Oesophageal cancer is the 6th most common cause of cancer death with incidence of adenocarcinomas (EAC) increasing in western countries. Long term survival is poor (<5%) (ESMO guidelines 2016) and mutational signatures of EAC suggest patients with "mutagenic" or "DDR" signatures can benefit from immune-checkpoint blockers (ICB) (Secriert et al. Nat gen 2016). However, there is uncertainty around the population to benefit from ICBs. Circulating tumour DNA (ctDNA) can be used to predict responses to immuno-oncology (IO) agents (Howell J, Trans res 2017). TP53 mutations is frequent in EAC 6 and ctDNA-TP53 mutations can be measured/followed in plasma to track tumour behaviour (response, clonal changes) during treatment (Zill O. Clin Can Res 2018, Fisher O. Gut 2017). Next-generation sequencing (NGS) provides high sensitivity, coverage and the possibility to interrogate tumour treatment-response and heterogeneity.
CALIBRATION is a single-centre, open-label, pilot trial of durvalumab (1500mg/4w) for patients with EAC progressing to standard chemotherapy. Pts with measurable disease undergo biopsies at screening/C3/progression alongside weekly blood sampling. Primary objective: asses if early changes in TP53 ctDNA variant allele fraction (VAF) levels, by weeks 4 and/ or 7 can predict durable (6 month) RECIST V 1.1 responses (Complete or Partial Response, Stable Disease). We plan to recruit 19 pts with a 5 % significance (one-sided) and 80 % power to detect if ctDNA changes correctly predict radiological response in ≥ 70 % pts. The trial opened to recruitment in October 2018, 13 pts have been pre-screened and 4 pts included. An interim analysis is planned for September 2019. Secondary endpoints include characterization of paired blood/biopsy samples from pts pre/post durvalumab of: • genomic heterogeneity (evolution of mutational signatures under IO) and changes in the tumour microenvironment (dynamics of T-cell populations). • changes in ctDNA and PBMC markers to identify biomarkers of resistance/response. • predictive value of the mutagenic and DDR signatures to predict response to IO compounds.
NCT03653052.
Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge.
AstraZeneca.
S. Dovedi: Leadership role: AstraZeneca.