LOXO-195 Shows Promise in Tumours with Acquired Resistance to First-generation TRK-targeted Agents

Results from patients enrolled in a phase I study and FDA expanded access programme presented at AACR 2019

LOXO-195 was safe, tolerable, and showed preliminary clinical efficacy in patients with solid tumours who had become resistant to prior TRK inhibition mediated by TRK kinase mutations, according to results from patients enrolled in a phase I trial and a US Food and Drug Administration (FDA) expanded access programme. The results were reported during the session on the next generation of clinical trials in molecularly driven therapy at the AACR Annual Meeting 2019 (Atlanta, 29 March – 3 April).

Larotrectinib is a selective TRK inhibitor approved in November 2018 by FDA for paediatric and adult TRK-fusion solid tumours, regardless of tumour origin. Emergent TRK kinase mutations are a common mechanism of resistance to TRK inhibitors. LOXO-195 is a selective TRK inhibitor developed to maintain potency against multiple TRK kinase domain mutations.

As of 3 December 2018, there were 20 patients who had received LOXO-195 through the phase I study (NCT03215511) and 11 patients who had received the second-generation TRK-targeted therapeutic through an FDA expanded access single patient protocol. Included patients had 11 different cancer types. All included patients, seven children and 24 adults, had previously been treated with at least one first-generation TRK-targeted agent.

In general, patients were eligible if were ≥4 weeks old with a locally identified TRK fusion and had progressed or were intolerant to at least one prior TRK inhibitor. Parallel 3+3 dose escalations were pursued in both adults and children, with intra-patient dose escalation permitted based on tolerance and pharmacokinetics. Patients aged <12 received body surface area-adjusted doses.

As of 3 December 2018, 29 of the patients were evaluable for response. Ten of the patients (34%) had a confirmed complete or partial response, as assessed by RECIST v1.1 criteria. 

When the researchers analyzed the data based on the mechanisms of underlying resistance to the first-generation TRK inhibitors, they found that nine of 20 patients (45%) whose tumours were determined to have become resistant by acquiring an NTRK gene mutation had a complete or partial response. None of the three patients whose tumours were determined to have become resistant by TRK-independent mechanisms responded to LOXO-195.

In the phase I study, a range of doses of LOXO-195, from 32 mg daily to 150 mg twice daily, were tested. Observed toxicities were consistent with the anticipated side effects of TRK inhibition. The most common adverse events were dizziness/ataxia, nausea/vomiting, anaemia, myalgia, abdominal pain, fatigue, and lymphopenia. Five patients in phase I study (all adults) had dose limited toxicities: ataxia/dizziness (4), and ataxia/vomiting (1). In terms of single patient protocol, one patient was dose-reduced and none discontinued for a treatment emergent adverse effect.

Dose selection is ongoing in both children and adults.

According to Dr David Hyman, Chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center in New York, US, the main limitations of the study are the small number of patients treated to date and the fact that some patients were treated through the FDA expanded access single patient protocol, which means that the completeness of data collection for these patients was less than for the patients enrolled in the clinical trial.

The study was funded by Loxo Oncology and Bayer.

Reference
Hyman D, Kummar S, Farago A, et al. CT127 - Phase I and expanded access experience of LOXO-195 (BAY 2731954), a selective next-generation TRK inhibitor (TRKi). American Association for Cancer Research Annual Meeting 2019; 29 March–3 April 2019: Atlanta, Georgia, USA.