Epigenetic ctDNA kinetics as a predictor of early progression in advanced E/GEJ cancers treated with CDK4/6 and VEGF inhibition therapy.

e16056 Background: Advanced esophageal and gastroesophageal junction (E/GEJ) tumors carry a poor prognosis and reliable early biomarkers for therapeutic efficacy are lacking. The utilization of ctDNA monitoring longitudinally is not standard of care at present. We hypothesized that a novel, tumor-naive, methylation-based pan-cancer assay could measure disease burden and provide a signal of early molecular response in E/GEJ patients. Methods: A Phase I/II trial (NCT04921904) evaluated the safety and efficacy of abemaciclib combined with ramucirumab in metastatic/recurrent E/GEJ adenocarcinoma patients who had progressed after frontline therapy. Primary endpoints focused on safety, with secondary endpoints including response, survival, and molecular profiling. Peripheral blood samples were collected from 20 enrolled patients pre-treatment and within 30 days on-treatment. These were analyzed using a methylation-based ctDNA assay that quantifies longitudinal changes across > 500 uniquely methylated loci to yield a Tumor Methylation score and the association of this score with therapeutic response, to assess changes in disease burden. Results: Safety and efficacy have previously been reported with a disease control rate of 40% and a duration of clinical response of 6.4 months in heavily pretreated (70% of patients being third line therapy or higher) advanced metastatic E/GEJ. 13 of 20 patients provided samples to assess ctDNA. We found that early molecular progressive disease (mPD), was significantly associated with a shorter progression-free survival (PFS) measured using RECIST v1.1 (Hazard Ratio = 4.9, 95% Confidence Interval 1.1-22). Notably, this association trended toward improved OS, yet not significant. Further analysis comparing patients with rapid progression (PFS ≤ 5.2 months) versus non-rapid progression revealed significant differences in baseline methylation patterns at 128 specific loci, including CCNA1 and CHL1. Conclusions: This exploratory study demonstrates that a tumor-naive, methylation-based ctDNA approach may be a viable tool for monitoring CDK4/6 pathway response in advanced E/GEJ cancers. Early mPD detection at one month by ctDNA kinetics strongly correlates with shorter PFS, offering a rapid signal of efficacy. This provides a substantial advantage over traditional radiographic evaluations (e.g., RECIST) and expands ctDNA's utility for response evaluation. Distinct baseline methylation patterns in rapid progressors highlight the potential of upfront epigenetic profiling to risk-stratify patients pre-treatment, guiding treatment selection and avoiding unnecessary toxicities. These findings suggest broad applicability for the tumor-agnostic approach targeting CDK4/6 specific alterations across various heavily pretreated solid tumors. Clinical trial information: NCT04921904 .