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

Abstract

Background NTRK1, 2 and 3 gene fusions occur across a wide array oftumors. 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 16C European Society for Medical Oncology 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]16C European Society for Medical Oncology 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected] an ongoingPhaseI dose escalation trial. Updated pharmacokinetic (PK) and safetydata for all enrolled patients (pts) are also reported. Methods This is an ongoing, open-label, multicenter, 3 + 3 dose escalation Phase I study.LOXO-101isadministeredorallyasaone-ortwice-dailydoseforcontinuous28- 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 sevenptswithNTRKfusionsacrossfivedifferenttumortypes.Sixofthesevenpatients were evaluable for response and all six have demonstrated a clinical response to LOXO- 101.Fiveofsixpatients(83%)haveachievedconfirmedRECISTpartialresponses.All sevenpatientsremainonstudywithadurationoftherapyfromonetofourteencycles. Noobjectiveanti-tumoractivityhasbeenobservedintreatedpatientswithoutanNTRK fusion. In total, 43 pts have been treated across five dose levels. Maximum plasma concentrationsofLOXO-101werereached30-60minutesfollowingdosing.The unbounddruglevelsofLOXO-101 appearsufficientforapproximately98%inhibition ofTRKA/B/Catpeakconcentrationsatalldoselevels.LOXO-101hasbeenwell 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 hasbeenwelltoleratedandhasshownpromisingandbroad anti-tumoractivityinpatientswithNTRKfusions.AllpatientswithNTRKfusionshave experienced objective tumor reductions and remain on study without disease progression.ThesedatasuggestthataLOXO-101 doseof100mgBIDiswell-tolerated andcapableofinducingdurablediseasecontrolinpatientswithNTRKgenefusions. Clinical trial indentification NCT02122913 Legal entity responsible for the study Loxo Oncology, Inc. Funding Loxo Oncology, Inc. Disclosure D.S.Hong:TravelpaidforbyLoxoOncology,Inc.S.Smith,S.Cruickshank: Consultant fees paid by Loxo Oncology, Inc. N. Nanda, M.C. Cox: Employee and stockholderofLoxoOncology,Inc.R.Doebele:ResearchgrantprovidedbyLoxo Oncology, Inc. All other authors have declared no conflicts ofinterest.