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Abstract BACKGROUND Von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome characterized by development of multiple neoplasms, including central nervous system (CNS) hemangioblastomas, renal cell carcinoma (RCC), pancreatic neuroendocrine tumors (pNETs), and retinal hemangioblastomas. Belzutifan, a hypoxia-inducible factor 2-alpha (HIF-2α) inhibitor, has demonstrated efficacy in treating VHL-associated tumors. This study evaluates our institutional experience with belzutifan in patients with VHL-related tumors. MATERIAL AND METHODS We conducted a retrospective cohort study across three Mayo Clinic sites, including patients aged ≥18 years with genetically confirmed VHL disease who received belzutifan between October 2021 and March 2025. Clinical/radiological data, and adverse events (AEs) were extracted from electronic health records. Tumor responses were assessed using RECIST v1.1 criteria for RCC, pNET, CNS hemangioblastoma. Retinal hemangioblastoma responses were evaluated through ophthalmologic assessments. RESULTS Forty-five patients were included (median age 44 58% female). Sixty-seven percent had RCC, 91% had CNS hemangioblastomas, 53% had pNETs, and 62% had retinal hemangioblastomas. The median duration of belzutifan therapy was 22.6 months (range 1.0-41.4 months). Among patients with RCC (n=26), overall response rate (ORR) was 19% and median time to best response (MTBR) was 7.4 months. Five patients had partial response (PR), 15 had stable disease (SD), and 1 had progressive disease (PD). For CNS hemangioblastomas (n=41), ORR was 12%, MTBR was 6.2 months. 5 patients had PR, 30 had SD, and none had PD. For pNET (n=17), ORR was 41%, MTBR was 8.2 months. One patient had CR, 6 patients had PR, 6 had SD, none had PD. For retinal hemangioblastomas (n=28), 6 (21%) showed improvement, 9 (32%) remained stable, and 3 (11%) showed progression. MTBR was 6.7 months. Treatment-related AEs occurred in 98% of patients. Common AEs included anemia (89%), fatigue (80%), hypoxia (18%), and headache (13%). Grade 3 AEs were observed in 20% of patients, including anemia (7%), hypoxia (9%), fatigue (4%), pneumonitis (2%), loss of consciousness (2%). One patient experienced a grade 4 event (status epilepticus). Anemia management involved iron supplementation (n=11), RBC transfusion (n=3), dose reduction (n=2), treatment holiday (n=8), permanent discontinuation (n=1). Hypoxia management included dose reduction (n=1), treatment holiday (n=3), discontinuation (n=1). CONCLUSION Belzutifan shows clinical activity across various VHL-associated neoplasms in real-world practice, with a manageable safety profile. The lower ORR compared to the phase III trial may reflect differences in baseline disease, including lower tumor burden in our cohort. These findings support its continued use in VHL disease, with attention to monitoring and managing treatment-related AEs.

Importance The prognosis of advanced pancreaticobiliary tumors is poor. Next-generation sequencing (NGS) of tissue samples is utilized to identify actionable alterations, but there are occasional limitations due to inadequate tissue acquisition. Circulating tumor DNA (ctDNA) is an alternative method, but its correlation with tissue-based NGS remains unexplored. Objectives To assess the mutation concordance (mCR) rates between ctDNA and tissue testing for patients with pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CC) and to evaluate how ctDNA performs as a treatment response biomarker. Design, Setting, and Participants This retrospective cohort study was conducted among patients with PDAC and CC treated at academic institutions from January 2014 to January 2025. Patients underwent ctDNA testing using 1 platform and tissue NGS testing using 2 platforms. Main Outcomes and Measures mCR, which measures the shared gene alterations observed by both ctDNA and tissue-based NGS testing, was calculated using the Spearman correlation for PDAC and CC. The performance of ctDNA as a treatment response biomarker was assessed by comparing serial ctDNA data with restaging scans and cancer antigen 19-9 levels in patients with PDAC. Results Our cohort included 790 patients: 570 with advanced PDAC (265 [46.5%] female; median [IQR] age, 64 [33-84] years) and 220 with advanced CC (95 [43.2%] female; median [IQR] age, 66 [42-88] years). Overall, 461 patients with PDAC (80.9%) and 192 patients with CC (87.2%) underwent ctDNA testing, while 239 patients with PDAC (41.9%) and 70 patients with CC (31.8%) had tissue NGS testing. Among patients with PDAC, 85 of 130 patients (65.4%) showed shared specific gene alterations between ctDNA and tissue testing; there was a significant mCR, with a Spearman correlation of 0.47 (95% CI, 0.28-0.62; P < .001). For patients with CC, 32 of 48 (66.7%) had shared alterations between ctDNA and tissue testing; there was a significant mCR, with a Spearman correlation of 0.56 (95% CI, 0.35-0.70; P < .001). A subgroup analysis of patients with PDAC who underwent serial ctDNA testing suggested that new TP53 subclones and increased ctDNA variant allele frequency levels of TP53 and KRAS were associated with higher odds of progressive disease (eg, increased TP53 frequency: odds ratio, 7.28; 95% CI, 2.15-24.66; P = .001). Conclusions and Relevance In this cohort study of patients with pancreaticobiliary tumors, there was a significant mCR between ctDNA and tissue NGS testing. Additionally, results suggest that ctDNA might detect resistant clones and enable assessment of treatment response.

