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Poster display session

3309 - FAK-PD1: a phase I/IIa trial of FAK (defactinib) & PD-1 (pembrolizumab) inhibition

Date

10 Sep 2017

Session

Poster display session

Topics

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

Presenters

Stefan Symeonides

Citation

Annals of Oncology (2017) 28 (suppl_5): v403-v427. 10.1093/annonc/mdx376

Authors

S. Symeonides1, T.R..J. Evans2, V. Coyle3, A. Serrels4, F. Thomson5, D. Currie6, S. Dillon6, J. Paul6, D.A. Fennell7, C. Ottensmeier8

Author affiliations

  • 1 Experimental Cancer Medicine Centre, University of Edinburgh, EH4 1NF - Edinburgh/GB
  • 2 Beatson West Of Scotland Cancer Centre, University of Glasgow, G61 1BD - Glasgow/GB
  • 3 Medical Oncology, Northern Ireland Cancer Centre, Belfast City Hospital, BT9 7AB - Belfast/GB
  • 4 Mrc Centre For Inflammation Research, University of Edinburgh, EH16 4TJ - Edinburgh/GB
  • 5 Translational Pharmacology Laboratory, Institute Of Cancer Sciences, University of Glasgow, G61 1QH - Glasgow/GB
  • 6 Cancer Research Uk Clinical Trials Unit, University of Glasgow, G12 0YN - Glasgow/GB
  • 7 Department Of Cancer Studies, University Hospitals of Leicester NHS Trust Leicester Royal Infirmary, LE1 5WW - Leicester/GB
  • 8 Cancer Research Uk Centre, Southampton General Hospital, Southampton University Hospitals NHS Trust, SO16 6YD - Southampton/GB
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Resources

Abstract 3309

Background

Focal Adhesion Kinase (FAK) is a pivotal intracellular mediator of extracellular contact interactions. It is over-expressed in cancer, with a long-established role in migration, invasion & survival, and is associated with poor prognosis. Recently FAK has been found to have a similar activity in recruitment of immunosuppressive cells to the tumour. We have shown that FAK inhibition can re-model the tumour immune microenvironment in vivo, shifting the balance from inhibitory Tregs, macrophages, fibroblasts and myeloid progenitors, to one which supports an active CD8+ adaptive immune response, resulting in tumour clearance and lasting immunity. FAK inhibition synergises with Programmed cell death receptor 1 (PD-1) blockade in more resistant models. Defactinib (VS-6063, Verastem) is a small molecule FAK inhibitor in Phase II development with an encouraging safety profile and biological activity. Pembrolizumab (MK-3475, MSD) is a humanized IgG4/kappa monoclonal antibody to PD-1, licensed for the treatment of an increasing number of tumour types. This recently open trial will assess the safety, tolerability and preliminary activity of defactinib plus pembrolizumab in patients with advanced solid malignancies.

Trial design

FAK-PD1 is an open label, phase I/IIa clinical trial, combining 200 mg pembrolizumab as a 3-weekly IV infusion, with defactinib given orally twice daily at either 200 mg or 400 mg, before leading into three tumour-specific expansions (non-small cell lung cancer, mesothelioma and pancreatic cancer) at the selected dose. Up to 60 patients, PS 0-1, with adequate blood parameters, measurable disease, baseline tissue, and without contraindications to either agent, will be treated for up to 2 years until clear clinical progression, unacceptable toxicity, or withdrawal. Primary endpoint is safety (NCI-CTCAE v4.03); secondary endpoints include objective response rate (irRECIST), progression-free survival, FAK Y397 phosphorylation and immune cell infiltrate effects. Exploratory endpoints include comprehensive cellular and molecular characterisation of baseline and on-treatment tumour samples, and serial blood immune cell and cytokine profiling. Positive data will support further development of the combination.

Clinical trial identification

FAK-PD1 EudraCT number: 2015-003928-31

Legal entity responsible for the study

University of Glasgow & NHS Greater Glasgow and Clyde

Funding

Cancer Research UK, Verastem Inc, and Merck Sharp and Dohme Ltd •Verastem Inc (via the Combinations Alliance program) and Cancer Research UK

Disclosure

All authors have declared no conflicts of interest.

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