No abstract

427 Background: Gastric and esophageal cancers (GECs) together account for a significant global burden in terms of new diagnoses and deaths. Over the last several years, the utility of ctDNA has ranged from estimating tumor burden and characterizing the genomic landscape of tumor biology and response to therapy in the metastatic setting to detection of minimal residual disease (MRD) and cancer surveillance in the locally advanced setting. We have previously studied the role of a commercial ctDNA assay for MRD detection and surveillance in locally advanced GECs. Herein, we present our experience with the same ctDNA assay in advanced stage settings for GECs. Methods: In this retrospective analysis of real-world data obtained from commercial circulating tumor DNA (ctDNA) testing, 53 patients with recurrent/ metastatic esophageal cancer were analyzed. A total of 216 plasma samples were collected between 10/29/2008 and 08/23/2022. The patients were divided into 3 cohorts: Cohort A (N=30) included patients with stage II/III disease who had confirmed clinical recurrence (R). Cohort B (N=25) included recurrent and Stage IV patients who achieved a state of no evidence of disease (NED) on imaging. Cohort C (N=5) included recurrent and Stage IV patients who transiently achieved NED on imaging. A personalized, tumor-informed multiplex PCR-based next-generation sequencing assay (Signatera) was used to quantify ctDNA either postoperatively, on adjuvant or palliative therapy, or during active surveillance. Results: Of 53 patients, 30 patients with recurrent stage II/III esophageal cancer had ctDNA status available postoperatively within 150 days of confirmed clinical recurrence. Cohort A: Among these cases, 25 patients were ctDNA-positive ahead of clinical recurrence (sensitivity 83.3%) with a median of 31 days (range: 1-147 days). Cohort B: Next, we explored the correlation between ctDNA status and imaging, wherein, 96% (24/25) of patients showed a significant correlation between ctDNA status (positive or negative) and disease status by imaging (Fisher exact test p=0.0001). Of the 23 patients, 17 patients were ctDNA-negative and showed NED on imaging (negative predictive value of 100%; 17/17). Cohort C: 100% of patients (N=6) who demonstrated recurrent disease on imaging after NED were ctDNA-positive prior to imaging (positive predictive value of 100%). Conclusions: Our data demonstrate the utility of ctDNA in accurately predicting disease progression and support the potential use of ctDNA to inform treatment decisions or prompt early radiographic imaging. ctDNA may ultimately supersede traditional radiographic surveillance with the advantage of being minimally invasive and cost-effective in monitoring patients during/post-treatment.

5 Background: A growing body of evidence supports the utility of circulating tumor DNA (ctDNA) as a useful biomarker for detecting molecular residual disease (MRD) in colorectal cancer (CRC). Immediately after surgery or during adjuvant therapy, high levels of cell-free DNA (cfDNA) from normal tissue may limit the detection of tumor-derived ctDNA. The optimal timing of blood collection for reliable MRD detection after surgery or adjuvant therapy remains unclear. Methods: In this retrospective, U.S.-based, multi-institutional study, data from commercial ctDNA testing in 16,347 patients with stage I-III CRC were analyzed. Complete clinical data were available for 417 patients with 2,538 plasma samples collected between 6/2019 and 4/2022. The median follow-up for relapsed and non-relapsed patients was 730 and 615 days, respectively. A personalized, tumor-informed multiplex PCR-based next-generation sequencing assay (Signatera) was used to quantify ctDNA prior to surgery and postoperatively in a longitudinal manner. We analyzed the kinetics of total cfDNA and compared it with the ctDNA MRD positivity rates at various time points after surgery. Results: Among all patients, cfDNA levels were higher immediately after surgery (0-2 weeks) and gradually declined during the subsequent 2-8 weeks (p<0.0001). Despite the higher cfDNA levels, among patients with immediate post-operative draws (0-2 weeks) 30.6% (113/369) of patients were ctDNA positive. Similar ctDNA detection rates were observed with conventional MRD windows after resection, whether the window was defined as 2-6 weeks (20.8%; 957/4605) or 2-8 weeks (20.9%; 1155/5534). In the clinically annotated cohort, ctDNA-positivity during the MRD time window of 2-8 weeks and during surveillance (>6 months post-operatively and subsequent to any adjuvant therapy) was significantly associated with worse recurrence-free survival as compared to ctDNA negative patients (MRD: HR 14.1, 95% CI: 5.8-34; p<0.0001; and surveillance HR 20.6, 95% CI: 10.6-37.6; p<0.0001), respectively. On analyzing cfDNA dynamics during adjuvant therapy, cfDNA levels gradually increased between 8 weeks and 8 months after surgery (p=0.0001), suggesting a potential impact of treatment on cell death and cfDNA shed. Conclusions: This is one of the first, large-scale in-depth studies evaluating treatment-based fluctuations in post-operative cfDNA and its correlation with ctDNA-positivity. Our analyses demonstrated no significant impact of plasma cfDNA levels on ctDNA detection rates across different MRD windows using a tumor-informed approach. This may affect real-world application of personalized ctDNA testing by allowing earlier testing windows, as well as guide clinical trial designs using ctDNA as an integral biomarker.

