Ailawadi, Sarina

Background: Atezolizumab plus bevacizumab (A + B) and durvalumab plus tremelimumab (D + T) are approved first-line systemic therapy options for advanced hepatocellular carcinoma (HCC), with no head-to-head comparison. In this propensity-matched analysis, we compared the survival of patients with advanced HCC who received either A + B or D + T therapy. Methods: Patients with advanced HCC who received A + B or D + T treatment in the first-line setting were identified using the TriNetX platform, a health research network that provides access to electronic health record data from 112 healthcare organizations. Propensity-score-matched (PSM) analysis was conducted, and the median overall survival (OS) was estimated using the Kaplan–Meier method. Results: We identified 2819 patients with HCC who were treated with A + B or D + T: 2031 patients received A + B and 788 received D + T. Compared to patients in the A + B cohort, those who received D + T were more likely to be older (median age: 68.4 vs. 66.9 years), have lower platelet counts (186.8 vs. 201.3), higher prevalence of hypoalbuminemia with levels < 2.7 g/dL (35.2% vs. 28.4%), higher prevalence of bilirubin levels between 2.0 and 2.9 mg/dL (28.8% vs. 23.8%), and decreased INR with levels between 0.0 and 1.6 (92.1% vs. 86.3%). After PSM, 1536 patients were included in the survival analyses, with all variables adequately matched. There was no significant difference in the median OS between those receiving A + B or D + T [16.3 vs. 22.5 months, hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.76–1.0]. Higher rates of immune-mediated colitis were noted in the D + T group. Conclusions: Similar survival rates were observed among patients with advanced HCC who received A + B and D + T in the first-line setting. Our study suggests that both A + B and D + T are valid treatment options, and that therapy can be tailored based on comorbidities, adverse effects, and patient preferences.

139 Background: Statins have been shown to reduce the risk of HCC in high-risk populations with metabolic diseases. However, emerging data suggests that GLP-1 RA’s may also offer hepatoprotection by reversing metabolic and inflammatory drivers contributing to HCC development. Patients with T2DM are at an increased risk of metabolic associated steatotic liver disease (MASLD) and HCC. To our knowledge, no real-world studies have directly compared the effectiveness of GLP-1 RA’s and statins for prevention of HCC in patients with T2DM. In this study, we aim to compare the incidence of HCC and hepatic decompensation events in patients with T2DM treated with GLP-1 RA’s vs statins. Methods: We performed a retrospective cohort study using data from TriNetX, a healthcare database of over 150 million patients in the United States. Adult patients with T2DM were identified and stratified by use of GLP-1 RA (semaglutide, dulaglutide, tirzepatide, exenatide, liraglutide, and lixisenatide) or statin (pitavastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin or lovastatin). Exposure groups were mutually exclusive with no overlap in GLP-1 RA or statin use. Propensity score matching was conducted between cohorts, matching for age, sex, race, tobacco use, alcohol use, hypertension, hyperlipidemia, obesity, MASLD, aspirin use, non-steroidal anti-inflammatory analgesic drug use, and other T2DM medications. Five-year incidence of HCC was compared between the GLP-1 RA and statin cohorts. In a subsequent analysis, hepatic decompensation events of ascites, hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP), and esophageal varices (EV) were compared. Results: We identified 1,411,022 patients with T2DM, including 254,832 GLP-1 RA users and 1,156,190 statin users. After PSM, 219,984 patients were included in the analysis. There was no significant difference in the five-year incidence of HCC between the GLP-1 RA and statin cohorts (0.14% vs 0.15%, odds ratio (OR) 0.95, 95% confidence interval (CI)0.81-1.11, p =0.5). In the subsequent analysis, GLP-1 RA use was associated with a lower incidence of ascites (0.98% vs 1.99%, OR 0.84, 95% CI 0.46-0.51, p <0.001), HE (0.18% vs 0.22%, OR 0.84, 95% CI 0.74-0.96, p =0.01), and SBP (0.05% vs 0.1%, OR 0.52, 95% CI 0.42-0.65, p <0.001). There was no difference in incidence of EV (0.33% vs 0.35%, OR 0.94, 95% CI 0.85-1.04, p =0.25). Conclusions: In patients with T2DM at elevated risk for MASLD and HCC, we found that GLP-1 RA use was associated with significantly lower incidence of hepatic decompensation events compared to statin use. However, there was no significant difference in HCC incidence between the cohorts. Prospective studies are warranted to confirm the hepatoprotective effect of GLP-1 RA medications and evaluate long-term oncologic outcomes.

