150O - Clinical safety and activity from a phase 1 study of LOXO-101, a selective TRKA/B/C inhibitor, in solid-tumor patients with NTRK gene fusions

Date 18 December 2016
Event ESMO Asia 2016 Congress
Session Developmental therapeutics
Topics Drug Development
Translational Research
Presenter David Hong
Citation Annals of Oncology (2016) 27 (suppl_9): ix46-ix51. 10.1093/annonc/mdw579
Authors D.S. Hong1, A. Dowlati2, H.A. Burris, III3, J.J. Lee4, M.S. Brose5, A.F. Farago6, T.M. Bauer3, M. Taylor7, A.T. Shaw6, S. Smith8, N. Nanda8, S. Cruickshank8, M.C. Cox8, R. Doebele9
  • 1Department Of Investigational Cancer Therapeutics, MD Anderson Cancer Center, 77030 - Houston/US
  • 2Hematology / Oncology, University Hospitals Case Medical Center, 44106 - Cleveland/US
  • 3Drug Development, Sarah Cannon Research Institute / Tennessee Oncology, PLLC, Nashville/US
  • 4Medical Oncology And Hematology, University of Pittsburgh Cancer Institute, Pittsburgh/US
  • 5Division Of Hematology/oncology, University of Pennsylvania, Philadelphia/US
  • 6Hematology / Oncology, Massachusetts General Hospital, Boston/US
  • 7Hematology / Oncology, Oregon Health Science University, Portland/US
  • 8Clinical Development, Loxo Oncology, Inc, 94107 - South San Francisco/US
  • 9Medical Oncology, University of Colorado Denver, 80247 - Denver/US

Abstract

Background

NTRK1, 2 and 3 gene fusions occur across a wide array of tumors. LOXO-101 is an orally bioavailable, potent, ATP-competitive, selective pan-TRK inhibitor. Here, we report response and durability data for patients with NTRK fusions enrolled in an ongoing Phase I dose escalation trial. Updated pharmacokinetic (PK) and safety data for all enrolled patients (pts) are also reported.

Methods

This is an ongoing, open-label, multicenter, 3 + 3 dose escalation Phase I study. LOXO-101 is administered orally as a one- or twice-daily dose for continuous 28-day cycles. Response is measured by RECIST. Plasma is obtained for PK analysis. Safety information is collected on all patients and reported regardless of their attribution to the study drug.

Results

As of March 25, 2016, 43 pts with solid tumors have been enrolled, including seven pts with NTRK fusions across five different tumor types. Six of the seven patients were evaluable for response and all six have demonstrated a clinical response to LOXO-101. Five of six patients (83%) have achieved confirmed RECIST partial responses. All seven patients remain on study with a duration of therapy from one to fourteen cycles. No objective anti-tumor activity has been observed in treated patients without an NTRK fusion. In total, 43 pts have been treated across five dose levels. Maximum plasma concentrations of LOXO-101 were reached 30-60 minutes following dosing. The unbound drug levels of LOXO-101 appear sufficient for approximately 98% inhibition of TRKA/B/C at peak concentrations at all dose levels. LOXO-101 has been well tolerated. The maximum tolerated dose has not been reached, and the most common adverse events are Grade 1 and 2 fatigue (33%), constipation (23%) and dizziness (23%).

Conclusions

LOXO-101 has been well tolerated and has shown promising and broad anti-tumor activity in patients with NTRK fusions. All patients with NTRK fusions have experienced objective tumor reductions and remain on study without disease progression. These data suggest that a LOXO-101 dose of 100mg BID is well-tolerated and capable of inducing durable disease control in patients with NTRK gene fusions.

Clinical trial indentification

NCT02122913

Legal entity responsible for the study

Loxo Oncology, Inc.

Funding

Loxo Oncology, Inc.

Disclosure

D.S. Hong: Travel paid for by Loxo Oncology, Inc. S. Smith, S. Cruickshank: Consultant fees paid by Loxo Oncology, Inc. N. Nanda, M.C. Cox: Employee and stockholder of Loxo Oncology, Inc. R. Doebele: Research grant provided by Loxo Oncology, Inc. All other authors have declared no conflicts of interest.