Notch pathway inhibition with LY3039478 in soft tissue sarcoma and gastrointestinal stromal tumours

Olivier Mir, Analia Azaro, Jaime Merchan, Rashmi Chugh, Jonathan Trent, Jordi Rodon, Ute Ohnmacht, J. T. Diener, Claire Smith, Eunice Yuen, Gerard Joseph Oakley, Axel Le Cesne, Jean Charles Soria, Karim A. Benhadji, Christophe Massard

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Background: LY3039478 is an orally bioavailable selective Notch inhibitor. This phase 1a/b trial evaluated the safety, pharmacokinetics and antitumour activity of LY3039478 in patients with soft tissue sarcoma (STS) and gastrointestinal stromal tumour (GIST). Methods: This multipart, phase 1 trial enrolled patients with refractory advanced/metastatic STS and GIST, measurable disease, Eastern Cooperative Oncology Group ≤1 and baseline tumour tissue. Eligible patients received LY3039478 50mg/75 mg three times per week, for 28-day cycle until disease progression. Safety assessments were based on Common Terminology Criteria for Adverse Events, V4.0. Tumour responses were assessed using Response Evaluation Criteria in Solid Tumours (RECIST 1.1) and Choi criteria. Primary objectives were to confirm the recommended phase 2 dose of LY3039478 and document the antitumour activity. Secondary objectives were safety and toxicity, pharmacokinetics (PK), progression-free survival (PFS) and overall survival (OS). Results: Sixty-nine patients were enrolled and received LY3039478 (27 males, 42 females; median age 58, range 31–78). 16/37 (43%) patients with evaluable samples were positive for Notch 1 immunohistochemistry. Per RECIST 1.1, in leiomyosarcoma (LMS) group (n = 29), ten (36%) had stable disease (SD) and one (4%) had unconfirmed partial response (PR). In GIST group (n = 13), four (31%) had SD. Among other STS subtypes (n = 27), one patient with angiosarcoma had unconfirmed PR, six (21%) had SD. Median PFS was 1.9 months (95% confidence interval:1.6–3.3) for LMS, 1.9 months (0.3–6.1) for GIST and 1.7 months (1.4–2.2) for other STS groups. Median OS was 7.4 months (4.3–non-evaluable [NE]) for LMS, 16.5 months (3.9–16.5) for GIST and 5.6 months (3.4-NE) for other STS groups. Most common adverse events were diarrhoea, nausea, vomiting and decreased appetite. Conclusion: LY3039478 suggested a modest clinical activity in patients with STS and GIST and had a manageable safety profile.

Original languageEnglish (US)
Pages (from-to)88-97
Number of pages10
JournalEuropean Journal of Cancer
Volume103
DOIs
StatePublished - Nov 2018

Keywords

  • Angiosarcoma
  • Gastrointestinal stromal tumours
  • Leiomyosarcoma
  • Liposarcoma
  • Notch inhibitor
  • Pleomorphic sarcoma
  • Rhabdomyosarcoma
  • Soft tissue sarcoma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Notch pathway inhibition with LY3039478 in soft tissue sarcoma and gastrointestinal stromal tumours'. Together they form a unique fingerprint.

  • Cite this

    Mir, O., Azaro, A., Merchan, J., Chugh, R., Trent, J., Rodon, J., Ohnmacht, U., Diener, J. T., Smith, C., Yuen, E., Oakley, G. J., Le Cesne, A., Soria, J. C., Benhadji, K. A., & Massard, C. (2018). Notch pathway inhibition with LY3039478 in soft tissue sarcoma and gastrointestinal stromal tumours. European Journal of Cancer, 103, 88-97. https://doi.org/10.1016/j.ejca.2018.08.012