ctDNA predicts radiological response to immune checkpoint inhibition for patients with advanced oesophageal adenocarcinoma: a pilot interventional phase 2 study

Background: Second line treatments for advanced oesophageal adenocarcinoma (OAC) have limited efficacy, and biomarkers for early relapse are needed. We evaluated the use of a Next Generation Sequencing (NGS) based circulating tumour DNA (ctDNA) assay to predict the efficacy of PD-L1 second line monotherapy in patients with advanced OAC in a prospective, single-centre, pilot study. Methods: 19 participants received Durvalumab every four weeks. ctDNA was analysed with Guardant 360® CDx at baseline, weeks 4 and 7. Radiological response at week 26 was assessed by RECIST v1.1. Concordance between ctDNA and CT results was pre-defined as either ≥50% increase in ctDNA mean variant allele frequency (VAF) with progressive disease, or ≥50% decrease with radiological response or stable disease. The primary endpoint was to explore whether early changes in ctDNA levels can predict 6-month response to durvalumab by RECIST criteria and considered positive with ≥70% concordance, Tissue biomarkers were assessed with 30X Whole Genome Sequencing. Results: At week four, 6/17 patients (35.3%) have ctDNA VAF changes ≥50%, of which 4/17 (23.5%) show concordance. At week seven, 8/12 (66.7%) have ctDNA changes ≥50%, with concordance in 6/12 participants (50.0%). In post-hoc analyses, 9/12 (75%) of patients show concordance with any ctDNA change at week seven, and the participants with any increase in ctDNA all have progression (5/5 week four, and 7/7 week seven). Conclusions: Although the study’s primary endpoint was not reached, our data supports assessing ctDNA for immunotherapy response prediction. We report that even a modest increase in ctDNA could indicate progressive disease, assisting decision-making to cease ineffective treatments. Further research for the use of ctDNA in OAC is needed.