LOXO-195 could be an option for tumors resistant to first-generation TRK inhibitors
medwireNews: Early findings point to the antitumor efficacy of the next-generation TRK inhibitor LOXO-195 in patients with NTRK fusion-positive cancers and NTRK resistance mutations acquired during treatment with first-generation agents.
Presenting the pooled results from a phase I clinical trial and an FDA expanded access program at the AACR Annual Meeting 2019 in Atlanta, Georgia, USA, David Hyman (Memorial Sloan Kettering Cancer Center, New York, USA) said that LOXO-195 could “provide a continuum of care” for these patients.
The trial included 20 pediatric, adolescent, or adult patients with NTRK fusion-positive cancers who had progressed on or were intolerant to a prior TRK inhibitor, while the 11 participants of the expanded access program had similar eligibility criteria but were unable to enroll in the trial due to medical comorbidity or logistical barriers.
LOXO-195, which is a selective inhibitor targeting multiple TRK kinase domain mutations, was administered at doses ranging from 50 mg once daily to 150 mg twice a day in the trial. Adult and adolescent participants of the expanded access program received doses ranging from 50–150 mg twice daily, whereas for the pediatric participants, the starting dose was 20 mg given twice every day.
The most common tumor type across the 31 patients was sarcoma (16%), but 14 other tumor types were observed in the cohort, including gastrointestinal stromal tumors (15%), pancreatic cancer (10%), breast cancer (10%), non-small-cell lung cancer (6%), and kidney cancer (3%).
Five patients in the clinical trial experienced dose-limiting toxicities – three cases each of ataxia and dizziness and two cases of vomiting. All of these were “on-target” toxicities, occurring as a result of TRK inhibition in the central nervous system, and all were reversible with dose interruption or reduction, said Hyman.
Ataxia (20%), dizziness (15%), and vomiting (10%) were also the most common adverse events of grade 3 in the trial, and there were no grade 4 or 5 toxicities.
The presenter stated that LOXO-195 was well tolerated at doses below 100 mg twice daily, but the “optimal dose and schedule [is] still being explored.”
The objective response rate for the 29 evaluable patients was 34%, with nine of the 10 responses observed in patients with acquired TRK kinase domain mutations.
Analysis by type of mutation showed that response rates were highest for individuals with solvent front (n=14) and xDFG (n=2) mutations, at 50% each, whereas only 25% of the four patients with gatekeeper mutations responded to treatment with LOXO-195.
“Additional data are needed to define activity in each specific kinase mutations,” Hyman commented.
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