Early Results for Next-Generation TRK Inhibitor LOXO-195 Look “Very Promising”

April 23, 2019
Christina Bennett, MS

The investigators tested the agent in patients who had solid tumors with NTRK gene fusions that had developed resistance to other TRK inhibitors.

The investigational next-generation tyrosine receptor kinase (TRK) inhibitor LOXO-195 appeared to be tolerable and showed clinical benefit in patients who had solid tumors with NTRK gene fusions that had developed resistance to other TRK inhibitors, according to data from a phase I trial (ClinicalTrials.gov identifier: NCT03215511) and US Food and Drug Administration (FDA) Expanded Access program. The results were presented at the 2019 American Association for Cancer Research (AACR) Annual Meeting, held March 29–April 3 in Atlanta, Georgia (abstract CT127).

“As in most targeted therapies, unfortunately patients develop resistance pretty quickly,” said Olivier Elemento, PhD, the director of the Englander Institute of Precision Medicine at Weill Cornell Medicine and NewYork-Presbyterian, during an interview with Cancer Network. He explained that the development of therapeutic resistance is largely due to mutations that form in the target of the drug and prevent the drug from binding. “Therefore, there has to be some thinking about what to do next.”

In the current study, a total of 31 patients (24 adults and 7 children) who had previously been treated with a TRK inhibitor and had developed resistance received the investigational agent LOXO-195; 20 patients received LOXO-195 as part of the phase I trial and 11 patients received LOXO-195 as part of an FDA Expanded Access program.

The median age of the patients was 37 years (range, 1.25–72 years), and the majority were female (71%). Most patients (69%) received larotrectinib as their prior TRK inhibitor; the remaining received entrectinib (28%) or PLX7486 (3%). The median duration of the prior TRK inhibitor was 11 months (range, 2–30 months). The TRK fusion patients had was NTRK1 (48%), NTRK2 (3%), or NTRK3 (48%). The population of patients on study represented 15 different solid tumor types.

For patients in the phase I trial, the most common grade 3 events were dizziness (15%), ataxia (20%), vomiting (10%), and anemia (10%). For patients in the FDA Expanded Access program, the only reported grade 3 event was diarrhea in 1 patient. No grade 4 events were seen in either group. Five patients had dose-limiting toxicities in the phase I trial, and no dose-limiting toxicities were seen in patients in the FDA Expanded Access program.

“The safety profile is somewhat similar to the original larotrectinib safety profile,” said Elemento. He described the adverse events as “pretty mild.”

The objective response rate was 45% in the phase I trial, with 9 patients having a complete or partial response, 6 having stable disease, and 2 having disease progression; 3 patients were nonevaluable. Responses were also assessed by resistance mechanism (ie, TRK kinase mutation), which revealed that 7 of 14 patients (50%) with a solvent-front mutation, 1 of 4 (25%) with a gatekeeper mutation, and 1 of 2 (50%) with an xDFG mutation had a complete or partial response. No responses were seen in the 3 patients with a bypass mutation.

“It’s a small number of patients, but the response rate is actually quite substantial,” said Elemento. He explained that the lack of response among patients with a bypass mutation makes sense, given that such a mutation is not in the drug target itself. Essentially, he said, the LOXO-195 is not effective because there’s no mutation in the target.

If patients progress on larotrectinib, the prognosis is “pretty dire,” commented Elemento. “Having a drug that seems tolerable and that has such high efficacy, even in 20 patients, I think is very promising.”