Short interval circulating tumor DNA (ctDNA) kinetics as a predictor of tumor response in patients with gastrointestinal (GI) cancer receiving immune checkpoint inhibitor (ICI)-based treatment.

836 Background: Circulating tumor DNA (ctDNA) has a short half-life (<2 hours) which may permit real-time monitoring of tumor status. This single-institution study aimed to assess the feasibility of rapid treatment response evaluation through serial short-interval ctDNA testing. Methods: Patients with gastrointestinal (GI) cancer undergoing immune checkpoint inhibitor (ICI)-based therapy were included. A personalized, tumor-informed ctDNA assay (Signatera, Natera, Inc.) was used in this study. We collected samples to measure the baseline ctDNA levels on cycle 1, day 1 (C1D1) of treatment or within 14 days prior to C1D1. A second ctDNA sample was obtained after 14-21 days depending on the cycle length of the treatment regimen employed (on cycle 2, day 1 [C2D1]). Changes in ctDNA levels between baseline and C2D1 were recorded, as well as the tumor response at the first radiographic assessment. Patients achieving partial response (PR) or better, or stable disease (SD) with tumor shrinkage supporting continuation of same treatment were considered responders. Results: The study cohort consisted of 14 patients aged 36-89 years (median age 66); 5 patients were female. Tumor types included advanced colorectal (n=5) and gastroesophageal (n=9) cancers. Treatments consisted of pembrolizumab alone (n=5), ICI + chemotherapy combinations (n=8), and regorafenib plus nivolumab (n=1). Baseline ctDNA levels were obtained on C1D1 in 9 patients, with the remaining 5 patients having baseline measurements within 14 days before C1D1. All patients had the second ctDNA level drawn on C2D1. The median interval between C1D1 and the first radiographic response assessment was 61 days (range, 45-84). A reduction in ctDNA levels by 50% or more (range: 66-100%) was observed in 9 patients (64%) after one cycle of treatment. All 9 patients were classified as responders at the time of first radiographic assessment: 7 with PR and 2 with SD but significant tumor shrinkage leading to continuation of the same treatment. In 3 patients (21%), ctDNA levels increased (range: 20-500%), correlating with progressive disease (PD) on first assessment scan. Two patients showed increased ctDNA levels of 82% and 22% after one cycle of treatment but achieved PR and SD, respectively. In both patients, however, the 3rd ctDNA level drawn before the first assessment scan dropped by >90%. Overall, short-interval ctDNA kinetics correlated with treatment response in 12 of 14 patients (86%), with a binomial test p = 0.0065. Conclusions: Short-interval ctDNA kinetics demonstrates a strong correlation with radiographic tumor response and clinical benefit in GI cancer patients receiving ICI-based treatments, providing early signal of tumor response. This approach has the potential to guide treatment decisions if validated in larger prospective studies.