Abstract CT127: Phase I and expanded access experience of LOXO-195 (BAY 2731954), a selective next-generation TRK inhibitor (TRKi)
Authors: Hyman David , Kummar Shivaani , Farago Anna , Geoerger Birgit , Mau-Sorensen Morten , Taylor Matthew , Garralda Elena , Nagasubramanian Ramamoorthy , Natheson Michael , Song Lucy , Capra Michael , Jorgensen Mette , Ho Alan , Shukla Neerav , Smith Steve , Huang Xin , Tuch Brian , Ku Nora , Laetsch Theodore W. , Drilon Alexander , Hong David 
Published: August 2019

Background: Larotrectinib, a selective TRKi, is now FDA approved for pediatric and adult TRK-fusion solid tumors, regardless of tumor origin. Emergent TRK kinase mutations are a common mechanism of resistance to TRKis. LOXO-195, a selective TRKi, was developed to maintain potency against multiple TRK kinase domain mutations.

Methods: Patients (pts) received LOXO-195 via a Phase I study (NCT03215511, n=20) or FDA expanded access single patient protocol (SPP, n=11). Eligible pts were ≥4-weeks old with a locally identified TRK fusion and had progressed or were intolerant to at least 1 priorTRKi. Parallel 3+3 dose escalations were pursued in adults and children, with intra-patient dose escalation permitted based on tolerance and pharmacokinetics. Pts aged &lt;12 received BSA-adjusted doses.

Results: As of 03-DEC-2018, a total of 31 TRK-fusion pts (7 children, 24 adults) with 11 cancer types had been treated. Median duration on last prior TRKi was 9.5 months (range, 2-30). In the Phase 1, doses of 32 mg QD to 150mg BID were explored, and TEAEs (all grades/cause, in &gt;3 pts) were dizziness/ataxia (65%), nausea/vomiting (50%), anemia (30%), myalgia, abdominal pain, fatigue, & lymphopenia (all 20%). Five Phase I pts (all adults) had DLTs: ataxia/dizziness (4), and ataxia/vomiting (1). For the SPPs: 1 pt dose-reduced and none discontinued for a TEAE. Cmax at doses ≥50 mg exceeded the predicted IC50 for TRK kinase mutations. Pretreatment tissue and/or plasma, as available, defined TRK kinase mutation status. Preliminary efficacy overall, and by TRK kinase mutation status, is shown in the Table.

Discussion: LOXO-195 had preliminary efficacy in pts with resistance to prior TRKi mediated by TRK kinase mutations. The subset of pts who develop TRK-independent resistance are unlikely to benefit from LOXO-195. Dose selection is ongoing in both children and adults.

Confirmed best overall response, all dose levels, investigator assessed per RECIST 1.1 (n=29≠)Patient CohortTotal Patients,nCR/PR, nStable Disease, nPD, nNon- evaluable, †nORRTRK Kinase Mutation20963245% (9/20)Solvent Front14742150% (7/14)Gatekeeper4111125% (1/4)xDFG2110050% (1/2)Identified bypass300210% (0/3)Other/ Unknown*61#31117% (1/6)Overall291096434% (10/29)≠ 2 pts still on study drug and awaiting 1st response assessment not included in Table.† 4 pts non-evaluable: 1 discontinued drug for unrelated new cancer diagnosis &lt;28 days after start of study drug and 3 withdrew within 14 days of study drug start.* Includes 1 pt with no identified TRK kinase resistance mutationor bypass alteration# and 5 pts who could not be tested.# Pt intolerant but not resistant to prior TRKi

Citation Format: David Hyman, Shivaani Kummar, Anna Farago, Birgit Geoerger, Morten Mau-Sorensen, Matthew Taylor, Elena Garralda, Ramamoorthy Nagasubramanian, Michael Natheson, Lucy Song, Michael Capra, Mette Jorgensen, Alan Ho, Neerav Shukla, Steve Smith, Xin Huang, Brian Tuch, Nora Ku, Theodore W. Laetsch, Alexander Drilon, David Hong. Phase I and expanded access experience of LOXO-195 (BAY 2731954), a selective next-generation TRK inhibitor (TRKi) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT127.