Posted: Thursday, April 7, 2022
Emily R. Blauel, MD, and Theodore B. Laetsch, MD, of the Children’s Hospital of Philadelphia, explored the success of recent clinical trials regarding the use of TRK inhibitors in cancers harboring NTRK fusions. Published in Cancer Genetics, their review focused on the use of approved first-generation and investigational second-generation TRK inhibitors in pediatric patients with NTRK fusion–driven cancers.
“The frequency and breadth in pediatric cancers harboring NTRK fusions continue to expand as more large-scale sequencing studies are conducted,” mentioned the study authors. “While these are rare events, their identification can lead to durable responses to well-tolerated targeted therapy. Thus, screening for NTRK fusions in the setting of a new diagnosis of tumors with a high prevalence of NTRK fusions and all high-risk, relapsed, and treatment-refractory tumors should be strongly considered.”
Larotrectinib is a selective inhibitor of TRK, and entrectinib is a multikinase inhibitor with additional activity against ALK and ROS1. Early-phase clinical trials evaluating these first-generation TRK inhibitors in children and adults demonstrated activity in tumors with NTRK fusions in a histology-agnostic manner. Notably, activity was observed in individuals with advanced and metastatic disease, as well as those who did not improve on previous therapy.
Many individuals exhibited acquired resistance to these agents, with these models resulting from amino acid substitutions that altered ATP-binding affinity, kinase domain conformation, and steric interference. Second-generation TRK inhibitors selitrectinib and repotrectinib were developed to tackle on-target resistance, although pediatric patients experience fewer cases of acquired resistance than adults, Drs. Blauel and Laetsch noted. Both agents are being evaluated in early-phase trials and have shown activity in patients with alterations in ROS1 and NTRK. However, acquired resistance to these inhibitors often still occurs, and studies regarding these resistance mechanisms are underway.
Disclosure: For full disclosures of the study authors, visit clinicalkey.com.