1482PD - Notch pathway inhibition with LY3039478 in soft tissue sarcoma (STS) and gastrointestinal stromal tumours (GIST)

Date 11 September 2017
Event ESMO 2017 Congress
Session Sarcoma
Topics Drug Development
Cancer in Adolescents
GIST
Sarcoma
Presenter Olivier Mir
Citation Annals of Oncology (2017) 28 (suppl_5): v521-v538. 10.1093/annonc/mdx387
Authors 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
  • 1Department Of Medical Oncology, Gustave Roussy Cancer Campus, 94800 - Villejuif/FR
  • 2Molecular Therapeutics Research Unit, Vall d'Hebron University Hospital, 08035 - Barcelona/ES
  • 3Department Of Medicine, Sylvester Comprehensive Cancer Center, 33136 - Miami/US
  • 4Medical Oncology, University of Michigan, 48109 - Ann Arbor/US
  • 5Department Of Medical Oncology, University of Miami Health System, 33136 - Miami/US
  • 6Department Of Oncology, md anderson cancer center, Houston/US
  • 7Department Of Medical Oncology, Eli Lilly and Company, Indianapolis/US
  • 8Department Of Medical Oncology, Eli Lilly and Company, Windlesham/GB
  • 9Department Of Medical Oncology, Gustave Roussy Cancer Campus, 94805 - Villejuif/FR
  • 10Department Of Drug Development, Gustave Roussy Cancer Campus, 94800 - Villejuif/FR

Abstract

Background

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.

Methods

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).

Results

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%).

Conclusions

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

Funding

Eli Lilly and Company

Disclosure

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.