This TRK fusion protein becomes constitutively active or overexpressed, which triggers a signalling cascade. They act as oncogenic drivers, leading to TRK fusion cancers that can occur anywhere in the body in both children and adults.
A potential treatment for this form of cancer is being developed by Loxo Oncology and Bayer. Larotrectinib is an oral TRK inhibitor.
Patients with TRK fusion-positive cancers were enrolled in a Phase I/II trial to evaluate its efficacy and safety.1 The Phase I part involved adults, a Phase I/II study was in children and a Phase II study enrolled adolescents and adults.
In all, 55 patients aged from 4 months to 76 years were enrolled and treated; there were 17 different TRK fusion-positive tumour types across the group. The overall response rate was 75%; and, after a year, 71% of the responses were ongoing, with 55% of patients remaining progression free. Adverse events were largely grade 1 and there were no drug-related discontinuations.
Results in a group of paediatric patients look promising. In a multicentre, open label Phase I/KK study, infants, children and adolescents aged from 1 month to 21 years with locally advanced or metastatic solid tumours or CNS tumours that had relapsed, progressed or were non-responsive to available therapies regardless of TRK fusion status, were enrolled.2
Patients with locally advanced infantile fibrosarcoma whose surgery would be disfiguring were also eligible.
A total of 24 patients, 17 of whom had a documented TRK fusion, were enrolled into three dose cohorts and given oral doses of larotrectinib twice a day in capsule or liquid format — on a continuous 28-day schedule — in increasing doses that were adjusted for age and body weight.
Cohorts 1 and 2 were given doses that were predicted to achieve an area under the curve equivalent to the adult doses of 100 or 150 mg twice daily; cohort 3 was given a dose of 100 mg/m2 twice a day, regardless of age.
The Phase I results have been reported and the Phase II part is ongoing. Adverse events were largely grade 1 or 2 and the most common were increased alanine and aspartate aminotransferase, leucopenia, a decreased neutrophil count and vomiting.
The maximum tolerated dose was not reached and 93% of those with TRK fusion-positive cancers achieved an objective response, whereas none of those with TRK fusion negative cancers did.
References
- A. Drilon, et al., N. Engl. J. Med. 378, 731 (2018).
- T.W. Laetsch, et al., Lancet Oncol. 19, 705 (2018).
