Utility of ctDNA assessment after six weeks of immunotherapy to predict radiological response in advanced oesophageal cancer

Abstract The prospective, single-arm CALIBRATION trial (NCT03653052) assessed liquid biopsies for early response concordance compared with CT scan assessment in patients with advanced oesophageal cancer given durvalumab (PD-L1 inhibitor) after at least one prior systemic therapy. 19 participants received 1500mg of durvalumab every four weeks. ctDNA was analysed retrospectively with Guardant 360® CDx at baseline, weeks 4 and 7. Response at week 26 was assessed by RECIST v1.1. Tumour samples underwent 30X Whole Genome Sequencing. 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 in VAF correlating with radiological response or stable disease. At week four, 4/17 patients (23.5%) showed concordance; at week seven, this rose to 6/12 patients (50.0%). We reduced ctDNA VAF thresholds sequentially from ±50% to ±1% and identified that with any change in ctDNA at week 7, 75% of cases (9/12) showed concordance. 14/18 (77.7%) of patients progressed in the cohort at 6 months. All patients with ctDNA increases progressed. Our data supports assessing ctDNA at week seven rather than week four for immunotherapy response prediction. ctDNA VAF increases, especially, could aid decision-making in early-phase clinical trials to cease non-beneficial interventions.