Mahipal, Amit

Abstract Background Optimal treatment following first-line immunotherapy for advanced hepatocellular carcinoma (HCC) remains uncertain. This study evaluated futibatinib, a pan-FGFR inhibitor, combined with pembrolizumab in previously treated patients with FGF19-expressing HCC. Methods Eligible patients were ≥18 years old with advanced HCC, prior systemic therapy, Child-Pugh A-B7 liver function, ECOG 0–2, and FGF19 overexpression. Patients received futibatinib 20 mg orally daily plus pembrolizumab 200 mg intravenously every 3 weeks. The primary endpoint was progression-free survival at 6 months (PFS6). Secondary endpoints included overall survival (OS), objective response rate (ORR), quality of life, and safety. Results Between August 2021 and March 2024, 14 patients enrolled and 13 were evaluable. Median age was 72 years (range, 60–87), 53.8% were male, 92.3% had Child-Pugh A liver function, and all had received prior immunotherapy. Median progression-free survival was 15 weeks (95% CI, 9.0–NE), with a PFS6 rate of 23.1% (95% CI, 8.6–62.3%). ORR was 0% (95% CI, 0–24.7%), while stable disease was observed in 53.9% of patients. Median OS was 55.7 weeks (95% CI, 47.3–NE). Grade ≥3 adverse events occurred in 69.2% of patients, and grade ≥4 adverse events in 15.4%. One grade 5 event (acute-on-chronic kidney injury) was deemed unrelated to treatment. Common adverse events included hyperphosphatemia, fatigue, diarrhea, elevated transaminases, dry eye, nail changes, rash, and oral mucositis. Conclusions Futibatinib plus pembrolizumab demonstrated an acceptable safety profile but did not meet efficacy thresholds supporting further study in FGF19-expressing HCC. Effective post-immunotherapy treatment strategies remain an unmet need.

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.

PURPOSE Deficient mismatch repair/microsatellite instability (dMMR, MSI-H) in biliary tract cancers (BTCs) is observed in 1%-5% of tumors. MSI-H across solid tumors has demonstrated durable response to immune checkpoint inhibitors (ICIs) regardless of the anatomic location. Here, we describe clinical outcomes and surgical conversion of MSI-H BTC treated with ICIs. Patients and Methods We conducted a multicenter, retrospective analysis of BTC patients with dMMR/MSI-H between 2017 and 2024 at Mayo Clinic, University of Michigan, and University Hospitals Seidman Cancer Center. Outcomes of interest were surgical resection rate, rate of pathologic response, 2-year overall survival (OS; time from initiation of treatment to death/last follow-up), and time to treatment discontinuation (TTD; time from initiation of treatment to cessation because of any cause). Analyses were descriptive. RESULTS Thirty patients with MSI-H BTC were identified: 19 with cholangiocarcinoma, three with gallbladder cancer, and 8 with BTC undefined. The median age at diagnosis was 61.5 years (range, 26-86). Twenty-six (86.7%) patients had advanced stage at diagnosis. Twenty-seven patients (90%) received first-line systemic therapy, and 13 (48.1%) continued onto second line. Six patients (23.1%) were restaged to resectable from advanced disease after ICI therapy and underwent resection; all remained recurrence-free at last follow-up. Of these six patients, 3 (50%) achieved a pathologic complete response. Among those receiving first-line therapy, the median TTD was 9.9 months (95% CI, 5.7 to 14.5 months) and the 2-year OS was 73% (95% CI, 56% to 94%). CONCLUSION ICI therapy in patients with MSI-H BTC demonstrated durable response and downstaged some BTC to a resectable stage. dMMR/MSI-H should be performed up-front to guide treatment decisions.

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.

