On 26 November 2018, the FDA granted accelerated approval to the first-in-class tropomyosin receptor-kinase (TRK) inhibitor larotrectinib (Vitrakvi®, Loxo Oncology/Bayer) for the treatment of adult and paediatric patients with solid tumours that are metastatic or not amenable to surgery, harbour the neurotrophic receptor tyrosine kinase (NTRK) gene fusion in the absence of known acquired resistance mutations, and whose cancer progressed following treatment or for whom are no satisfactory other treatment options available.

LOXO-TRK-14001, SCOUT, and NAVIGATE

The FDA approval was based on the pooled of three multicentre, open-label, single-arm clinical studies; the LOXO-TRK-14001 (NCT02122913), the SCOUT (NCT02637687), and the NAVIGATE (NCT02576431) which enrolled 55 patients with unresectable or metastatic solid tumours who had progressed following prior systemic therapy and with a confirmed NTRK gene fusion identified by next-generation sequencing (NGS) or fluorescence in situ hybridisation (FISH). In three paediatric patients, NTRK gene fusions were assumed based on documented ETV6 translocations by FISH. The efficacy outcome measures included the overall response rate (ORR) by RECIST 1.1 and the duration of response (DoR), as confirmed by a blinded independent review committee (BIRC).

Of the 55 enrolled patients, 12 were less than 18 years old. The participants displayed a total of 12 different cancer types, including salivary gland tumours (22%), soft tissue sarcoma (20%), infantile fibrosarcoma (13%), and thyroid cancer (9%). The ORR by BIRC measured 75% (95% CI, 61-85%), which was made up of 22% complete responses and 53% partial responses. The 6-month response rate (RR) was 73%, the 9-month RR 63% and the 12-month RR was 39%. At the time of database lock, the median DoR had not yet been reached.

Safety

The larotrectinib safety analysis included 176 patients (44 paediatric) who participated in the three clinical trials. Common adverse reactions (≥20%) with larotrectinib included fatigue, nausea, dizziness, vomiting, increased aspartate transaminase (AST), cough, increased alanine transaminase (ALT), constipation, and diarrhoea.

Full prescribing information Vitrakvi®.