THIS year’s American Society of Clinical Oncology (ASCO) 2025 gastrointestinal (GI) sessions presented pivotal data across different GI cancers, reshaping standards of care in these malignancies. Herein, the authors highlight several key studies presented at this year’s meeting.

Importance Pathologic complete response (pCR) is increasingly used as a surrogate end point for survival in randomized clinical trials (RCTs) in the field of gastrointestinal oncology. Although this approach has been endorsed by the US Food and Drug Administration, it is still novel and incompletely verified. Objective To evaluate the trial-level association between pCR and survival in rectal cancer RCTs examining the effectiveness of neoadjuvant therapy. Data Sources A meta-analysis was conducted to identify eligible RCTs in PubMed, EMBASE, and Cochrane databases published between database inception to January 3, 2024. Study Selection RCTs evaluating neoadjuvant therapies in patients with rectal cancer who underwent subsequent surgical resection and reported pCR, overall survival (OS), and disease-free survival (DFS) were included. Data Extraction and Synthesis Two investigators extracted the data, which were verified by a third author. The risk of bias and the certainty of the evidence were evaluated using the Cochrane Risk of Bias Tool, version 2, and the Grading of Recommendations Assessment, Development, and Evaluation tool, respectively. Adjusted odds and hazard ratios with their 95% CIs were extracted. Weighted linear regression was used to assess the correlation between pCR and both OS and DFS. Main Outcomes and Measures Trial-level correlation between pCR and both OS and DFS. Results Twenty-five RCTs, including 11 882 patients, met the inclusion criteria. On meta-regression analysis, pCR was not correlated with OS (β = 0.37; 95% CI, −0.98 to 1.71; P = .57). Similarly, pCR was not correlated with DFS (β = −0.84; 95% CI, −2.55 to 0.87; P = .32). Two studies (8%) used in the meta-analysis had high risk of bias. On sensitivity analysis excluding these studies, pCR was still not associated with OS or DFS. Subgroup analysis of RCTs using total neoadjuvant therapies was not possible due to limited sample size. Conclusions and Relevance In this systematic review and meta-analysis of RCTs comparing neoadjuvant therapies in rectal cancer, there was no trial-level association between pCR and survival. These results suggest that the use of pCR as a surrogate end point for survival should be reexamined and used more cautiously.

Multidisciplinary case conferences have been shown to improve patient outcomes. However, such case conferences may be unavailable in some settings. This multidisciplinary discussion of 4 challenging hepatobiliary cases was presented at the 2023 Society of Advanced Body Imaging Annual Meeting in Dallas, TX. The cases include an “imaging occult” pancreatic tumor, a large pancreatic mass, an intraductal biliary mass, and a polypoid intraluminal gallbladder mass.