138 Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RA’s) have advanced the treatment of type 2 diabetes mellitus (T2DM), yet their association with cancer risk remains subject of ongoing research. Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is a well-established risk factor for colorectal cancer (CRC). Studies have shown a reduced risk of CRC with GLP-1 RA use however, the impact of GLP-1 RA therapy in the high-risk IBD population is unknown. In this study, we aim to evaluate the association between GLP-1 RA use and CRC incidence among patients with IBD, and among those with IBD and T2DM. Methods: We performed a retrospective cohort study using data from TriNetX, a healthcare database of over 150 million patients in the United States. In the first analysis, adult patients with pre-existing IBD were identified and stratified by use of a GLP-1 RA (semaglutide, dulaglutide, tirzepatide, exenatide, liraglutide, and lixisenatide) or not. Propensity score matching (PSM) was conducted between GLP1-RA users and non-users, matching for age, sex, race, tobacco use, alcohol use, hypertension, hyperlipidemia, obesity, IBD subtype (CD or UC), steroid use, immunosuppressive use including biologics, and other T2DM medications. Five-year incidence of CRC was compared between GLP-1 RA users and non-users in the matched cohort between 2015 and 2025. We then restricted the cohort to patients with IBD and T2DM and repeated this analysis. Results: We identified 1,137,300 patients with IBD, including 70,303 GLP-1 RA users and 1,066,997 non-users. After PSM with all variables adequately matched, 69,221 patients were included in the analyses. GLP-1 RA use was associated with a lower 5-year incidence of CRC (0.2% vs. 0.43%, odds ratio (OR) 0.49, 95% confidence interval (CI) 0.3-0.57, p <0.001). We then identified 209,649 patients with IBD and T2DM, including 38,567 GLP-1 RA users and 171,082 non-users. After matching for all variables, 37,740 patients were included in the analyses. Among patients with IBD and T2DM, GLP-1 RA use was associated with a lower 5-year incidence of CRC (0.31% vs. 0.57%, OR 0.54, 95% CI 0.43-0.68, p <0.001). Conclusions: GLP-1 RA use was associated with a significantly reduced incidence of CRC in all patients with IBD, as well as the subpopulation with both IBD and T2DM. Given the elevated CRC risk in IBD, these findings suggest a potential protective effect of GLP-1 RA use in this high-risk population. Prospective studies will be important to further analyze and confirm this potential benefit.

e16246 Background: First line systemic therapy for advanced hepatocellular carcinoma (HCC) includes immune checkpoint inhibitor (ICI) combination therapy, with tyrosine kinase inhibitors (TKIs), lenvatinib or cabozantinib, commonly used as second line therapy. However, there is limited data comparing efficacy of TKIs following first line ICI therapy. In the present study, we compared survival and risk of hospitalization in a propensity score matched analysis of patients who received lenvatinib or cabozantinib following progression on first line ICI therapy in patients with advanced HCC. Methods: We performed a retrospective cohort study using data from TriNetX, a healthcare database of over 150 million patients in the United States. We identified adult patients with a history of HCC who received atezolizumab plus bevacizumab (A+B) or durvalumab plus tremelimumab (D+T) as first line treatment. We then stratified patients by use of lenvatinib or cabozantinib in the subsequent line setting. Propensity score matching (PSM) was conducted between those who received lenvatinib and those who received cabozantinib, matching for demographic factors (age, sex, race), clinical characteristics (history of alcohol use, ascites, esophageal varices, or viral hepatitis), and laboratory parameters [platelets, albumin, bilirubin, INR and alpha-1-fetoprotein (AFP)]. Results: We identified 416 patients who were initially treated with either A+B or D+T, with 327 patients receiving A+B and 89 patients receiving D+T. Of these, 336 patients (80.8%) subsequently received lenvatinib and 80 patients (19.2%) received cabozantinib. Baseline characteristics of demographic factors, clinical characteristics, and laboratory parameters were comparable between patients in the lenvatinib arm and cabozantinib arm with all standardized mean differences (SMD) < 0.10. After PSM, 76 patients were included in the analyses, with all variables adequately balanced. There was no significant difference in the risk of hospitalization between those receiving lenvatinib or cabozantinib at 3 months [31.6% vs 34%, odds ratio (OR) 1.13, 95% confidence interval (CI) 0.57-2.2]. There was also no significant difference in mOS between those receiving lenvatinib and cabozantinib [9.5 vs 9.0 months, hazard ratio (HR) 1.03, 95% CI 0.62-1.7]. Conclusions: In patients with HCC who received lenvatinib or cabozantinib as second-line therapy following first-line ICI combination therapy, we found no significant differences in rate of hospitalization or survival. These findings suggest that either option may be appropriate, and decisions may be based in side effect profile and patient preferences. Prospective studies will be important to further assess differences in patient outcomes.

