Therapeutics: anticancer agent: larotrectinib

TRK (tropomyosin receptor kinase) fusion cancers occur when an NTRK gene fuses with another, unrelated gene, leading to the formation of an altered TRK protein

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

  1. A. Drilon, et al., N. Engl. J. Med. 378, 731 (2018).
  2. T.W. Laetsch, et al., Lancet Oncol. 19, 705 (2018).

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