The FAK-PD1 trial (A Phase I/IIA Study to Assess Safety, Tolerability and Preliminary Activity of the Combination of FAK (Defactinib) and PD-1 (Pembrolizumab) Inhibition in Patients with Advanced Solid Malignancies), is an ECMC Combinations Alliance trial, led by Edinburgh (Symeonides) in collaboration with Southampton, Glasgow, Belfast and Leicester. This first-in-combination trial was developed from the exciting CRUK Edinburgh Centre pre-clinical discovery of the role of FAK in tumour microenvironment signalling (Alan Serrels, Margaret Frame; Serrels et al, Cell 2015) and was the first Combinations Alliance trial to bring together two different pharma companies (MSD and Verastem), in keeping with the Alliance’s original goal.
The Combinations Alliance framework, and support from CRUK New Agents Committee (NAC), brought >£1m funding from the Pharma partners for the trial and its multi-centre translational analyses. Opened Jun 2017, phase I recruitment completed June 2018, mesothelioma phase 2a arm February 2019 and the pancreatic arm August 2019. The lung arm was affected by changes in standard of care and then COVID-19 but has now closed, with translational analyses now in progress at the Southampton and Edinburgh ECMCs.
Selection biomarkers across ovarian cancer sub-types [example of translational biomarker research]
The Gourley laboratory outlined the molecular landscape of endometrioid ovarian cancer using whole exome sequencing, WES (Hollis et al, Nat Commun 2020). TP53 and CTNNB1-mutations segregate the patients into two main prognostic subgroups groups, defining clear stratification biomarkers for therapeutic trials. Key targetable pathways (MAPK/RAS, WNT and PI3K) were identified to aid development of new rational personalised therapy.
We also used whole genome sequencing (WGS) to identify BRCA1/2 loss by structural variation as an underappreciated aberration conferring PARP inhibitor sensitivity in high grade serous ovarian cancer (HGSOC) and other tumours (Ewing et al, Clin Cancer Res 2021). This is being further investigated with a view to incorporation as a selection tool in future PARP inhibitor trials (see Section 6 below). We subsequently performed multiomic characterisation to paint a high-resolution picture of the molecular landscape in HGSOC, better defining patients who benefit most from specific molecular therapeutics and highlighting those for whom novel treatment strategies are required (Hollis et al, Clin Cancer Res 2022).
Work in rarer cancers has included leading a study demonstrating that ovarian carcinosarcoma is phenotypically distinct (Hollis et al, Br J Cancer 2022), contributing to a study demonstrating the molecular landscape of mucinous ovarian cancer (Cheasley et al, Nat Commun, 2019) and leading the correlative translational analysis of GOG281/LOGS, the first ever positive randomised trial in low grade serous ovarian cancer, LGSOC (Gershenson et al, Lancet 2022).
NXP900 (eCF506) [example of clinical translation activity]
The Edinburgh Cancer Discovery Unit (ECDU) combines high-content multi-parametric phenomic drug discovery and mechanistic deconvolution, with an innovative iterative medicinal chemistry strategy in representative tumour models. eCF506/NXP900, the lead asset, is a first-in-class conformational inhibitor of SRC and YES1, blocking both enzymatic and scaffolding activity to inhibit a key cancer pathway that previous kinase inhibitors could not adequately target, resulting in strong preclinical activity across multiple tumour types (Temps et al, Cancer Res 2021). In October 2021 it was licensed to Nuvectis Pharma in a $327m licensing deal (the largest ever for University of Edinburgh) and it is now at IND/CTA-enabling stage after large-scale manufacture and toxicology. Early clinical involvement with the ECMC Phase I unit (Symeonides) shaped the clinical approach plans and selection of clinical development partner, who will continue to work with the Edinburgh team and ECMC network.