On 26 November 2018, the US Food and Drug Administration (FDA) granted accelerated approval to larotrectinib (VITRAKVI, Loxo Oncology Inc. and Bayer) for adult and paediatric patients with solid tumours that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, that are either metastatic or where surgical resection is likely to result in severe morbidity, and who have no satisfactory alternative treatments or whose cancer has progressed following treatment.
This is the second tissue-agnostic FDA approval for the treatment of cancer.
Approval was based on data from three multicentre, open-label, single-arm clinical trials: LOXO-TRK-14001 (NCT02122913), SCOUT (NCT02637687), and NAVIGATE (NCT02576431). Identification of positive NTRK gene fusion status was prospectively determined in local laboratories using next generation sequencing (NGS) or fluorescence in situ hybridization (FISH). NTRK gene fusions were inferred in three paediatric patients with infantile fibrosarcoma who had a documented ETV6 translocation by FISH. The major efficacy outcome measures were overall response rate (ORR) and response duration, as determined by a blinded independent review committee according to RECIST v1.1.
Efficacy was evaluated in the first 55 patients with unresectable or metastatic solid tumours harbouring an NTRK gene fusion enrolled across the three trials. All patients were required to have progressed following systemic therapy for their disease, if available, or would have required surgery with significant morbidity for locally advanced disease. Twelve patients were less than 18 years of age. A total of 12 cancer types were represented, with the most common being salivary gland tumours (22%), soft tissue sarcoma (20%), infantile fibrosarcoma (13%), and thyroid cancer (9%).
The ORR was 75% (95% CI: 61%, 85%), including 22% complete responses and 53% partial responses. At the time of database lock, median duration of response had not been reached. Response duration was 6 months or longer for 73%, 9 months or longer for 63%, and 12 months or longer for 39% of patients.
The safety of larotrectinib was evaluated in 176 patients enrolled across the three clinical trials, including 44 paediatric patients. The most common adverse reactions (≥20%) with larotrectinib were fatigue, nausea, dizziness, vomiting, increased AST, cough, increased ALT, constipation, and diarrhoea.
The recommended larotrectinib doses are 100 mg orally twice daily for adults and 100 mg/m2 orally twice daily (maximum of 100 mg per dose) for paediatric patients.
Full prescribing information for VITRAKVI is available here.
This indication is approved under accelerated approval and continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. FDA granted this application priority review, breakthrough therapy designation and orphan product designation.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System.