Abstract Peptide receptor radionuclide therapy (PRRT) with lutetium-177-Dotatate (177Lu-DOTATATE) has transformed neuroendocrine tumor (NET) treatment, improving progression-free survival, symptom control, and quality of life. However, long-term hematologic toxicities, including therapy-related myeloid neoplasms (tMN), are increasingly recognized. These rare but severe complications, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), appear multifactorial, influenced by prior cytotoxic therapies, radiation exposure, clonal hematopoiesis, and germline predispositions. This review synthesizes data on PRRT-related hematologic toxicities, including findings from pivotal studies and real-world evidence. We explore risk factors, underlying mechanisms, and the potential role of biomarkers, such as clonal hematopoiesis and germline mutations, in predicting toxicity. Emerging approaches, including alpha particle radioligand therapy and advanced dosimetry, are explored as strategies to optimize patient selection and minimize adverse outcomes. To maximize the benefits of PRRT while safeguarding patient safety, future efforts should focus on integrating predictive biomarkers, refining treatment sequencing, and developing personalized risk-stratified approaches to therapy.

Abstract Malignant insulinomas are rare pancreatic neuroendocrine tumors characterized by excessive insulin secretion and a high propensity for metastasis, leading to challenging management. This study retrospectively analyzed 57 patients treated for malignant insulinoma at Mayo Clinic sites between 1992 and 2024, focusing on the efficacy of systemic therapies in improving hypoglycemic control and survival outcomes. The most commonly used therapies included somatostatin analogs (SSA), everolimus, capecitabine-temozolomide (CAPTEM), and peptide receptor radionuclide therapy (PRRT). PRRT demonstrated the highest efficacy in controlling hypoglycemia (93%), followed by CAPTEM (68%) and everolimus (62%). SSA, chemotherapy, and streptozocin were less effective, with hypoglycemic improvement seen in 37.5, 33.3, and 28.6% of patients, respectively. Overall survival (OS) was longest with SSA at 84.67 months, followed by CAPTEM at 81.67 months and everolimus at 74.07 months. PRRT demonstrated a median OS of 49.73 months. In contrast, chemotherapy and streptozocin-based therapies had significantly shorter OS times of 15.23 and 8.35 months, respectively. These findings highlight significant variability in systemic therapy efficacy for malignant insulinoma, with PRRT emerging as a promising treatment for refractory hypoglycemia and long survival. Cox regression analysis identified primary tumor resection and a history of benign insulinoma as associated with longer OS. Optimal sequencing of therapies remains unclear, and individualized treatment plans based on hypoglycemic burden and tumor characteristics are critical for improving survival and quality of life in these patients.

e16265 Background: The pivotal TOPAZ-1 trial established durvalumab plus gemcitabine and cisplatin (GC) as a new first-line standard of care for advanced biliary tract cancer (ABTC). However, weekly administration of GC can lead to significant toxicity limiting its tolerability in clinical practice. Based on previous studies, we implemented biweekly regimen of GC on days 1 and 15 together with durvalumab on day 1 of each 28-day cycle to optimize the treatment delivery and improve tolerability. Here, we report the Mayo Clinic experience with biweekly GC with monthly durvalumab in patients with ABTC. Methods: At our three-site institution, we retrospectively identified patients with ABTC between January 2021 and August 2024, who received biweekly GC with monthly durvalumab. Patient demographics, tumor characteristics, treatment details - treatment related adverse events (trAEs) graded according to the NCTCAE V5.0 were collected. Outcomes included median progression-free survival (mPFS), median overall survival (mOS) and clinically assessed overall response rate (ORR) and disease control rate (DCR). Results: 57 patients were included in our analysis, median age was 68 years (range 35-90), and 57.9% were females. 91.2% of patients had ECOG performance status of 0-1. 71.9% had intrahepatic cholangiocarcinoma, 19.3% extrahepatic cholangiocarcinoma and 8.7% gallbladder carcinoma. 70.2% had metastatic disease, 21 % locally advanced unresectable disease and 8.7% recurrent metastatic disease. Patients were followed for a median of 9.1 months (2.3-28.5). 91.2% of the patients received biweekly GC plus monthly durvalumab while 8.8% switched from weekly to biweekly GC plus monthly durvalumab due to treatment toxicities. Median number of treatment cycles was 5. Maintenance regimens included durvalumab (19.3%), gemcitabine/durvalumab (8.8%) and GC/durvalumab (8.8%). Median duration of follow up was 9.1 months (range 2.3 – 28.5). ORR was 36.9% and DCR was 72% (complete response 5.3%, partial response 31.6% and stable disease 35.1%). mPFS was 7.2 months, while mOS was 16 months. Grade(G) 3 or 4 trAEs included abnormal liver function tests (15.7%), infections (11.5%), anemia (8.7%), thrombocytopenia (5.2%), peripheral neuropathy (1.7%), acute kidney injury (1.7%). Immune-related AEs were noted in 6 patients (10.5%) including colitis, gastritis, hepatitis, myocarditis and hypothyroidism. There was no patient with severe neutropenia or febrile neutropenia. Only 5 patients (8.8%) stopped treatment due to trAEs. Conclusions: Biweekly GC on days 1 and 15 plus durvalumab on day 1 of each 28-day cycle is associated with a more favorable toxicity profile while maintaining efficacy similar to that observed in the TOPAZ-1 trial indicating that a de-escalation strategy is feasible with improvement in patient centered outcomes.

