Dr. George also discussed updated data for sorafenib in the treatment of desmoid tumors, as well as the importance of larotrectinib in TRK fusion-positive tumors.
Abnormally expressed Trk receptors or chimeric Trk fusion proteins are also well-characterized oncogenic drivers in a variety of neurogenic and non-neurogenic human neoplasms and are currently the focus of intensive clinical research.
After targeted RNA-sequencing, dual FISH fusion and array-CGH analysis, 7 of 13 tumors exhibited NTRK rearrangements (6 TPM3-NTRK1 and 1 EML4-NTRK3) and 3 a COL1A1-PDGFB fusion; in the other 3 neoplasms, all of which were positive with S100 (2 diffuse, 1 focal), we identified no rearrangement.
We provide recommendations for screening pediatric tumors for the presence of TRK fusions, including the use of immunohistochemistry or fluorescence in situ hybridization for patients with tumors likely to harbor TRK fusions.
Chromosomal rearrangements involving the NTRK1, NTRK2, and NTRK3 genes (NTRK genes), which encode the high-affinity nerve growth factor receptor (TRKA), brain-derived neurotrophic factor/neurotrophin-3 (BDNF/NT-3) growth factor receptor (TRKB), and neurotrophin-3 (NT-3) growth factor receptor (TRKC) tyrosine kinases (TRK proteins), act as oncogenic drivers in a broad range of pediatric and adult tumor types.
In patients with progressive disease, we routinely send tumor tissue for next generation sequencing (NGS) to assess for the presence of actionable genomic alterations such as HER2, BRAF, and TRK fusions and offer them the option of enrollment on clinical trials with agents targeting those or other identified alterations.
A recent "basket" study of larotrectinib, a TRK inhibitor, has demonstrated significant efficacy in TRK fusion-positive tumors of all types from infants to the elderly.
Genes encoding TRK are oncogenic drivers in multiple tumour types including infantile fibrosarcoma, papillary thyroid cancer and high-grade gliomas (HGG).
Both the anti-PD-1 mAbs and the TRK-targeting therapies share some basic features: (a) biomarker-based, well-defined rare patient population; (b) exceptionally high clinical efficacy, e.g., near 40% overall response rate (ORR) for pembrolizumab across 15 tumor types with MSI-H/dMMR and 75% ORR for larotrectinib across more than 12 tumor types with NTRK-fusion proteins; (c) durable responses lasting at least 6 months with complete responses observed; and (d) parallel development in adult and pediatric populations.
The treatment of patients with NTRK fusion-positive cancers with a first-generation TRK inhibitor, such as larotrectinib or entrectinib, is associated with high response rates (>75%), regardless of tumour histology.
The TRK inhibitor larotrectinib was well tolerated in paediatric patients and showed encouraging antitumour activity in all patients with TRK fusion-positive tumours.
Entrectinib's activity against both ALK and TRK proteins suggests a possible role in NB treatment, and it is currently under investigation in both pediatric and adult oncology patients.
Here, through an evaluation for TRK fusions across more than 7,000 patients with hematologic malignancies, we identified TRK fusions in acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), histiocytosis, multiple myeloma, and dendritic cell neoplasms.
This approach led to rapid tumor responses and extended the overall duration of disease control achieved with TRK inhibition in both patients.<b>Significance:</b> LOXO-195 abrogated resistance in TRK fusion-positive cancers that acquired kinase domain mutations, a shared liability with all existing TRK TKIs.
Analysis of the residual, resected tumor identified a chromoplectic TPM3-ALK rearrangement that involved many other known oncogenes and was confirmed by rtPCR.
Results from a phase I study show that the TRK inhibitor LOXO-101 is well tolerated and effective, with patients whose tumors bear NTRK fusions responding well and durably to this targeted therapy.