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1605 - Notch pathway inhibition with LY3039478 in soft tissue sarcoma (STS) and gastrointestinal stromal tumours (GIST)


11 Sep 2017




Clinical Research;  Cancers in Adolescents and Young Adults (AYA);  GIST


Olivier Mir


Annals of Oncology (2017) 28 (suppl_5): v521-v538. 10.1093/annonc/mdx387


O. Mir1, A. Azaro2, J.R. Merchan3, R. Chugh4, J.C. Trent5, J. Rodon6, U. Ohnmacht7, C. Smith8, G.J. Oakley III7, A. Le Cesne9, J. Soria10, K. Benhadji7, C. Massard9

Author affiliations

  • 1 Department Of Medical Oncology, Gustave Roussy Cancer Campus, 94800 - Villejuif/FR
  • 2 Molecular Therapeutics Research Unit, Vall d'Hebron University Hospital, 08035 - Barcelona/ES
  • 3 Department Of Medicine, Sylvester Comprehensive Cancer Center, 33136 - Miami/US
  • 4 Medical Oncology, University of Michigan, 48109 - Ann Arbor/US
  • 5 Department Of Medical Oncology, University of Miami Health System, 33136 - Miami/US
  • 6 Department Of Oncology, md anderson cancer center, Houston/US
  • 7 Department Of Medical Oncology, Eli Lilly and Company, Indianapolis/US
  • 8 Department Of Medical Oncology, Eli Lilly and Company, Windlesham/GB
  • 9 Department Of Medical Oncology, Gustave Roussy Cancer Campus, 94805 - Villejuif/FR
  • 10 Department Of Drug Development, Gustave Roussy Cancer Campus, 94800 - Villejuif/FR


Abstract 1605


LY3039478 (LY) is an orally bioavailable selective Notch inhibitor (Notch 1-4). Here we report on safety, pharmacodynamics (PD), and anti-tumour activity of LY in patients (pts) with STS/GIST.


This ongoing, multi-part, phase 1 trial enrolled pts with refractory advanced or metastatic STS and GIST, measurable disease, ECOG score ≤1, and baseline tumour tissue. Eligible pts received LY 50 mg three times per week (TIW), for a 28-day cycle until disease progression. Safety assessments were based on CTCAE V4.0. Tumour responses were assessed using RECIST 1.1 and Choi criteria. Primary objectives are to confirm the recommended phase 2 dose of LY and document antitumour activity. Secondary objectives are safety and toxicity, PD, progression-free survival (PFS) and overall survival (OS).


63 pts have been enrolled and received LY (24 males, 39 females; median age 58, range 31-76). 26 pts had leiomyosarcoma (LMS), 9 liposarcoma, 7 pleomorphic sarcoma, 6 angiosarcomas, 5 rhabdomyosarcoma and 10 GIST. 18 out of 39 (46%) pts with evaluable tumour samples were positive for Notch 1 ICD. 5% and 13% were positive for Notch 2 ICD, and Notch 3 respectively. Per RECIST, 2 out of 53 pts with STS had unconfirmed PR, and 20 SD. In GIST group, 4 pts had SD. Using Choi Criteria, 5 pts in STS had unconfirmed PR. Overall median PFS was 1.74 months (95% CI: 1.68-2.60) and consistent across histology groups (median PFS=2.23, 1.91 and 1.68 months for LMS, GIST and other STS, respectively). PFS rate at 3 months was 42% in LMS, 39% in GIST and 15% in other STS respectively. OS and biomarker/histologic analyses of pre and post treatment biopsies will be presented at the meeting. Most frequent related adverse events (all grades) occurring in ≥ 20% of pts included diarrhoea 44 (70%), vomiting 24 (38%), nausea 21 (33%), decreased appetite 17 (27%), fatigue 17 (27%) asthenia 16 (25%), hypophosphataemia 14 (22%).


LY suggested activity in pts with STS and GIST and had a manageable safety profile.

Clinical trial identification

Trial protocol number: Protocol I6F-MC-JJCA(e) Clinicaltrials.gov ID: NCT01695005 Release date: 08-July-2016

Legal entity responsible for the study

Eli Lilly and Company


Eli Lilly and Company


O. Mir: Speaker Bureau: Eli Lilly, Roche. Consulting/advisory board member: Amgen, Astra-Zeneca, Bayer, BMS, Eli Lilly, Netcancer, Novartis, Pfizer, Roche, Servier. A. Azaro: Member of Orion SMB. J.R. Merchan: Consulting/Advisory role: Exelixis. Research Funding: Rexahn, Eli Lilly, Novartis, Tocagen, Agensys, Tracon. R. Chugh: Stakeholder: Portala. Advisory board member: EMD Serano, Epizyme. Research funding: Eli Lilly, Novartis, Morphotek, Mabvax, Epizyme. J.C. Trent: Member of advisory board: Eli Lilly, Janssen, Eisai, Novartis, Eayer, Blueprint, Deciphera. J. Rodon: Advisor/board member: Eli Lilly, Novartis, and Servier. U. Ohnmacht: Stakeholder: Eli Lilly and Company. A. Le Cesne: Received honoraria: PharmaMar, Lilly, Amgen, Novartis, and Pfizer. J-C. Soria: Advisory board member: Eli Lilly and Company. C. Massard: Advisory board member, speaker, investigator: Amgen, Astellas, Astra Zeneca, Bayer, Celgene, Genentech, Ipsen, Janssen, Eli Lilly, Novartis, Pfizer, Roche, Sanofi, Orion. All other authors have declared no conflicts of interest.

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