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e16449 Background: Pancreatic cancer (PC) carries a dismal 5-year survival of < 12%, and no FDA-approved agents exist for primary prevention. PC risk is strongly linked to obesity, diabetes, and chronic inflammation. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) directly target obesity-driven inflammatory pathways, reduce metabolic stress, and modulate signaling pathways (PI3K/AKT/mTOR) that drive cancer apoptosis. Based on this biological rationale, we conducted the first large-scale real-world study to evaluate the safety and efficacy of GLP-1RA for primary prevention of PC in high-risk patients. Methods: Leveraging a large real-world database (TriNetX), we identified patients aged 18-90 years with ≥1 PC risk factor (tobacco use, obesity, type 2 diabetes, alcohol use disorder, chronic pancreatitis, first-degree relative with PC, genetic susceptibility to PC) based on ICD-10 codes. Patients were stratified by GLP-1RA exposure into two cohorts: Cohort A (GLP-1RA users with ≥ 2 months of prescriptions) and Cohort B (controls). The primary endpoint was incident PC, and the secondary endpoints were adverse events related to GLP-1RAs. Patients with outcomes before the study window were excluded. Propensity score matching adjusted for confounders. Multivariate logistic regression was used to estimate odds ratios for categorical outcomes, and the Cox proportional hazards model was used to estimate hazard ratios for time-to-event outcomes. Subgroup and sensitivity analyses were employed to validate the strength of our results. Results: Median follow-up was 3,397 days for GLP-1RA users and 2,531 days for controls. Demographics were balanced between cohorts (mean age 42 years; 74% White, 15% Black; 72% female). Among 572,330 high-risk patients (286,165 per cohort), PC incidence was significantly lower among GLP-1RA users (0.05%; 134/286,165) than among non-users (0.13%; 362/286,097), with a 2.6-fold reduction in the absolute incidence of PC among high-risk patients (NNT of 1,255). GLP-1RA use was associated with a 71% reduction in PC incidence (HR 0.289; 95% CI 0.237–0.352). GLP-1RA use was associated with an increased risk of gastrointestinal adverse events, including nausea/vomiting (HR 1.108; 95% CI 1.096–1.121), abdominal pain (HR 1.081; 95% CI 1.066–1.097), diarrhea (HR 1.199; 95% CI 1.182–1.217), and constipation (HR 1.159; 95% CI 1.143–1.176). Conclusions: GLP-1RA use significantly reduced PC incidence by 71% in high-risk patients, the strongest real-world signal yet for a pharmacologic prevention of this lethal malignancy. Although the absolute incidence remained low, the magnitude of the risk reduction underscores the transformative potential of GLP-1RA in preventive oncology. These findings address a critical unmet need in pancreatic oncology. Prospective mechanistic and randomized studies are warranted to validate these associations.

