Ultra-sensitive, tumor-informed ctDNA profiling in patients with gastroesophageal cancer and treated with pembrolizumab and longitudinal ctDNA kinetics

4040 Background: Metastatic esophagogastric cancer (mEGC) is a lethal disease with poor long-term survival. Recent studies have established anti-PD-1 therapy in combination with chemotherapy as the standard of care for first-line therapy for mEGC. KeyLargo (NCT03342937) was a single arm phase II study of pembrolizumab in combination with oxaliplatin and capecitabine in the first line treatment of patients (pts) with HER2 negative mEGC. While high response rates were noted, not all pts received benefit, emphasizing the need for better biomarkers. Paired tumor biopsies and plasma were collected for optimal biomarker testing. In this retrospective study, we employed a novel, tumor-informed ctDNA approach as a tool for longitudinal disease monitoring and dynamic tumor evolution. Methods: Thirty-six pts were enrolled between January 2018 and January 2020. Of 34 evaluable pts, 25 pts achieved a response (ORR = 74%), including 6 pts with a complete response (CR) and 19 pts with a partial response (PR). Our initial analysis includes baseline tumor samples collected from 16 pts with over 59 corresponding on-treatment (OT; up to cycle 35) plasma samples. NeXT Personal, a tumor-informed ctDNA assay, generated personalized liquid biopsy panels derived from somatic variants (SV) from tumor whole genome sequencing. Each personalized assay includes up to 1,800 SVs for sensitive minimal residual disease (MRD) detection and a constant set of 2,100 clinically actionable variants (CAV). Results: Of the 36 pts who enrolled on KeyLargo, 32 pts had baseline tumor and longitudinal plasma samples collected and stored for testing. In this initial cohort of 16 pts, MRD events dynamically varied from 5.3 to 302,000 parts per million (PPM). 16/16 (100%) pts were MRD-positive at baseline, with a limit of detection between 1.5 and 4.6 PPM. OT samples were collected every 3 cycles (9 weeks). The ratio of PPM (rPPM) between baseline and the first available OT sample (typically Cycle 4 to 7) correlated with progression free survival (PFS; p = 0.0004, logrank). rPPM was significantly reduced in pts having a best overall response of PR/CR (98% mean rPPM) versus progressive disease (25% mean rPPM, p < 0.037, U-test). Two pts demonstrated CR, each with 11/11 (100%) MRD-negative plasma samples over approximately two years. CAVs were identified in longitudinal samples with TP53 repeatedly detected in 5 patients and a PIK3CA mutation emerging in the final 3 (of 9) timepoints from one patient. Conclusions: ctDNA was present in all pts at baseline; OT PPM reductions correlated with PFS and best overall response. CAV profiling suggested a de novo PIK3CA variant arising during therapy in one patient. These findings suggest that tumor-informed plasma-based ctDNA profiling in mEGC may detect known CAVs arising during therapy, and with subsequent investigations, may inform therapeutic decisions.