e16157 Background: The optimal treatment for resectable gastric/GEJ AC is unclear due to limited direct comparisons among chemotherapy and chemoradiation regimens. Addressing this gap is critical to improve patient outcomes. We performed this network meta-analysis (NMA) to determine the relative efficacy of multimodality regimens for resectable gastric/GEJ AC. Methods: MEDLINE, EMBASE, Scopus, and CENTRAL were searched from inception till September 20, 2024, to identify phase III trials evaluating perioperative/neoadjuvant systemic therapy ± radiation in resectable gastric/GEJ AC. Primary outcomes were disease-free survival (DFS) and overall survival (OS). A frequentist NMA was conducted to compare hazard ratios (HR) and 95% CI for each outcome. Relative treatment rankings were assessed using P-scores. Results: Fifteen trials (8,072 patients) were analyzed. pFLOT (perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel) ranked highest for DFS in the overall population (P score 91%) (Table), significantly outperforming surgery alone (HR 0.48, 95% CI 0.38-0.60) and nCROSS (neoadjuvant paclitaxel, carboplatin and radiotherapy) (0.67, 0.56-0.81). For OS, nPLF+nCRT(EP) (neoadjuvant cisplatin, leucovorin and fluorouracil for induction, followed by etoposide, cisplatin, and radiotherapy) (P score 90%) and pFLOT (P score 87%) were the top regimens, with pFLOT significantly outperforming surgery alone (0.57, 0.45-0.72), and nCROSS (0.73, 0.60-0.89). Adding neoadjuvant chemoradiation to pFLOT provided no additional OS (1.14, 0.76-1.72) or DFS (1.22, 0.83-1.82) benefit. Similarly, adding pembrolizumab to perioperative chemotherapy (CF/CX) (cisplatin and fluorouracil/capecitabine) was not superior to pFLOT in terms of DFS (1.10, 0.71-1.69) or OS (1.09, 0.69-1.72). Conclusions: pFLOT demonstrated superior efficacy in resectable gastric/GEJ AC, surpassing surgery alone, nCROSS, and other perioperative regimens. The additive role of immunotherapy to pFLOT requires further investigation to refine patient selection and optimize outcomes. Regimen Overall Population GEJ cohort OS DFS OS DFS nPLF+nCRT(EP) 1 (90) 2 (84) 1 (85) NA pFLOT 2 (87) 1 (91) 2 (79) 2 (88) pPembrolizumab+CF/CX 3 (75) 3 (81) 5 (41) - nECX 4 (61) 5 (55) - - pCF 5 (59) 8 (51) 3 (72) - pECF/ECX 6 (47) 6 (55) 7 (40) 3 (57) nECX+aCRT(CX) 7 (45) 7 (52) 9 (31) - nCF 8 (42) 10 (28) 6 (40) - nCROSS 9 (41) 9 (35) 8 (34) 4 (43) pECF/ECX/FLOT+nCRT(F/X) 10 (38) 4 (57) 4 (72) 1 (90) nCRT(CF) 11 (9) 11 (6) - 5 (14) Surgery 12 (7) 12 (5) 10 (5) 6 (9) Data reported as rank (P-score). Abbreviations: n: neoadjuvant; p: perioperative; ECX: epirubicin + cisplatin + capecitabine; CF: cisplatin + fluorouracil; ECF: epirubicin + cisplatin + fluorouracil; aCRT(CX): adjuvant radiotherapy + cisplatin + capecitabine; CRT(F/X): fluorouracil/capecitabine + radiotherapy; CRT(CF): cisplatin + fluorouracil + radiotherapy.