Larotrectinib Has Antitumor Activity in TRK⁺ Pediatric Solid Tumors

Oncogenic gene fusions involving the neurotrophin tyrosine kinase receptor (TRK) genes NTRK1, NTRK2, and NTRK3 occur across a range of pediatric and adult malignancies. An orally administered ATP-competitive TRK inhibitor, larotrectinib, has demonstrated clinical activity in patients with tumors harboring NTRK fusions. Laetsch and colleagues sought to determine the safety and efficacy of larotrectinib in pediatric patients in an open-label phase I dose-escalation study. A total of 24 patients, 17 of whom harbored NTRK fusions, were enrolled and treated with larotrectinib in three dose cohorts. Of the TRK fusion–positive patients, 8 had infantile fibrosarcoma, 7 had other soft-tissue sarcomas, and 2 had papillary thyroid cancer. The primary endpoint was safety of larotrectinib, including dose-limiting toxicity. Secondary endpoints included identification of the maximum tolerated and recommended phase II doses of larotrectinib and assessment of antitumor activity. The majority of adverse events were grade 1–2. No treatment-related grade 4–5 adverse events occurred, and 2 treatment-related serious adverse events occurred. The maximum tolerated dose was not reached, and the recommended phase II dose was established at 100 mg/m². Overall, 14 of 15 (93%) patients with TRK fusion–positive tumors achieved objective responses to larotrectinib, including 9 patients with NTRK1 fusions, 1 patient with an NTRK2 fusion, and 7 patients with NTRK3 fusions, and the remaining patient exhibited tumor regression that did not meet the criteria for objective response. Further, none of the patients with TRK fusion–negative tumors responded to larotrectinib. Altogether, these findings indicate that larotrectinib is well tolerated and exhibits antitumor activity in pediatric patients with TRK fusion–positive solid tumors, supporting further clinical investigation, which is currently under way.

Laetsch TW, DuBois SG, Mascarenhas L, Turpin B, Federman N, Albert CM, et al. Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study. Lancet Oncol 2018 Mar 29 [Epub ahead of print].

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