Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children

Abstract

Background: Fusions involving one of three tropomyosin receptor kinases (TRK) occur in diverse cancers in children and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK inhibitor, in adults and children who had tumors with these fusions.

Methods: We enrolled patients with consecutively and prospectively identified TRK fusion-positive cancers, detected by molecular profiling as routinely performed at each site, into one of three protocols: a phase 1 study involving adults, a phase 1-2 study involving children, or a phase 2 study involving adolescents and adults. The primary end point for the combined analysis was the overall response rate according to independent review. Secondary end points included duration of response, progression-free survival, and safety.

Results: A total of 55 patients, ranging in age from 4 months to 76 years, were enrolled and treated. Patients had 17 unique TRK fusion-positive tumor types. The overall response rate was 75% (95% confidence interval [CI], 61 to 85) according to independent review and 80% (95% CI, 67 to 90) according to investigator assessment. At 1 year, 71% of the responses were ongoing and 55% of the patients remained progression-free. The median duration of response and progression-free survival had not been reached. At a median follow-up of 9.4 months, 86% of the patients with a response (38 of 44 patients) were continuing treatment or had undergone surgery that was intended to be curative. Adverse events were predominantly of grade 1, and no adverse event of grade 3 or 4 that was considered by the investigators to be related to larotrectinib occurred in more than 5% of patients. No patient discontinued larotrectinib owing to drug-related adverse events.

Conclusions: Larotrectinib had marked and durable antitumor activity in patients with TRK fusion-positive cancer, regardless of the age of the patient or of the tumor type. (Funded by Loxo Oncology and others; ClinicalTrials.gov numbers, NCT02122913 , NCT02637687 , and NCT02576431 .).

Figure 1. Efficacy

Panel A shows a waterfall plot of the maximum change in tumor size, according to tumor type. One patient (asterisk) had a tropomyosin receptor kinase (TRK) solvent front resistance mutation (NTRK3 G623R) at baseline owing to previous therapy. One patient (dagger) had a pathological complete response. Data for 1 patient are not shown; the patient had clinical deterioration and no tumor measurements after baseline were recorded. GIST denotes gastrointestinal stromal tumor, and IFS infantile fibrosarcoma. Panel B shows a swimmer plot of outcomes in all 55 patients. One patient (double dagger) had a missing restaging scan after the confirmed response was established, and progression-free survival was censored at 3.7 months.

Figure 2. Kaplan–Meier Plots of Duration of Response among 44 Patients with a Response and Progression-free Survival among All 55 Patients

At 6 months, 83% of the responses were ongoing, and at 1 year, 71% of the responses were ongoing (Panel A). Tick marks indicate censored data. At 6 months, 73% of the patients were progression-free, and at 1 year, 55% of the patients remained progression-free (Panel B).