Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study

Abstract

Summary Background Gene fusions involving NTRK1, NTRK2, or NTRK3 (TRK fusions) are found in a broad range of paediatric and adult malignancies. Larotrectinib, a highly selective small-molecule inhibitor of the TRK kinases, had demonstrated activity in preclinical models and in adults with tumours harbouring TRK fusions. The primary aim of this study was to assess the safety of larotrectinib in paediatric patients. Methods This multicentre, phase 1 study enrolled infants, children and adolescents aged 1 month to 21 years with locally advanced or metastatic solid or central nervous system tumours regardless of TRK fusion status. Other key inclusion criteria included evaluable and/or measurable disease according to disease specific criteria, Karnofsky (≥16 years of age) or Lansky (<16 years of age) performance score of ≥50, adequate organ function, and full recovery from the acute toxic effects of all prior anticancer therapy. Larotrectinib was administered orally, twice daily (BID) on a continuous 28-day schedule, in increasing dose levels, according to a rolling six design. The primary endpoint of the phase 1 dose escalation component was the safety of larotrectinib, including dose limiting toxicity, in paediatric patients with advanced solid or primary central nervous system tumours treated with at least one dose of larotrectinib. Secondary endpoints included the maximum tolerated dose or appropriate dose of larotrectinib for further clinical investigation, pharmacokinetics, and an assessment of antitumour activity including the objective response rate (ORR). Reported here are the patients enrolled to the phase 1 dose escalation cohort which has completed enrolment. Follow-up of these patients and enrolment to phase 2 cohorts are ongoing on this protocol. This trial is registered with ClinicalTrials.gov, number NCT02637687. Results Twenty-four patients (17 with tumours with TRK fusions, seven without) with a median age of 4·5 years (range 0·1–18) were enrolled to three dose cohorts. Patients with TRK fusion cancers had diagnoses of infantile fibrosarcoma (n=8), other soft tissue sarcomas (n=7) and papillary thyroid cancer (n=2). Adverse events were predominantly grade 1; the most common were increased alanine and aspartate aminotransferase [10 (42%) of 24 each] and leukopenia and decreased neutrophil count [5 (21%) of 24 each]. Grade 3 alanine aminotransferase elevation in a patient without a TRK fusion with progressive disease was the only dose limiting toxicity and resulted in larotrectinib discontinuation. No other patients discontinued larotrectinib for adverse events. No grade 3 treatment-related adverse events occurred in more than one patient and no grade 4 or 5 treatment-related adverse events were observed. Two larotrectinib related serious adverse events were observed: grade 3 nausea and grade 3 ejection fraction decrease during the 28-day follow-up after discontinuing larotrectinib and while on anthracyclines [1 (4%) of 24 each]. The maximum tolerated dose was not defined. A dose of 100 mg/m2 (maximum of 100 mg/dose) BID was determined to be the recommended phase 2 dose based on pharmacokinetics and antitumor activity. In patients with TRK fusion cancers and measurable disease by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1, the objective response rate (ORR) was 93% (14 of 15 patients), with the remaining patient that did not meet RECIST partial response criteria showing tumour regression. In patients without documented TRK fusion cancers, the ORR was 0% (0 of 7 patients). Interpretation The TRK inhibitor larotrectinib was well tolerated in paediatric patients. A recommended phase 2 dose of 100mg/m2 (cap of 100 mg) was defined for infants, children, and adolescents, regardless of age. Larotrectinib demonstrated antitumour activity in all patients with TRK fusion-positive tumours. Funding Loxo Oncology