40 Background: While TARE with yttrium-90 (Y90) microspheres can induce tumor responses and improve progression-free survival (PFS) in pts with CRLM, randomized trials have not shown an overall survival (OS) benefit. It is unclear whether this is due to suboptimal pt selection and/or trial design vs. possibly a radiation-induced delayed liver damage which compromises OS. The objective was to describe real world OS with TARE for pts evaluated at an academic center (University of California Irvine) with a dedicated multidisciplinary liver tumor board (MTB). Methods: Retrospective study of consecutive pts with CRLM undergoing TARE between 01/2016-07/2020. We performed descriptive analyses for relevant pt and tumor characteristics, Wilcoxon Signed-Rank Test for comparison of continuous variables, and Kaplan-Meier estimates for survival. Results: N=55 pts were included. Follow-up time was at least 24 mo. Median age was 60 yrs (range 36-84), 61.8% were female, Caucasian/Hispanic/Asian/Other= 54.4%/16.4%16.4%/12.7%, ECOG 0/1/2= 32.7%/58.2%/9.1%, tumor sidedness: left/right/unknown 72.7%/23.6%/3.6%, number or prior lines of systemic treatment 1/2/3+= 38.2%/26.4%/21.8%. MSI-High= 3.6% and RAS/RAF mutations were present/absent/unknown in 34.5%/49.1%/16.4%. Baseline and post-TARE liver function tests are shown in the table. Median time from diagnosis to first TARE was 16.4 mo (1.7-95.6) and 36.4% were treated within the first 12 mo of diagnosis. Median OS from diagnosis and first TARE were 43.2 mo (29.5-68.7) and 16.7 mo (9.9-35.2), respectively. Conclusions: The observed OS of pts with CRLM treated with TARE with a mature follow-up of at least 2 years exceeds 40 mo, despite early integration of TARE in a third of the pts within the first 12 mo of diagnosis. Evaluation of pts with CRLM for TARE at experienced centers with dedicated MTB might lead to improved outcomes. [Table: see text]

98 Background: Salvage treatments for refractory mCRC are an unmet need. This study determined the safety and Recommended Phase 2 Dose (RP2D) of the multi-kinase inhibitor Cabo in combination with FDT/TPI in mCRC. Methods: Single institution investigator-initiated phase 1 study using 3+3 design. Patients (pts) with mCRC previously treated with a fluoropyrimidine, oxaliplatin, irinotecan and appropriate biologics were eligible. Cabo was given orally (p.o.) at 20 mg (dose level [DL] 0) or 40 mg (DL 1) daily on days 1-28, and FTD/TPI p.o. at 35 mg/m2 on days 1-5 and 8-12 every 28 days. Prophylactic growth factors were allowed. The primary endpoint was Dose Limiting Toxicity (DLT) at 28 days. Secondary endpoints included overall survival (OS), progression-free survival (PFS), objective response rate and CEA response. Results: 12 pts were enrolled. Median age 57 years (31-80), male (9/12), ECOG 0/1 = 7/5, Caucasian/Hispanic/Asian = 7/4/1. 3 pts were treated at DL 0 with no observed DLT. Another 9 pts (n = 6 pts to determine RPD2 and additional n = 3 pts in expansion) were treated at DL 1, none exhibiting a DLT. The most common any grade (G) treatment related adverse events (TRAE) were diarrhea (50%), nausea (42%), neutropenia (42%), fatigue (33%) and rash (25%). G3-4 TRAE in > 5% of patients were neutropenia (25%) and thrombocytopenia, hypokalemia, weight loss (each 8%). No serious TRAE or G5 were reported. The RP2D was determined to be DL 1. Median PFS and OS were 4.1 (95% CI 1.9-6.8) and 6.7 (95% CI 2.2-not evaluable) months, respectively. The disease control rate was 75%. 5/12 (42%) pts had a CEA decline > 30%. Conclusions: The combination of Cabo and FTD/TPI is feasible and tolerable and showed encouraging clinical activity in refractory mCRC. Additional pts are being enrolled at DL 1 and will be presented at the meeting. Clinical trial information: NCT04868773 .