Efficacy and safety of larotrectinib in neurotrophic tyrosine receptor kinase fusion-positive solid tumors: A multicenter retrospective cohort study in Korea

초록

Background: Larotrectinib is a specific tropomyosin receptor kinase (TRK) inhibitor that received the approval for neurotrophic tyrosine receptor kinase (NTRK) fusionpositive solid tumors. To date, in addition to the combined results of prospective phase I/II clinical trials, efficacy and safety of larotrectinib in NTRK fusion-positive solid tumors have been mainly evaluated in case reports or series. Furthermore, the pivotal clinical trial includes only selected and fit patients with small proportion (less than 5%) of Asian ethnicity. Methods: We retrospectively analyzed patients who were treated with larotrectinib in Korea between November 2020 and August 2023. Patients who were diagnosed with an NTRK fusion-positive solid tumor using next-generation sequencing (NGS) and treated with larotrectinib at any line of therapy were eligible for the study. Patients who were administered larotrectinib in another prospective, interventional clinical trial were excluded. The primary endpoints were objective response rate (ORR) and time on treatment (TOT). Results: Thirty-four patients with 10 different cancer types were enrolled in 10 institutions. Eight patients (23.5%) were treatment-naive, and the remaining patients had undergone other anticancer therapies. NTRK fusion was detected by DNA and/or RNA NGS using 10 different panels. The ORR, including one complete response (CR), was 45.5%. One out of five patients harboring ETV6::NTRK3 fusion achieved CR, three had a partial response, and one had stable disease. Four patients with unknown fusion partner did not respond to larotrectinib. The median TOT was 11.3 months (95% confidence interval, 4.9eNE) and tended to be longer in the treatment-naive group than in previously treated patients. The most frequently observed adverse events of grade 3 were dizziness (5.9%) and an increased level of alanine or aspartate aminotransferase (5.9%). There was no permanent discontinuation of treatment due to adverse event. Conclusions: False positive, non-canonical fusion and co-existing oncogenic driver might have affected the lower clinical response in our data. Identification of a true oncogenic NTRK fusion is a key to effective use of TRK inhibitor.