
improvement after Larotrectinib clinically and radiologically by the
assessment of Neuro-oncology (RANO) criteria. It is worth mentioning
that there were no side effects over fourteen months of follow-up.(27)
In an earlier study, a case of LLG and CLIP2:NTRK2 fusion was treated
with the TRK inhibitor larotrectinib, which resulted in a 40% reduction
in volume that was detectable on magnetic resonance 54 days after the
therapy began. The reduction in radiological volume was accompanied by
significant clinical improvement and no drug-related toxicity.
Unfortunately, tumor progression and clinical decline were discovered
after 22 months of targeted therapy. The patient died five months later
as a result of tumor progression to the brainstem.(25) This case can be
considered as one of the cases of the treatment resistance development
that has been proposed suggesting the probability of first-generation
inhibitors resistance. At least two broad resistance mechanisms have
been identified. The first is associated with off-target alterations
that reactivate one of the cellular pathways associated with NTRK
fusions, typically the mitogen-activated protein kinase (MAPK). In fact,
the MAPK signaling cascade can be activated by a variety of signal
transducers unrelated to NTRK. This resistance mechanism includes the
acquisition of BRAFV600E or KRASG12D mutations, as well as
Mesenchymal-Epithelial Transition (MET) amplification. The second tumor
escape strategy (so-called on-target resistance) is linked to NTRK
fusion protein point mutations (i.e., solvent front, gatekeeper, and
xDFG mutations), which prevent drug binding. Next-generation NTRK
inhibitors (e.g., repotrectnib—TPX-0005, LOXO-195-BAY2731954) have
been developed in this regard, and have shown promising efficacy in
targeting these mutated fusion proteins.(24)