Posted: Friday, July 22, 2022
Hedwig E. Deubzer, MD, of Charité—Universitätsmedizin Berlin, and colleagues presented a case of ETV6-NTRK3–driven infantile fibrosarcoma that developed resistance to first- and second-generation TRK inhibitors. According to the investigators, an increase in the dose of the second-generation TRK inhibitor selitrectinib combined with the MEK1/2 inhibitor trametinib offered a significant treatment benefit, without detectable evidence of organ toxicity. This case report was published in JCO Precision Oncology.
A 13-month-old patient presented with progressing respiratory insufficiency that required invasive mechanical ventilation. A large right-sided intrathoracic mass was identified, but histopathologic analysis remained inconclusive. After two cycles of adjuvant chemotherapy, a third biopsy confirmed ETV6-NTRK3 fusion–positive infantile fibrosarcoma. The patient was then enrolled in a phase I/II trial for the first-generation TRK inhibitor larotrectinib but experienced disease progression after 4 months of treatment; the tumor continued to grow with subsequent chemotherapy.
Single-nucleotide variant analysis detected a mutation in NTRK3 that rendered larotrectinib ineffective, and therefore the patient was enrolled in a phase I/II trial of selitrectinib. A partial response was achieved after 2.5 months on treatment, but disease progression continued after 3 months. Selitrectinib was administered again after a gross tumor resection with bilobectomy was performed, but there was notable disease progression 6 weeks after surgery.
Due to the resistance to monotherapy with TRK inhibitors, the study authors increased the total dose of selitrectinib to 87 mg/m2 twice daily and combined it with trametinib. The reason for the addition of this agent was because oncogenic NTRK fusions may mediate elevated RAS/MAPK/ERK signaling cascade activity. After being administered this combination treatment, the patient did not experience disease progression for more than 1 year.
Disclosure: For full disclosures of the study authors, visit ascopubs.org.