O'Donnell, C.

e16488 Background: Small bowel adenocarcinoma (SBA) and ampullary adenocarcinoma (ampullary AC) are rare gastrointestinal (GI) malignancies. Treatment strategies are largely extrapolated from colorectal cancer, where oxaliplatin-based regimens are the most common first-line therapy in advanced disease. Although bevacizumab is considered safe in metastatic SBA, its efficacy remains unproven, and evidence is limited to small retrospective studies. We assessed the association of adding bevacizumab to FOLFOX with survival and toxicity in a large real-world cohort. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network (January 2000-December 2025), including data from 105 healthcare organizations. Adults (≥18 years) with SBA or ampullary AC treated with FOLFOX with or without bevacizumab were identified. Cohorts were propensity score-matched on age, sex, race, comorbidities, and metastatic sites. Outcomes included overall mortality, GI perforation, bleeding, venous thromboembolism (VTE), hospital admission, and emergency department (ED) visits. Kaplan-Meier and Cox proportional hazards models were used for time-to-event analyses. Results: After matching, 818 patients were included in each cohort. In the FOLFOX + bevacizumab cohort, mean age was 66.1 ± 12.0 years and 53.8% were male; 63.7% were White, 13.8% Black, 5.6% Asian, 12.0% Unknown/Other, and 4.4% Hispanic/Latino. Over a median follow-up of 13 months, FOLFOX + bevacizumab was associated with higher overall mortality compared with FOLFOX alone (55.3% vs 45.2%; HR 1.24 [95% CI 1.1-1.4]; p = 0.002) and shorter median OS (15.1 vs 19.5 months). Rates of GI perforation (15.5% vs 16.7%; HR 0.90 [95% CI 0.71-1.15]; p = 0.39), GI bleeding (13.1% vs 13.6%; HR 0.96 [95% CI 0.73-1.25]; p = 0.74), and VTE (19.1% vs 21.4%; HR 0.88 [95% CI 0.71-1.09]; p = 0.23) were similar between groups. Hospital admissions were higher in the FOLFOX + bevacizumab cohort (2.8% vs 1.3%; HR 2.1 [95% CI 1.0-4.3]; p = 0.04). Findings were consistent at 5-year follow-up. Conclusions: In this real-world cohort, the addition of bevacizumab to FOLFOX was not associated with improved survival and was associated with higher healthcare utilization. Prospective, disease-specific studies are needed to define its role in this population. Outcomes at median 13-month follow-up after propensity matching (FOLFOX + bevacizumab vs FOLFOX). Outcome % vs % HR p Overall mortality 55.3 vs 45.2 1.24 0.002 Hospital admission 2.8 vs 1.3 2.1 0.04 ED visit 45.2 vs 42.4 1.02 0.75 GI perforation 15.5 vs 16.7 0.90 0.39 GI bleeding 13.1 vs 13.6 0.96 0.74 VTE 19.1 vs 21.4 0.88 0.23

e16435 Background: Peritoneal metastasis in pancreatic ductal adenocarcinoma (PDAC) is historically associated with a dismal prognosis and limited response to systemic therapy alone. The role of locoregional therapy remains controversial. This study evaluated the survival impact and safety of HIPEC, with or without cytoreductive surgery (CRS), compared to standard-of-care systemic therapy in patients with peritoneal metastatic PDAC. Methods: We conducted a comparative analysis of 130 patients with peritoneal metastatic PDAC, comprising a study cohort treated with HIPEC (n = 33) and a control group treated with systemic chemotherapy alone (Non-HIPEC, n = 97). HIPEC patients received induction chemotherapy (predominantly FOLFIRINOX) followed by HIPEC ± CRS. Co-primary endpoints included 12 months survival, and 6 months progression free survival (PFS). Secondary endpoints evaluated Overall Survival (OS ), safety of CRS, and impact of germline mutation status on survival. Study was approved under IRB protocol 25-008762. Results: The 12-month OS rate was significantly higher in the HIPEC group compared to the chemotherapy-only control group (100% vs. 52.6%, P < 0.001). The 6-month PFS rate in the HIPEC group was 63.0% vs. 47.94 in-only control group (P < 0.001). For secondary endpoints, the HIPEC group demonstrated a significantly longer median OS of 33.0 months vs. 17.0 months for controls (P < 0.001). Within the HIPEC cohort, the addition of CRS (n = 25) significantly improved outcomes compared to HIPEC alone (n = 8): median OS improved from 21.5 to 36.0 months (P = 0.03). Germline testing was performed in 61% of HIPEC patients and 48% of controls, identifying pathogenic mutations in 25% and 17%, respectively. Identified pathogenic mutations in both groups included ATM (n = 4), MUTYH (n = 2), BRCA2 (n = 1), CHEK2 (n = 1), PALB2 (n = 1), and KIT (n = 1). In the control group, specific mutations drove divergent outcomes; ATM median OS: 23.5 months vs. MUTYH : 8.0 months (P = 0.04). Conversely, in the HIPEC+CRS cohort, survival was excellent regardless of genetic profile: mutation carriers achieved a median OS of 33.0 months compared to 31.0 months in wild-type patients (P = 0.85). Despite a 34.8% postoperative complication rate in the HIPEC group, there was no perioperative mortality. Conclusions: In selected patients with peritoneal metastatic PDAC, HIPEC provides a substantial survival advantage over systemic therapy alone, achieving a 100% 12-month survival rate and more than doubling the median overall survival. Importantly, germline mutation status did not preclude survival benefit, with mutation carriers deriving equal efficacy from the multimodal approach. These findings support HIPEC+CRS as a highly effective strategy that may overcome adverse biologic drivers.

