Expanding the Landscape of Effective Therapy for Patients with Relapsed Mesothelioma


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Dean A. Fennell1, Gareth Griffiths2, Angela Casbard3, Lisette Nixon3, Catharine Porter3, Matthew Krebs4, Anne Thomas1, Amy King1, Catrin Pritchard1, James Harber1, Cathy Richards1, Amrita Bajaj5, Charlotte Poile1, Liz Darlison5, Apostolos Nakas5, Alan Dawson1, Aleksandra Bzura1, Jake Spicer1, Nada Nusrat1, Adam Pullen1, Hongji Yang1, Phillip Pan De Zhang1, Min Zhang6, Ed Hollox1, Frank Dudbridge1, Qianqian Sun6
1University of Leicester, 2University of Southampton, 3Cardiff University – Centre for Trials Research, 4Cancer Research UK (CRUK) Manchester Centre, 5University Hospitals of Leicester NHS Trust, 6Novogene

Abstract

Background

Mesothelioma remains a rapidly lethal cancer, particularly in the relapsed treatment setting. New, more effective treatments are required given the lack of any licensed therapy in this treatment space. We have expanded the treatment landscape of relapsed mesothelioma through the development of a portfolio of UK-based investigator-led, randomised and clinical trials coupled to hypothesis-driven translational research to define rational approaches to stratify patients likely to benefit.

Method

Multiple collaborative networks were established to undertake two randomised trials, the Cancer Research UK funded CONFIRM phase III (NCT03063450), VIM (NCT02139904) phase II trials, and MIST (NCT03654833) , a parallel multi-arm umbrella trial in patients with molecularly stratified, relapsed mesothelioma. Tissue has been centralised to enable transcriptome and 19-plex (immunofluorescence), and whole exome sequencing 

Results

CONFIRM, a double-blind placebo-controlled, randomised phase III trial met its primary endpoint of overall survival (OS hazard ratio (HR) 0.72), being the first ever positive phase III in this treatment space. VIM randomised vinorelbine+active symptom control (ASC) vs ASC and also met its primary endpoint, progression free survival, HR 0.6 (p=0.001). MIST1 (rucaparib) and MIST 2 (abemaciclib) both met their primary endpoints of 12 week disease control. Pre-planned biomarkers PDL1 (CONFIRM) and BRCA1 (VIM/MIST1) were not predictive respectively, highlighting the need for deeper exploration of the molecular features underpinning response. Tissue collected from responder/refractory tumours, are being RNA sequenced with 19-plex immunofluorescence to decipher tumour microenvironment correlatiions with response, along with whole exome sequencing. We are implementing machine learning based feature extraction to robustly infer predictive biomarkers. Orthogonal cross-validation of immune-checkpoint inhibitor response will be conducted in arms 3,4 and 5 of MIST, and their prognostic impact explored in our phylogenetic study MEDUSA.  

Conclusion

Coupling multi-omic interrogation of tissue from our mesothelioma trial cohorts presents an unprecedented opportunity to identify and validate molecular features that could reliably stratify patients with relapsed mesothelioma for effective therapy. 

Impact statement

Our UK trial portfolio in relapsed mesothelioma have shaped UK practice (CONFIRM), and established the first ever molecularly stratified mesothelioma trial (MIST) that is underpinning future randomised phase II studies (including AERO & NERO) whilst collectively, providing a translational platform to underpin predictive biomarker discovery.