Dr Massarelli on NTRK Inhibitors in NTRK Fusion+ NSCLC

Erminia Massarelli MD, PhD, MS, codirector, Lung Cancer and Thoracic Oncology Program, section chief, Thoracic Oncology, associate professor, Department of Medical Oncology & Therapeutics Research, City of Hope, discusses efficacy and safety data with the NTRK inhibitors larotrectinib (Vitrakvi) and entrectinib (Rozlytrek) in patients with non–small cell lung cancer (NSCLC) harboring NTRK fusions.

Approximately 0.2% of all patients with NSCLC cases have NTRK fusion–positive disease, Massarelli says. There are currently 2 FDA-approved agents for this population: larotrectinib and entrectinib. Larotrectinib was approved in 2018 for adult and pediatric patients with NTRK fusion–positive solid tumors. In 2019, entrectinib received accelerated approval for adult and pediatric patients at least 12 years of age with NTRK fusion–positive solid tumors.

Both entrectinib and larotrectinib have elicited strong and durable responses in patients with NSCLC, and both have effective brain penetration, which is important as 40% to 50% of patients with NTRK fusion–positive NSCLC can eventually develop brain metastases, Massarelli notes. Updated efficacy and safety data from an integrated analysis of the locally advanced or metastatic NTRK fusion–positive NSCLC cohorts of the pivotal phase 1 ALKA-372-001 (EudraCT 2012-000148-88), phase 1 STARTRK-1 (NCT02097810), and phase 2 STARTRK-2 (NCT02568267) trials were presented at the 2023 ASCO Annual Meeting. In this analysis, entrectinib elicited an intracranial overall response rate of 60.0% (95% CI, 26.2%-87.8%). The median duration of response in patients with baseline central nervous system metastases was 29.4 months (range, 5.6-29.4). Additionally, the median duration of intracranial response was not evaluable (NE; 95% CI, 8.0 months-NE).

The safety profiles of entrectinib and larotrectinib are manageable, with few grade 3 treatment-related adverse effects (TRAEs) observed with either agent in their respective pivotal trials. Grade 3 TRAEs associated with larotrectinib include anemia and decreased white blood cell counts, and grade 1/2 TRAEs associated with entrectinib include dysgeusia, fatigue, and diarrhea, Massarelli explains. Patients who receive entrectinib may also experience weight gain or fluid retention, Massarelli concludes.