4163 Background: Standard first-line systemic therapy for hepatocellular carcinoma involves immune checkpoint inhibitors, including A+B and the STRIDE regimen consisting of D+T. However, there is limited data comparing outcomes of patients receiving these two regimens. We aimed to compare the survival and safety profiles of patients receiving A+B versus D+T as first-line systemic therapy for advanced HCC in a propensity score matched analysis. Methods: We performed a retrospective cohort study using data from TriNetX, a healthcare database of over 150 million patients in the United States. We identified adult patients with a history of HCC and included those who received A+B or D+T as first line treatment. Propensity score matching (PSM) was conducted, matching for patient demographics (age, sex, race), clinical history (alcohol use, ascites, esophageal varices, viral hepatitis), and laboratory parameters [platelets, albumin, bilirubin, INR, alpha-1-fetoprotein (AFP)]. Median overall survival (mOS) and relevant patient safety events were compared between those who received A+B or D+T. Results: We identified 2,762 patients who had HCC who were treated with A+B or D+T, of which 2,030 patients received A+B and 723 patients received D+T. Compared to patients in the A+B cohort, those who received D+T were more often older (68.5 vs 66.9 years, standardized mean difference (SMD) = 0.17), had lower platelet counts (186.4 vs 198.6, SMD = 0.11), had higher prevalence of ascites (33.1% vs 20.3%, SMD = 0.29), and alcohol use (23.8% vs 18.8%, SMD = 0.12). After PSM, 723 patients were included in survival analyses, with all variables adequately balanced except for albumin, which was higher in the A+B group (3.6 vs 3.5, SMD = 0.19). At 90 days after starting therapy, D+T was associated with higher incidence of immune-mediated colitis [5.3% vs 2.6%, odds ratio (OR) 2.1; 95% confidence interval (CI), 1.2-3.7], and a higher risk of hospitalization [35.4% vs 27.9%, OR 1.4; 95% CI, 1.1-1.8]. At 6 months, the risk of hypertension and proteinuria was higher in the A+B cohort [21.9% vs 13.7%, OR 0.57; 95% CI, 0.34-0.95], which persisted at 1 year [28.1% vs 16.5%, OR 0.51; 95% CI, 0.32-0.81]. There was no significant difference in mOS between those receiving A+B or D+T [18.3 months vs 22.8 months, hazard ratio (HR) 0.94; 95% CI, 0.79-1.1]. Conclusions: In patients with advanced HCC who received A+B or D+T as first-line systemic therapy, we found that A+B was associated with higher risk of hypertension and proteinuria, while D+T was associated with a higher risk of immune-mediated colitis and hospitalization. No significant difference in mOS was observed between the cohorts. These findings suggest that safety profiles, rather than survival differences, may be used to guide optimal first-line treatment regimens. Prospective studies are warranted to further assess differences in patient outcomes.

733 Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RA) have advanced the treatment of type 2 diabetes mellitus (T2DM) yet their association with cancer risk remains subject of ongoing research. While case reports and pharmacovigilance data have linked GLP-1RA’s to pancreatitis, large randomized trials and observational studies have not consistently shown an increased risk of pancreatic cancer. Chronic pancreatitis (CP) is a well-established risk factor for pancreatic cancer, yet the impact of GLP-1 RA therapy in this high-risk population is unknown. In this study, we aim to evaluate the association between GLP-1 RA use and pancreatic cancer incidence among patients with CP, and among those with CP and T2DM. Methods: We performed a retrospective cohort study using ICD-10 codes within TriNetX, a healthcare database of over 150 million patients in the United States. In the first analysis, adult patients with pre-existing CP were identified, and the 5-year incidence of pancreatic cancer between GLP-1 RA (semaglutide, dulaglutide, tirzepatide, exenatide, liraglutide, and lixisenatide) users and non-users was compared from 2015-2025. In the subsequent analysis, we restricted the cohort to adults with CP and T2DM and repeated the comparison. Patients with prior diagnosis of pancreatic cancer were excluded from both analyses. All cohorts were propensity score matched (PSM) on age, sex, race, tobacco use, alcohol use, hypertension, hyperlipidemia, obesity, and pancreatic cysts. Results: We identified 95,391 with CP, including 3,139 GLP-1 RA users and 92,252 non-users. After PSM, GLP-1 RA use was associated with a lower incidence of pancreatic cancer (0.6% vs. 1.5%, OR 0.39 [0.22, 0.67]). Similarly, amongst patients with CP and T2DM, GLP-1 RA use was associated with a lower incidence of pancreatic cancer (0.7% vs. 1.6%, OR 0.44 [0.25, 0.75]). Conclusions: GLP-1 RA use was associated with a significantly reduced incidence of pancreatic cancer in all patients with CP and in those with CP and T2DM. Given the elevated cancer risk in CP, these findings suggest a potential protective effect of GLP-1RA use in this high risk population. Prospective studies will be important to further analyze and confirm this potential benefit.

