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

Abstract

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. 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.

Method

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.