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


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Stefan Symeonides1,Dean Fennell2,Christian Ottensmeier3,Rachel Nirsimloo4,Pavlina Spiliopoulou5,Harriet Walter2,Richard Wilson6,Alan Serrels7,Fiona Thomson8,Dawn Currie9,Susan Dillon9,James Paul9,Vicky Coyle6,T.R. Jeffry Evans5
1University of Edinburgh & Edinburgh Cancer Centre,2University of Leicester & University Hospitals of Leicester NHS Trust,3University of Southampton & Southampton University Hospitals NHS Trust,4Edinburgh Cancer Centre, NHS Lothian,5University of Glasgow & Beatson West of Scotland Cancer Centre,6Queen's University Belfast & Northern Ireland Cancer Centre,7MRC Centre for Inflammation Research, University of Edinburgh,8Translational Pharmacology Laboratory, University of Glasgow,9Cancer Research UK Clinical Trials Unit, University of Glasgow



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. 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 trial is assessing the safety, tolerability and preliminary activity of defactinib plus pembrolizumab.


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, are being 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.