e16018 Background: Intrahepatic cholangiocarcinoma (iCCA) exhibits marked heterogeneity in outcomes that is incompletely explained by stage or treatment timing. Although treatment delay is frequently cited as a modifiable risk factor, its prognostic significance in real-world practice remains unclear. We applied machine learning (ML) to model iCCA as a dynamic disease process and to evaluate whether longitudinal disease trajectories better explain outcomes than treatment timing alone. Methods: We conducted a population-based retrospective analysis of adults diagnosed with iCCA using the Surveillance, Epidemiology, and End Results (SEER) database (2000–2022). Time from diagnosis to first cancer-directed therapy was categorized as ≤30 days, 31–60 days, or > 60 days. Associations between treatment delay, disease characteristics, and overall survival (OS) were assessed using multivariable logistic and Cox regression models. To capture real-world disease evolution, each patient’s clinical course was encoded as an ordered longitudinal sequence of diagnosis, treatment states (surgery, chemotherapy, radiation), and outcome. Unsupervised ML was used to identify latent disease-course trajectories. A supervised ML model using variables available at diagnosis was developed to predict membership in high-risk trajectories. Results: The cohort included 18,312 patients with iCCA. Treatment initiation beyond 30 days occurred in more than half of patients and was more common in localized than advanced disease. In adjusted survival analyses, shorter time to treatment was paradoxically associated with worse OS, consistent with confounding by disease severity rather than a protective effect of delay. Unsupervised ML identified four distinct and reproducible disease trajectories with markedly different outcomes. Median OS ranged from approximately 2 months in early-failure trajectories to approximately 15 months in favorable multimodality trajectories. Trajectory membership was not fully explained by stage or treatment timing. A supervised ML model predicted high-risk trajectory membership with good discrimination (AUC 0.82). Key predictors included tumor grade, age, tumor burden, and incomplete staging, whereas treatment timing had minimal influence. Conclusions: In iCCA, treatment delay reflects underlying disease biology and care prioritization rather than independently determining survival. ML-based trajectory modeling reveals clinically meaningful disease courses that better explain outcome heterogeneity than treatment timing or stage alone and enables early identification of patients at highest risk for unfavorable real-world outcomes.

e15501 Background: CP is the backbone of first-line therapy for recurrent or metastatic ASCC. In practice, Q3-week CP has been explored as a potential alternative to the standard (d1,8,15 Q28-day cycle) dosing, though its efficacy is not known. This study evaluated CP scheduling and clinical survival associations in metastatic ASCC. Methods: This multicenter retrospective cohort study included patients with metastatic ASCC treated with first-line CP, identified using the Mayo Data Explorer database. Electronic health records were reviewed to collect baseline clinical characteristics, treatment regimens, responses, progression-free survival (PFS), and overall survival (OS). Descriptive statistics were used to summarize patient demographics. Survival was estimated using Kaplan–Meier methods. Multivariable Cox proportional hazards models were used to compare survival by dosing schedule, adjusting for age, ECOG performance status, HPV (p16) status, liver metastasis, and prior chemoradiation. Results: 54 patients treated between 2020-2025 with first-line CP for metastatic ASCC were included. Baseline patient demographics were balanced between dosing groups (Table 1). Median follow-up time was 26.2 months. For Q3-week CP (n = 21), median PFS and OS were 9.8 (95% CI 8.1, NR) and 27.0 (95% CI 15.7, NR) months, respectively, while median PFS was 6.5 (95% CI 4.5,15.3) months with standard CP (n = 33) and median OS was not reached (95% CI 11.2, NR). Response rate was 76% with Q3-week and 60.6% with standard CP (p = 0.23) dosing. Survival outcomes were similar when comparing Q3-week CP relative to standard CP dosing using multivariable analysis (PFS HR 0.68, 95% CI 0.33–1.41; OS HR 1.67, 95% CI 0.67–4.14). Higher ECOG and liver metastasis were independently associated with inferior outcomes, while HPV was associated with improved survival. Subsequent therapy patterns were similar between CP schedule groups. Ten patients (16.9%) received local therapy, and 24 of 28 patients with progression received further systemic therapy, including 21 (87.5%) treated with immunotherapy. Conclusions: Survival outcomes were similar across dosing schedules, suggesting Q3-week CP may be a reasonable alternative to standard CP, with potential to reduce treatment-related burden in metastatic ASCC. Future analysis will compare toxicity profiles between CP dosing schedules, including in combination with PD1 inhibitors given the results of the POD1UM-303 trial. Patient demographics (n=54). Variable Q3-week CP (n=21) Standard CP (n=33) p-value Sex Female 16 (76.2%) 24 (72.7%) 0.77 Male 5 (23.8%) 9 (27.3%) Age Median (Q1, Q3) 62 (50.5, 69) 64 (55.5, 70) 0.57 BMI Median (Q1, Q3) 27.1 (21.9, 34.4) 27.4 (22.5, 31.7) 0.72 ECOG 0 9 (42.9%) 11 (34.4%) 0.53 ≥ 1 12 (57.1%) 21 (65.6%) Confirmed HPV (p16) Positive 16 (76.2%) 24 (72.7%) 0.77 Prior chemoradiation Yes 17 (81.0%) 21 (63.6%) 0.17

