ETV6-NTRK3 G623R

Patients treated with RET protein tyrosine kinase inhibitors (TKIs) selpercatinib or pralsetinib develop RET TKI resistance by secondary RET mutations or alterative oncogenes, of which alterative oncogenes pose a greater challenge for disease management because of multiple potential mechanisms and the unclear tolerability of drug combinations. Preclinical experiments validated selpercatinib plus larotrectinib or entrectinib inhibited RET/NTRK3 dependent cells, whereas selpercatinib plus entrectinib was necessary to inhibit cells with RET/NTRK3/ALK triple alterations or a mixture of cell population carrying these genetic alterations. Thus, RET-altered MTC adapted to selpercatinib and larotrectinib with acquisition of ETV6::NTRK3 and EML4::ALK oncogenes can be managed by combination of selpercatinib and entrectinib providing proof-of-concept of urgency of incorporating molecular profiling in real-time and personalized N-of-1 care transcending one-size-fits-all approach.

An ETV6:NTRK fusion detected in tumor tissue, was treated with larotrectinib; at progression, sequencing of cfDNA identified an NTRK3 G623R alteration as the acquired mechanism of resistance; the patient enrolled in a clinical trial of a second generation TRK inhibitor with clinical benefit. In metastatic PanNENs, cfDNA-based NGS identified tumor-associated mutations in 66% of plasma samples with a high level of plasma-tissue agreement in PanNEN associated genes. Clonal evolution, actionable alterations, and resistance mechanisms were detected through circulating cfDNA genotyping.

One patient who was treated with larotrectinib for an ETV6:NTRK3 fusion detected on tumor sequencing ultimately developed resistance with a NRTK3 G623R alteration identified through sequencing of cfDNA at radiographic disease progression. NGS of cfDNA in metastatic PanNENs, across the spectrum of WHO-defined tumor grade/differentiation, revealed tumor-associated genetic alterations in 66% of plasma samples. Clonal evolution, actionable alterations, and resistance mechanisms can be detected through circulating cfDNA genotyping and may serve as a powerful tool to better understand disease biology of a disease that often changes over time and through therapy.

Drugs targeting tyrosine kinases TrkA/B/C and ROS1, such as larotrectinib and entrectinib, are proven highly efficacious in diverse adult and pediatric tumor types (ORR > 75%)...The use of second generation of TKI, such as repotrectinib to against these acquired resistance mutations, has been explored in clinical trials and reported unsatisfied efficacy in patients under acceptable dosages, which might due to its broader inhibition of multiple kinases... Collectively, these studies have shown SIM1803-1A is a potent Trk/ROS1 dual inhibitor with better safety potentially from improved kinase selectivity. SIM1803-1A is currently at IND submission stage and represents a promising clinical candidate for the treatment-naïve and acquired-resistance NTRK/ROS1 fusion-positive malignancies. Research Funding: None