The TARGET trial: molecular profiling of circulating tumour DNA to stratify patients to early phase clinical trials


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Dominic Rothwell1,Mahmood Ayub1,Sakshi Gulati1,John Brognard1,Andrew Wallace2,Crispin Miller1,Emma J. Dean3,Natalie Cook3,Fiona Thistlethwaite3,Hui Sun Leong1,Helen Eaton2,Emma Howard2,Andrew Hudson3,Carla Siswick3,Joanne Dransfield3,Marianna Christodolou3,Nigel Smith1,Louise Carter3,Robert Metcalf3,Sreeja Aruketty3,Jaseela Chiramel3,Andrew Hughes3,Richard Marais1,Caroline Dive1,Ged Brady1,Matthew G. Krebs3
1CRUK Manchester Institute,2Central Manchester NHS Foundation Trust (CMFT),3Christie NHS Foundation Trust, Manchester

Abstract

Background

The Tumour chARacterisation to Guide Experimental Targeted Therapy Trial (TARGET) tests the hypothesis that molecular profiling of both archival/fresh tumour and circulating tumour DNA (ctDNA) can be used to stratify patients to early phase trials of targeted therapies to maximise patient benefit.

Method

Patients were consented for molecular analysis of tumour and blood. Tumour was analysed by Sequenom OncoCarta using a 19 gene panel. ctDNA was subjected to next generation sequencing (NGS) and bioinformatic analysis of a panel of >600 genes known to be frequently mutated in cancer. Clinical reports from tumour and blood were discussed in a monthly Molecular Tumour Board (MTB) to identify possible driver aberrations and to aid clinicians in selection of relevant experimental medicine trials. 

Results

The initial stages of the trial have focused on process development, optimisation of ctDNA sequencing, bioinformatics analysis and establishing the MTB. The current ctDNA pipeline identified at least one mutation within ctDNA from 87.5% (35/40) samples.  For the first 20 samples concordance between tumour and ctDNA was 90%. Eight patients had clinically relevant mutations, confirmed in ctDNA by droplet digital PCR and/or repeat NGS.  The MTB has been optimized to review and interpret tumour and ctDNA reports within 3-4 weeks of consent and has identified relevant clinical trials for individual patients.

Conclusion

Our results support the use of ctDNA for routine molecular characterisation.  The success of the overall approach has led to scale up of patient recruitment to ~350 patients over the next 2-3 years. The focus of ongoing work will be to allocate patients to clinical trials based on ctDNA and/or tumour profiling and facilitate monitoring of treatment response and emerging resistance mechanisms using serial blood samples. Outcome measures will include numbers of patients allocated and recruited to matched experimental medicines, response rates and survival outcomes.