605 Background: Multiple treatment modalities are available for localized hepatocellular carcinoma (HCC), and current Barcelona Clinic Liver Cancer (BCLC) guidelines recommend ablation for patients with a limited number of small tumors, not amenable to resection or transplantation. However, in recent years, stereotactic body radiation therapy (SBRT) has been increasingly used for localized disease. Patient outcomes based on treatment modality are not well understood. Methods: We conducted a retrospective analysis using the National Cancer Database (NCDB) to identify patients with a history of stage I/II HCC with tumors ≤ 5 cm who had received local therapy with either radiofrequency ablation (RFA) or SBRT between 2006 and 2021. A propensity score matched analysis was conducted accounting for patient demographics, facility region and tumor level characteristics, as well as an inverse probability of treatment weight-adjusted (IPTW) analysis. Overall survival was estimated using the Kaplan-Meier method. Results: We identified 14,516 patients meeting inclusion criteria, including 13,036 who received RFA and 1,480 who received SBRT. Demographic factors associated with receipt of SBRT included age >50 years, female sex, and treatment in the Middle Atlantic and East North Central regions, as well as clinical factors including larger tumor size (>3 to 5 cm), severe fibrosis/cirrhosis, and stage II disease ( p <0.05 for all). Factors associated with receipt of RFA include black race, higher Charlson-Deyo Comorbidity Scores, treatment at a comprehensive cancer program or integrated network cancer program, and treatment in the East South Central, West North Central, West South Central, Mountain, and Pacific Regions ( p <0.05 for all). Median time from diagnosis to treatment initiation was longer for those who received SBRT (66.3 vs 84.6 days, p <0.001). In a propensity matched analysis, mOS was 45.1 months for those receiving RFA vs 30.8 months for those receiving SBRT ( p <0.001). An IPTW analysis showed similar survival benefit with RFA over SBRT (mOS 51.0 vs 30.5 months, p <0.001). This OS benefit was observed in subset of patients with tumors <3cm in size. Conclusions: In this propensity matched analysis controlling for relevant patient and tumor factors, RFA was associated with improved survival. Prospective studies will be important to further analyze differences in patient outcomes.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have advanced the treatment of type 2 diabetes mellitus (T2DM), yet their association with cancer risk remains subject of ongoing research. Chronic pancreatitis (CP) is a well-established risk factor for pancreatic cancer, yet the impact of GLP-1 RA therapy in this high-risk population is unknown. In this study, we aimed to evaluate the association between GLP-1 RA use and pancreatic cancer incidence among patients with CP, and among those with CP and T2DM. Methods: We performed a retrospective cohort study using data from TriNetX, a healthcare database of over 150 million patients in the United States. In the first analysis, adult patients with pre-existing CP were identified and stratified by use of a GLP-1 RA (semaglutide, dulaglutide, tirzepatide, exenatide, liraglutide, lixisenatide, and albiglutide). Propensity score matching (PSM) was conducted between GLP1-RA users and non-users, matching for age, sex, race, tobacco use, alcohol use, hypertension, hyperlipidemia, obesity, and pancreatic cysts. Five-year incidence of pancreatic cancer was compared between GLP-1 RA users and non-users in the matched cohort between 2015 and 2025. We then restricted the cohort to patients with CP and T2DM and repeated this analysis. Results: We identified 89,596 patients with CP, including 3183 GLP-1 RA users and 86,413 non-users. After PSM, GLP-1 RA use was associated with a lower 5-year incidence of pancreatic cancer (hazard ratio (HR) 0.49, 95% confidence interval (CI) 0.30–0.80, p < 0.005). Similarly, amongst patients with CP and T2DM, GLP-1 RA use was associated with a lower 5-year incidence of pancreatic cancer (HR 0.53, 95% CI 0.31–0.91, p < 0.05). Conclusions: GLP-1 RA use was associated with a significantly reduced incidence of pancreatic cancer in all patients with CP, as well as the subpopulation with both CP and T2DM. Given the elevated cancer risk in CP, these findings suggest a potential beneficial effect of GLP-1RA use in this high-risk population. Prospective studies will be important to further analyze and confirm this potential benefit.