e16443 Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with KRAS mutations present in approximately 90% of cases. Patients with advanced or metastatic PDAC who have progressed after standard chemotherapy face limited treatment options, with historical outcomes showing objective response rates (ORR) below 10% and median progression-free survival (PFS) and overall survival (OS) of approximately 2-4 months and 6-8 months, respectively. The development of covalent KRAS G12C inhibitors—including sotorasib, adagrasib, garsorasib, glecirasib, and divarasib—has opened new therapeutic options for this molecularly defined subset of PDAC patients. Methods: We conducted a systematic review and meta-analysis of clinical trials evaluating KRAS G12C inhibitor monotherapy in patients with advanced/metastatic pancreatic ductal adenocarcinoma. Data were extracted from 3 studies (Strickler 2022, Li J 2025, and Tanios 2023) encompassing a total of 91 patients with KRAS G12C-mutant PDAC who had received 1-2 prior lines of chemotherapy. Pooled estimates were calculated using random-effects meta-analysis models (DerSimonian-Laird method). For proportion outcomes (ORR and DCR), standard errors were calculated using binomial distribution, and for continuous outcomes (PFS and OS), inverse-variance weighting was employed. Heterogeneity was assessed using the I² statistic and Cochran's Q test. All confidence intervals were calculated at the 95% level. Results: The pooled analysis revealed clinically meaningful efficacy across all endpoints. The pooled objective response rate (ORR) was 32.9% (95% CI: 17.0% to 48.9%), with moderate heterogeneity (I² = 64.0%). The pooled disease control rate (DCR) was substantially higher at 88.3% (95% CI: 80.5% to 96.1%), with low heterogeneity (I² = 27.7%), indicating consistent disease stabilization across studies. For survival outcomes, the pooled median progression-free survival (PFS) was 4.98 months (95% CI: 3.62 to 6.34 months), with low heterogeneity (I² = 32.3%). The pooled median overall survival (OS) was 8.73 months (95% CI: 6.07 to 11.39 months), though with substantial heterogeneity (I² = 77.0%). Conclusions: KRAS G12C inhibitor monotherapy demonstrates clinically significant and durable efficacy in pretreated adults with advanced/metastatic PDAC harboring the KRAS G12C mutation. The pooled ORR of approximately one-third, together with a DCR near 90%, indicates substantial tumor control in a population with historically poor outcomes. Median PFS of approximately 5 months and OS of nearly 9 months represent clinically relevant improvements over standard salvage therapies, supporting KRAS G12C inhibitors as a viable option after chemotherapy failure.

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.

e16405 Background: Pancreatic cancer remains one of the most lethal malignancies, with a rising incidence and persistently poor survival outcomes. Gemcitabine plus nab-paclitaxel is an established standard regimen for advanced disease, however, the conventional triweekly schedule is frequently associated with significant toxicity. Biweekly dosing has been proposed to enhance tolerability while maintaining efficacy, although evidence remains limited and heterogeneous. The objective was to evaluate the efficacy and safety of biweekly versus standard gemcitabine/nab-paclitaxel in patients with advanced pancreatic cancer. Methods: A systematic search of PubMed, Embase, and the Cochrane Library was conducted to identify studies comparing Biweekly versus Standard Triweekly: gemcitabine / nab-paclitaxel in patients with advanced pancreatic cancer. The primary outcomes of interest included partial response, and treatment-related toxicities, specifically anemia, neutropenia, and use of growth factors. Statistical analyses were performed using Review Manager. Heterogeneity was assessed using the I 2 statistic, and risk of bias was evaluated using the ROBINS-I tool. Results: A total of 1357 patients from eight observational studies were included. Comparative analysis showed no significant difference in partial response between biweekly and standard triweekly gemcitabine/nab-paclitaxel in patients with advanced pancreatic cancer with a risk ratio (RR) of 0.77 (95% CI 0.57,1.04, p = 0.09). Similarly, no significant differences were observed between regimens in the incidence of anemia (RR = 1.09; 95% CI 0.74–1.59; p = 0.66) or neutropenia (RR = 1.09; 95% CI 0.86–1.37; p = 0.48). however, growth factor use was significantly lower with biweekly dosing (RR = 0.71; 95% CI 0.58–0.87; p = 0.0009). Overall survival was comparable between groups RR = 1.02 (95% CI 0.71, 1.45 p = 0.93). Conclusions: Administration of gemcitabine/nab-paclitaxel biweekly yielded clinical outcomes and safety profiles comparable to the conventional regimen, while significantly reducing the need for growth factors as supportive care. These data suggest that a biweekly regimen could be an effective alternative; however, further prospective randomized studies are necessary to verify these findings and better understand their clinical application.

