Abstract B064: Utility of ctDNA assessment after six weeks of immunotherapy to predict radiological response in advanced esophageal cancer
Authors: Azizi Alexander , Linossi Constanza , Machin Andrea , Dayimu Alimu , Demiris Nikos , Miremadi Ahmad , O'Donovan Maria , Godfrey Edmund , Mennea Paulius D , Zhou Ze , An Angela , Smyth Elizabeth , Faull Iris , Dovedi Simon J , Fitzgerald Rebecca C , Roshan Amit , Pacey Simon 
Published: February 2025

Background: The investigator-initiated, prospective, single-arm CALIBRATION trial (NCT03653052) was designed to evaluate early (weeks 4 and 7) liquid biopsies for concordance with meaningful treatment response (week 26) in patients with advanced esophageal cancer. Participants were given durvalumab (a PD-L1 inhibitor) following at least one prior systemic therapy. Methods: Participants received 1500 mg of durvalumab every four weeks. Circulating tumor DNA (ctDNA) was analyzed with Guardant 360® CDx at baseline, week 4, and week 7. Tumor biopsies were taken for 30X whole-genome sequencing. CT scans at week 26 were assessed using RECIST v1.1 criteria. The trial's primary endpoint was concordance between ctDNA changes and response. Concordance was pre-defined and ctDNA was compared to baseline: a ≥50% increase in mean variant allele frequency (VAF) of ctDNA was concordant with disease progression or a ≥50% decrease in VAF was concordant with radiologic response or stable disease. Results: By week 26, 13 of 18 (72.2%) evaluable patients experienced disease progression (PD), 2 of 18 (11.1%) had stable disease (SD), and 3 of 18 (16.7%) achieved a partial response (PR). 2 participants (11.1%) with PR have remained on treatment for over two years post-enrollment. Due to clinical deterioration or non-compliance, not all planned ctDNA samples were collected. At week 4, 4 of 17 patients (23.5%, 95% confidence interval [CI] 6.8–49.9) showed concordance; at week 7, this rose to 6 of 12 patients (50.0%, 95% CI 21.1–78.9). For subjects with a ≥50% increase in ctDNA at week 7, median survival was 9.7 months (n=4/12, 95% CI 7.3–NA), compared to 13.6 months (n=4/12, 95% CI 11.5–NA) for those with a ≥50% decrease. Patients with PR at week 26 showed mean ctDNA VAF decreases of -41% at week 4 and -85% at week 7, while patients with PD exhibited mean increases of +38% and +172%, respectively. Importantly, all patients with any increase in ctDNA VAF at either week 4 (5 patients, 29%) or week 7 (6 patients, 50%) experienced progression. Tumor biopsies, available for 15 patients, revealed numerous mutations and copy number aberrations, with MYC and AR gains common across samples. No specific mutation, aneuploidy state, nor tumor mutational burden was significantly associated with response, though the trial was not powered for this analysis. Safety was consistent with published information. In a post hoc analysis, we progressively reduced the threshold for ctDNA changes from ±50% to ±1%. The three clinical outcomes (PD, SD, and PR) were more clearly resolved using week 7 samples. At a ±1% threshold at week 7, 75% of cases (9 of 12, 95% CI 42.8–94.5) showed concordance. Conclusions: Our results align with the growing body of literature supporting early ctDNA dynamics as a predictive marker for immunotherapy response. Specifically, increases in ctDNA VAF could help guide the discontinuation of ineffective immunotherapies. These findings highlight week 4 and, particularly, week 7 as key timepoints to assess ctDNA dynamics and inform therapeutic decisions.

Citation Format: Alexander Azizi, Constanza Linossi, Andrea Machin, Alimu Dayimu, Nikos Demiris, Ahmad Miremadi, Maria O'Donovan, Edmund Godfrey, Paulius D Mennea, Ze Zhou, Angela An, Elizabeth Smyth, Iris Faull, Simon J Dovedi, Rebecca C Fitzgerald, Amit Roshan, Simon Pacey. Utility of ctDNA assessment after six weeks of immunotherapy to predict radiological response in advanced esophageal cancer [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B064.