PURPOSE For patients with advanced biliary tract cancer (BTC), cancer-related time spent in health care systems, time toxicity, represents a critical but understudied burden affecting quality of life. This study aimed to quantify time toxicity in patients receiving first-line systemic therapy and evaluate whether the addition of durvalumab to gemcitabine plus cisplatin (GC) increases health care contact time. METHODS This international, multicenter, retrospective cohort study included patients with advanced BTC seen between January 2019 and April 2024 at Mayo Clinic Enterprise (US), and between January 2021 and April 2024 at Kyorin University Hospital (Japan), and Hospital Israelita Albert Einstein (Brazil). Patients received GC plus durvalumab (GCD) or GC. Time toxicity was recorded from treatment initiation until discontinuation or last follow-up during first-line systemic therapy. Multiple regression analysis identified factors associated with high time toxicity. RESULTS Among 193 patients (102 GCD, 91 GC; median age 65 years; 50% male; 49% Eastern Cooperative Oncology Group performance status [PS] 0), median time on treatment (TOT) was 156 days (95% CI, 122 to 190). The median proportion of total time toxicity was 14.4% (IQR, 10.9-20.6). Planned visits accounted for 11.9%, while unplanned visits were infrequent (1.8%). Time toxicity strongly correlated with TOT ( r = 0.824) and progression-free survival ( r = 0.827). Despite longer treatment in the GCD group than the GC group (212 v 134 days; P = .027), total time toxicity was similar (27 v 18 days; P = .19). Younger age and poor PS were independent factors of higher time toxicity. CONCLUSION Time toxicity represents a meaningful metric that allows for more comprehensive integration of the net benefit in patients with advanced BTC with a limited lifespan.

837 Background: A recent randomized trial suggested that CR may influence ICI activity in patients with lung cancer. However, the same has not been established in GI cancers, where reports have shown mixed results with variable definitions of 'early' vs 'late' IT. We evaluated multiple approaches to assess the impact of CR on first-line ICI in GI malignancies. Methods: This retrospective study included patients from three Mayo Clinic sites (N=455). Both previously reported IT cutoffs and a new cutoff derived from ROC analysis were evaluated. Patients were categorized by the median of all ITs, the median of the first four ITs, and whether ≥20% of ITs occurred before the identified cutoff. Univariate and multivariate Cox regression (adjusting for age, MSI status, type of cancer, metastasis status, number of cycles, and receipt of chemotherapy with ICI) assessed associations with OS. KM analyses were performed to illustrate survival differences. The primary endpoint was OS. Results: When patients were categorized based on whether ≥20% of infusions occurred before 14:00 (ROC-derived cutoff), a significant association with OS was observed. On univariate analysis, early infusion timing was associated with improved survival (HR 2.30, 95% CI 1.58–3.32, p <0.001). This remained significant after multivariable adjustment (HR 2.11, 95% CI 1.41–3.16, p < 0.001). Median OS was 14.2 months in the early group vs 3.8 months in the late group (log-rank p < 0.001). Using previously defined cutoffs, categorization by the median IT of all infusions or the median of the first four infusions did not demonstrate a significant association with OS in either univariate or multivariate Cox regression analyses. Conclusions: These findings highlight the potential role of infusion timing as a chronotherapy factor in GI cancers. Given the retrospective design and heterogeneous population, prospective studies are warranted to validate this signal and clarify its clinical relevance. Baseline demographics of patients by infusion timing (early vs late). Variables Early N=412 (%) LateN=43(%) Total N=455(%) p-value Age <70 249(60.4) 21(48.8) 270 (59.3) 0.1 >70 163(39.6) 22(51.2) 185 (40.7) Gender F 118(28.6) 16(37.2) 134 (29.5) 0.3 M 294(71.4) 27(62.8) 321 (70.5) Cancer Type Gastroesophageal 109 (26.5) 8 (18.6) 117 (25.7) 0.1 Hepatocellular 159 (38.6) 24 (55.8) 183 (40.2) Biliary 86 (20.9) 4 (9.3) 90 (19.8) MSI-H 58 (14.1) 7 (16.3) 65 (14.3) Metastasis No 150 (36.4) 22 (51.2) 172 (37.8) 0.1 Yes 262 (63.6) 21 (48.8) 283 (62.2) Immunotherapy Cycle Number <6 189 (45.9) 33 (76.7) 222 (48.8) <0.001 >6 223 (54.1) 10 (23.3) 233 (51.2)