e16377 Background: 1L systemic treatment of mPDAC can lead to severe adverse events (AEs). To contextualize the safety profile of irinotecan-based regimens, real-world data were used to characterize AEs and their management in patients receiving 1L mPDAC treatment with FOLFIRINOX (FFX) or gemcitabine+Nab-paclitaxel (Gem+NabP). Methods: De-identified data from Mayo Clinic electronic health records (all sites; records collected 2010–2023) were used. Natural language processing was leveraged to confirm staging and metastatic classification and to extract treatment data. Adults with mPDAC with stage IV and/or TNM staging of M1 who received ≥ 1 dose of FFX or Gem+NabP were included. Primary endpoint: proportion of patients with AEs of interest (diarrhea, nausea, vomiting, neuropathy, and neutropenia) following initiation of 1L treatment. Secondary endpoints: proportion of patients who received treatment for each AE of interest, median time to resolution and treatment of each AE of interest, and proportion of patients who switched mPDAC treatment or had dose reductions due to AEs. Results: In total, 405 patients (FFX, 197; Gem+NabP, 208) were identified. The proportions of patients who experienced and were treated for any-grade AEs of interest are reported in the Table. Of the AEs of interest, neutropenia resolved most quickly (median time from onset to resolution, FFX: 9.5 days; Gem+NabP: 12.5 days); neuropathy took the longest time to resolve (FFX: 44.0 days; Gem+NabP: 74.0 days). Median time to AE treatment was shortest for nausea and vomiting (both 0.0 days for FFX and for Gem+NabP). Time to treatment was longest for neuropathy (FFX: 158.5 days; Gem+NabP: 70.0 days). Only 5.1% of patients on FFX and 13.4% on Gem+NabP received treatment for neuropathy. Of patients in the FFX group who switched/reduced treatment (n=140), 58.6% received a dose reduction and 7.1% switched to Gem+NabP due to AEs. Conclusions: At the Mayo Clinic sites, incidence of any-grade AEs associated with 1L mPDAC treatment were similar or higher than rates of any-grade or ≥ 2/3–4 grade AEs reported in the literature. Nausea, vomiting and diarrhea were the most commonly treated AEs for both irinotecan-based (FFX) and non-irinotecan-based (Gem+NabP) 1L regimens; neutropenia and neuropathy were less commonly treated. FFX dose reductions were commonly attempted before switching regimens. Proportion experiencing any-grade AE (AE incidence in the literature) Proportion experiencing AE treated for an AE FFX Gem+NabP FFX Gem+NabP Diarrhea 74.6% (50–80%, any grade) 43.8% (< 5%, any grade) 92.5% 56.0% Nausea 81.7% (45%, any grade) 72.1% (20%, grade ≥ 2) 98.8% 96.7% Vomiting 54.8% (10%, any grade) 42.8% (20%, grade ≥ 2) 98.1% 98.9% Neutropenia 58.9% (45%, grade 3–4) 48.1% (12–21%, grade 3–4) 62.1% 46.0% Neuropathy 59.9% (25%, grade 3–4) 32.2% (30%, grade 3–4) 5.1% 13.4%

e16335 Background: Splanchnic vein thrombosis (SVT) is a rare but serious complication in gastrointestinal (GI) cancer patients. This study investigated its features and outcomes in U.S. hospitalizations. Methods: Hospitalizations (≥18 years old) with a GI malignancy (ICD-10-CM C15–C26) and portal vein thrombosis (PVT) (I81), hepatic vein thrombosis (HVT) (I82.0), or mesenteric/splenic vein thrombosis (MSVT) (I82.890 + K55) in any of the 40 diagnosis fields were found in 2022 National Inpatient Sample. Exclusions: non-GI cancers (C00-C14, C27-C96), thrombophilia (D68.5, D68.6, D45, D47.1, D59.5), or cirrhosis (K74, K70.3). Demographics and outcomes (in-hospital mortality, length of stay [LOS], and total hospital charges [TOTCHG]) were compared between SVT and non-SVT groups using unweighted descriptive statistics (medians, IQRs), χ², and Mann-Whitney U tests. Multivariable regression of mortality, LOS, and TOTCHG were adjusted for age, sex, race, income quartile, insurance type, hospital region and bed size, and comorbidity burden (elixsum). Stata 17.0 was used. Results: Among 51,940 GI cancer hospitalizations (mean age 68.37 ± 12.79 years; 44.46% female), 833 (1.60%) had SVT. SVT group was younger (66.60 ± 11.76 vs. 68.40 ± 12.80 years; p < 0.001). Sex distribution was similar (58.34% vs. 55.50% male; p = 0.101). Common cancers in SVT: liver (n=427; 51.26%), pancreas (n=310; 37.21%), and colorectal (n=42; 5.04%). SVT prevalence was highest in liver (7.10%), pancreatic (3.14%), gallbladder (2.65%), and biliary (2.13%) cancers. PVT was the predominant subtype (n=788; 94.60%), followed by HVT (n=21; 2.52%), MSVT (n=4; 0.48%), and multiple SVT sites (n=20; 2.40%). SVT subtype distribution was: PVT (n=788; 94.60%), HVT (n=21; 2.52%), MSVT (n=4; 0.48%), and multiple sites (n=20; 2.40%). SVT had longer median LOS (5 [3–10] vs. 4 [3–8] days; z = -6.666, p < 0.001), similar median charges ($65,053 [I33,560–130,026] vs. $66,433 [35,897–121,038]; z = -0.76, p = 0.447), and higher mortality (9.48% vs. 4.41%; χ² = 49.042, p < 0.001). In adjusted analyses, SVT had higher mortality (aOR = 2.23, 95% CI 1.74–2.85, p < 0.001), longer LOS by 1.50 days (95% CI 0.99–2.02, p < 0.001), and 14.63% higher TOTCHG (coefficient 0.136, 95% CI 0.051–0.222, p = 0.002). Conclusions: SVT affects ~1.6% of GI cancer hospitalizations, is most prevalent in liver cancer, and associated with longer stays and higher mortality, underscoring the need for proactive monitoring. Multivariable regression analyses of SVT on clinical outcomes (unweighted sample). Outcome SVT Effect 95% CI P-value Interpretation In-hospital mortality OR 2.23 1.74–2.85 <0.001 SVT doubles odds of in-hospital death Length of stay (days) +1.50 0.99–2.02 <0.001 SVT associated with ~1.5 extra hospital days Total hospital charges ($) +0.136 (log scale) 0.051–0.222 0.002 SVT increases hospital costs by ~14.63%

e16334 Background: Liver cancer remains a leading cause of cancer-related mortality in the United States. Although overall mortality has increased over the past two decades, age-specific patterns and demographic disparities are not fully characterized. Here, we analyzed U.S. liver cancer mortality trends from 1999 to 2023, with a focus on age-related, racial and ethnic, and geographic differences. Methods: Mortality data for U.S. adults aged ≥25 years from 1999 to 2023 were obtained from the CDC WONDER database (ICD-10 codes C22.0–C22.9). Age-adjusted mortality rates (AAMRs) were standardized to the 2000 U.S. population. Joinpoint regression was used to estimate annual percent change (APC) and average annual percent change (AAPC) across age groups, sex, race/ethnicity, U.S. census regions, and levels of urbanization. Results: From 1999 to 2023, overall liver cancer AAMRs increased from 6.95 to 10.1 per 100,000. Marked age-specific differences were observed. Mortality among adults aged 45–54 and 55–64 years peaked in the mid-2010s and subsequently experienced significant declines through 2023 (recent APCs < −4.5% for both groups; P < 0.001). Specifically, while the overall AAPC for the 55–64 age group was +1.89%, mortality significantly reversed after 2016 (APC, −4.59%). In contrast, mortality continued to rise among older adults, including those aged 65–74 years (AAPC, +2.26%), 75–84 years (AAPC, +1.69%), and aged ≥85 years (AAPC, +1.77%) (all P < 0.001). Differences in mortality trends were also identified across racial and ethnic groups. Sustained increases were observed among Non-Hispanic White individuals (AAPC, +1.89%; P < 0.001), while Hispanic/Latino populations experienced declines after 2013 (APC, −0.67%; P = 0.003). Non-Hispanic Black individuals demonstrated a significant decrease in mortality between 2017 and 2020 (APC, −3.82%; P = 0.03). Regionally, liver cancer mortality declined in the Northeast after 2013 (APC, −0.66%; P < 0.001), whereas no significant post-peak declines were observed in the South or West. Conclusions: U.S. liver cancer mortality trends exhibit substantial heterogeneity by age, race and ethnicity, and geographic region. The recent, sharp declines among middle-aged adults (APCs < −4.5%) likely reflect the success of large-scale viral hepatitis screenings and highly effective antiviral therapies, whereas continued increases among older adults may relate to the cumulative impact of metabolic risk factors and delayed diagnosis. Persistent racial and regional disparities highlight the need for targeted, age-specific prevention and surveillance strategies.