Abstract Prostate-specific membrane antigen (PSMA) is highly expressed in tumor-associated neovasculature in hepatocellular carcinoma (HCC), highlighting its promise as a theranostic target. This prospective study aimed to evaluate the utility of novel biomarkers derived from PSMA positron emission tomography computed tomography (PET/CT) to assess treatment response in advanced HCC patients (pts) receiving first line immune checkpoint inhibitors (ICI). Methods: This study (NCT05176223) enrolled unresectable, advanced HCC pts eligible for first-line ICI (atezolizumab/bevacizumab [A/B] or durvalumab/tremelimumab [D/T]) with measurable disease according to RECIST criteria. Primary endpoints: progression-free survival (PFS) per RECIST 1.1 and mRECIST; overall survival (OS); and best overall response. The survival distribution was estimated using the Kaplan-Meier method. Observed agreement is defined as the proportion of pts whose responses, as classified by PET/CT or CT, were concordant. Weighted kappa and Cohen’s kappa were used to quantify the strength of agreement between PET/CT and CT. Pts completed up to five 68Ga-PSMA PET/CT scans and blood collections. Results: Twenty-six pts were enrolled (25 evaluable) between Oct 2022 and Nov 2024. Median follow up was 22.1 months (m) (Q1, Q3: 14.5-23.7). Median age 68 yrs, 72% male, 88% White, 68% Child-Pugh [CP] A, 32% CP B, 32% Barcelona Clinic Liver Cancer [BCLC] stage B, 68% BCLC stage C, 36% with microvascular invasion; 56% received A/B and 40% received D/T treatment. PSMA was positive in 96% of pts at baseline with median SUVmax 14.3 (range 5.1-40.5) and median background liver SUVmax 3.9 (range 2.1-6.8). Median (95%CI) PFS was 5.6 m (4.6-12.5) by both RECIST and mRECIST. Median (95%CI) OS was 18.6 m (7.2-not estimable), with 56% deceased. The observed agreement between PET/CT adapted PERCIST criteria compared to RECIST and mRECIST in determining the best response was 46% and 50% and weighted kappa of 0.63 (95% CI: 0.37-0.90) and 0.66 (0.41-0.92), respectively. Observed agreement between PERCIST compared to RECIST and mRECIST for responders’ assessment was 67% and 71% with Cohen’s kappa of 0.36 (0.03-0.68) and 0.43 (0.11-0.76), respectively. Conclusion: In this cohort, PSMA PET/CT avidity was observed in all but one pt with advanced HCC, each demonstrating moderate to high SUVmax values. Median OS and PFS were consistent with outcomes reported in clinical trials. Response assessment using 68Ga-PSMA PET/CT according to PERCIST criteria showed good concordance with both RECIST and mRECIST standards. Analysis of immune biomarkers is ongoing. Citation Format: Nguyen H. Tran, Jacob Hirdler, Ajith Antony, Jacob Teske, Sudhakar K. Venkatesh, Amit Mahipal, Michael S. Torbenson, Scott M. Thompson, Thor R. Halfdanarson, Zhaohui Jin, Lionel Aurelien Kankeu Fonkoua, Leslie A. Washburn, Alexander Revzin, Haidong Dong, Robert R. Mcwilliams, Aminah Jatoi, Hani M. Babiker, Mitesh J. Borad, Tanios Bekaii-Saab, Gregory J. Gores, Lewis R. Roberts, Geoffrey B. Johnson, Ajit H. Goenka. Prospective evaluation of 68Ga-PSMA PET imaging in advanced hepatocellular carcinoma patients undergoing first line immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2611.

Abstract Background The incidence of gastroesophageal cancer diagnosed at ages younger than 50 years is increasing. Assessment of the clinicopathologic and molecular characteristics of these cancers is limited currently. Methods This analysis used Tempus’ clinicogenomic database to compare patients diagnosed with gastroesophageal cancer at ages younger than 50 vs 50 years and older who completed tumor molecular profiling between December 2017 and July 2024. The spectrum of biomarkers, somatic alterations, and germline alterations were compared between those diagnosed with gastroesophageal cancer at ages younger than 50 years and those aged 50 years and older, and a multivariate analysis was conducted to identify factors associated with longer survival. Results Among 5863 gastroesophageal cancer patients, 785 had gastroesophageal cancer diagnosed at ages younger than 50 years. There were more females (35% vs 25%, P &lt; .001) and fewer White patients (69% vs 80%, P &lt; .001) with gastroesophageal cancer at ages younger than 50 years. Fewer tumors of patients with gastroesophageal cancer at ages younger than 50 years had high tumor mutational burden (3.2% vs 10.2%, P &lt; .001) or high microsatellite instability (1.7% vs 5.1%, P &lt; .001), but there was no difference in PD-L1 positivity (49% vs 51%, P = .3). Higher incidence of somatic CDH1 mutations was seen in those with gastroesophageal cancer at ages younger than 50 years (16.1% vs 6.6%, q &lt; 0.001) with lower incidence of TP53 (65.6% vs 74.1%), CDKN2A (12.5% vs 19.8%), and KRAS (11.7% vs 18.3%, P &lt; .001 for all) alterations. The most statistically significant germline difference was higher incidence of CDH1 (2.2% vs 0.3%, q = 0.001) and TP53 (0.6% vs 0%, q = 0.039) alterations among those with gastroesophageal cancer at ages younger than 50 years. Median survival for patients with metastatic disease was longer for gastroesophageal cancer at ages younger than 50 years (11 vs 8.5 months, P = .002), and gastroesophageal cancer at ages younger than 50 years, ERBB2 amplification, and high microsatellite instability were associated with superior survival. Conclusions Unique molecular and germline profiles were seen in patients with gastroesophageal cancer at ages younger than 50 years, which may suggest differences in causal factors yet undiscovered.

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.