e16323 Background: Advanced EP-NEC are typically treated with the combination of platinum plus etoposide. Despite therapy, outcomes remain poor, with reported median overall survival (OS) of 12-13 months. Early initiation of systemic therapy is commonly practiced given the aggressiveness; however, recent data from small cell lung carcinoma (SCLC) suggest that shorter TTI does not necessarily improve OS. The impact of TTI on outcomes in EP-NEC has not been well studied. Methods: We conducted a multicenter retrospective cohort study across three Mayo Clinic sites including adults with biopsy-confirmed stage IV EP-NEC diagnosed between 2005 and 2025. TTI was defined as days from pathologic diagnosis to initiation of first-line systemic therapy. A binary cutoff (≤14 vs > 14 days) was determined using receiver operating characteristic (ROC) analysis, and TTI was also analyzed as a continuous variable. OS and progression-free survival (PFS) were estimated using the Kaplan–Meier method and evaluated using Cox proportional hazards models. Multivariable analyses adjusted for age, sex, ECOG performance status, presence of liver metastases, and first-line treatment strategy (chemotherapy alone vs chemotherapy plus immunotherapy). Results: Among 248 pts, median age was 61 years. Median OS for the cohort was 13.9 months (95% CI, 11.7–16.7), and median PFS was 5.7 months (95% CI, 5.3–6.3). Pts with TTI > 14 days had longer median OS compared with those treated within ≤14 days (16.4 vs 10.1 months), with improved OS on unadjusted analysis (HR 0.69, 95% CI 0.50–0.96; p = 0.028), though this association was not statistically significant after multivariable adjustment (HR 0.74, 95% CI 0.53–1.05; p = 0.097). Pts with TTI > 14 days also had longer median PFS compared with ≤14 days (6.5 vs 4.8 months), with improved PFS on unadjusted analysis (HR 0.67, 95% CI 0.51–0.88; p = 0.0038). On multivariable analysis, TTI > 14 days remained independently associated with improved PFS (HR 0.75, 95% CI 0.56–1.00; p = 0.047). However, when analyzed as a continuous variable, TTI was not independently associated with OS (HR 0.99, 95% CI 0.98–1.00; p = 0.173) or PFS (HR 0.99, 95% CI 0.98–1.00; p = 0.089). Conclusions: In this multicenter cohort of pts with metastatic EP-NEC, earlier initiation of systemic therapy (≤14 days) was not associated with improved overall survival, and longer time-to-treatment was independently associated with improved PFS. However, when TTI was analyzed as a continuous variable, no statistically significant associations were observed, suggesting that the observed benefit with delayed treatment may reflect pt selection or clinical context rather than a direct biological effect. These findings may provide reassurance in scenarios where short delays are necessary—for biomarker testing or clinical trial enrollment—and highlight the need for further investigation in the era of precision oncology.

e16322 Background: Small intestine neuroendocrine carcinoma (NEC) is a rare, aggressive malignancy comprising less than 0.1% of gastrointestinal cancers. Population-level data remain limited, restricting understanding of long-term survival patterns, demographic disparities, and evolving disease burden. We evaluated survival outcomes, demographic predictors, and incidence trends of small intestine NEC in the United States. Methods: We conducted a retrospective population-based cohort study using SEER Research Data (17 registries, November 2024 submission). Patients diagnosed with malignant small intestine NEC (ICD-O-3 morphology code 9.3.3.1.2) between 2000 and 2022 were identified using SEER*Stat (v9.0.4.2). Variables including age group, sex, race, year of diagnosis, survival time, and vital status were analyzed in R (v4.5.1). Overall survival (OS) was estimated using Kaplan–Meier methods and compared using log-rank testing. Cox proportional hazards models identified independent predictors of OS. Annual case counts were modeled using time-series forecasting to project future incidence. Results: A total of 506 patients were included. Estimated OS was 94.4% (95% CI 92.4–96.4) at 1 year, 88.1% (85.3–91.0) at 3 years, and 82.4% (79.0–85.9) at 5 years, with a subset demonstrating survival beyond 15 years. Increasing age was associated with worse survival (log-rank p = 0.058). Significant racial differences in OS were observed (log-rank p < 0.0001). In multivariable analysis, race remained independently associated with OS. Incidence forecasting projected a modest increase in annual case burden over the next decade. Conclusions: Small intestine NEC demonstrates heterogeneous survival outcomes, significant demographic disparities, and projected growth in disease burden. These findings highlight the need for improved risk stratification, equitable access to care, and integration of molecular and treatment-level data to optimize management of this rare malignancy

e16304 Background: Hepatic reserve is a critical determinant of outcomes in hepatocellular carcinoma (HCC), yet traditional scoring systems such as MELD are frequently unavailable or underpowered in real-world datasets. The albumin–bilirubin index (ALBI) is a validated, objective measure of liver function derived from routine laboratory values and has emerged as a pragmatic alternative for risk stratification. However, the impact of ALBI on longitudinal outcomes following locoregional therapy (LRT) for HCC in routine clinical practice remains incompletely characterized. Methods: We performed a retrospective cohort study using TriNetX to identify adults with HCC treated with locoregional therapies (transarterial chemoembolization, yttrium-90 radioembolization, stereotactic body radiation therapy, or thermal ablation). Hepatic reserve was assessed using an albumin–bilirubin–based definition with labs within 30 days pre-therapy. Low ALBI (preserved function) was defined as albumin ≥3.5 g/dL and bilirubin ≤2.0 mg/dL, and high ALBI (impaired function) as albumin < 3.5 g/dL or bilirubin > 2.0 mg/dL. Propensity score matching (1:1) balanced demographics and comorbidities. Outcomes at 6 months, 1, 3, and 5 years included mortality, hepatic failure, ascites, portal hypertension, and esophageal varices. RD, RR, OR, and HR with 95% CIs were reported. Results: After matching, 509 patients were included in each ALBI group. High ALBI was consistently associated with significantly worse outcomes across all time points. Overall mortality was higher in the high-ALBI group at 6 months (19.6% vs 8.7%), 1 year (31.0% vs 13.9%), 3 years (51.0% vs 28.3%), and 5 years (57.1% vs 35.6%). Corresponding hazard ratios for mortality ranged from 2.32 to 2.65 across time points (all p < 0.05). High ALBI was also associated with substantially increased risks of hepatic failure (5-year RD 23.9%, HR 3.29), ascites (5-year RD 18.5%, HR 2.50), and esophageal varices (5-year RD 8.5%, HR 2.60). These associations persisted from early through long-term follow-up, demonstrating durable prognostic separation by ALBI status. Conclusions: In this large, real-world cohort of HCC patients undergoing locoregional therapy, impaired hepatic reserve as defined by a high albumin–bilirubin index was strongly and consistently associated with worse short- and long-term survival and higher rates of hepatic decompensation. An albumin–bilirubin–based ALBI classification represents a pragmatic and clinically meaningful tool for risk stratification when MELD is unavailable and may inform treatment selection, prognostication, and post-therapy surveillance in routine clinical practice.