Hálfdánarson, Þorvarður R.

635 Background: [ 212 Pb]VMT-a-NET is an alpha therapy agent targeting somatostatin receptor subtype 2 (SSTR2)-expressing tumors. Here, we report the results of a prospective, open-label, Phase I/IIa trial (NCT05636618), assessing safety, tolerability, pharmacokinetics, and preliminary efficacy of [ 212 Pb]VMT-a-NET in patients with advanced neuroendocrine tumors (NETs). Methods: Adults with well-differentiated unresectable or metastatic SSTR2-expressing NETs, who are peptide receptor radionuclide therapy (PRRT) naïve, and who progressed on at least one prior line of systemic therapy, are eligible. Participants can receive up to four cycles of [ 212 Pb]VMT-a-NET at the assigned dose level. Participants are followed for dose-limiting toxicity (DLT) observation up to 42 days after the first dose. Efficacy is evaluated by investigators according to RECIST criteria v1.1. Results: As of 16-Aug-2025 (data cut-off [DCO]) a total of 48 participants were enrolled into cohorts 1 and 2 and received at least one dose of [ 212 Pb]VMT-a-NET (n=2 in Cohort 1, and n=46 in Cohort 2 at a dose level of 92.5 MBq and 185 MBq, respectively). Among all participants treated with at least one dose of [ 212 Pb]VMT-a-NET (n=48), no DLTs, no grade 4 or 5 adverse events (AEs), and no treatment-related discontinuations, were observed. Median follow-up time was 28 weeks (range: 6-93). Nine participants were followed for DLT observation (n=2 in cohort 1 and n=7 in cohort 2).Seven of these patients were with no progression as of the DCO. Three out of the seven participants enrolled at the dose level of 185 MBq achieved a confirmed partial response (PR). Median follow-up time for participants included in the efficacy group was 72 weeks (range: 6-93). Cohort 3, at a dose level of 222 MBq, has recently been opened for enrollment. At the DCO, 4 participants were enrolled in this cohort. Updated safety outcome for all participants along with updated efficacy findings for participants in Cohort 1 and 2 with sufficient maturity, will be presented during the congress. Conclusions: [ 212 Pb]VMT-a-NET showed a favorable safety profile and promising clinical benefit for patients with advanced SSTR2-expressing NETs treated at the dose levels of 92.5 MBq and 185 MBq. The study is ongoing with Cohort 3 (222 MBq) currently open for enrollment. Clinical trial information: NCT05636618 .

632 Background: Paltusotine is an oral, nonpeptide, selective somatostatin receptor 2 agonist. In a phase 2 study, treatment with once-daily paltusotine reduced the frequency and severity of carcinoid syndrome (CS) symptoms and was well tolerated. The effect of paltusotine on biomarkers of serotonin and 5-hydroxyindoleacetic acid (5-HIAA) was further explored. Methods: This exploratory study, without formal power calculations, included an 8-week randomized treatment phase (completed) and a 102-week open-label extension phase (currently ongoing). The purpose was to evaluate safety, pharmacokinetics, and exploratory efficacy endpoints, including changes in biomarkers of paltusotine treatment. Enrolled patients were adults with a stable, documented grade 1 or 2 neuroendocrine tumor (NET) and CS. These patients were actively symptomatic and either untreated with somatostatin receptor ligand (SRL) therapy (average of ≥4 bowel movements [BMs] per day or >2 flushing episodes per day in ≥2 days over a 2-week period) or washed out of SRL therapy (symptoms previously controlled on SRL), with demonstrated symptom worsening after washout. Patients were randomized to once-daily paltusotine 40 mg or 80 mg; one optional uptitration (from 40 mg to 80 mg or 80 mg to 120 mg) was permitted. Blood samples for assessment of biomarkers (serum serotonin and plasma 5-HIAA) were collected longitudinally from screening to end of treatment. Upper limit of normal was prespecified as 541 ng/mL for serotonin and 22 ng/mL for 5-HIAA. This analysis focuses on changes in biomarker from baseline to the end of 8-week randomized treatment phase and after approximately one year (48 weeks). Results: Thirty-six patients (n=9 untreated; n=27 SRL washout) were randomized. Mean age was 60.8 years (range 35-83), and 52.8% were female. Nineteen patients had grade 1 NETs, and 17 had grade 2 NETs. As reported previously, treatment with once-daily, oral paltusotine was well tolerated and reduced the frequency and severity of CS symptoms, justifying further clinical development of the 80 mg dose. Mean serum serotonin decreased from 1553.0 ng/mL at baseline to 643.9 ng/mL at Week 8, and mean plasma 5-HIAA decreased from 245.1 ng/mL to 159.7 ng/mL. There was a trend of untreated patients achieving a greater reduction in comparison to washout patients. At 48-week follow-up, mean serum serotonin was stabilized at 791.50 ng/mL (n=20), and mean plasma 5-HIAA was stabilized at 190.45 ng/mL (n=20). Conclusions: Paltusotine significantly reduced serotonin and 5-HIAA levels, with effects maintained at 48 weeks. Biomarker reductions paralleled reductions in BM and flushing frequency. These findings support further investigation in the ongoing phase 3 study (CAREFNDR, NCT07087054). Clinical trial information: NCT05361668 .

629 Background: NENs are a heterogeneous group of tumors with variable clinical behavior. While most NENs occur sporadically, a subset arises in the context of germline cancer predisposition syndromes. The prevalence of GPVs in NENs is increasingly recognized, but the reported frequency and spectrum of genes involved remain inconsistent across studies. Therefore, systematic review and meta-analysis is helpful to clarify the prevalence and clinical significance of PGVs in pts with NENs. Methods: A systematic review with meta-analysis of prospective and retrospective studies reporting germline testing in pts with NENs was conducted according to the PRISMA guidelines. The primary outcome was the prevalence of GPVs. Random-effects models (GLMM) with logit transformation were applied to estimate pooled prevalence with 95% confidence intervals (CIs). Results: Nine studies comprising 1304 patients with NENs were included. The median age was 53.8 (10-88.5) years, 52% were female (n=678/1304), and 56% (n=736/1304) were unselected cohorts (all-comers) and 44% (568/1304) were selected cohorts (testing based on clinical suspicion and high-risk features defined by each study). Across all cohorts, the pooled prevalence of PGVs was 19.6% (95% CI: 10.68–33.15%), with high heterogeneity (I² ≈ 96%). Subgroup analyses demonstrated comparable GPV prevalence between selected (13.2%, 95% CI 6.3–25.8) and unselected cohorts (23.0%, 95% CI 12.0–39.6) (p=0.25). GPV prevalence stratified by pancreatic NENs (17.8%, 95% CI 12.6–24.5) and other NENs (10.6%, 95% CI 6.5–17.0) was also not statistically different (p=0.08). The most altered genes involved DNA repair and cellular signaling pathways, including APC, ATM, BRCA1/2, BAP1, CHEK2, MEN1, MUTYH, VHL, RET, and TSC1/2. Germline variants in mismatch repair (MMR) genes were reported in approximately 2.5% of cases. Conclusions: This study represents the first systematic review and meta-analysis evaluating the prevalence of germline mutations in NENs. Approximately 20% of pts with NENs harbor a germline pathogenic variant, underscoring the importance of genetic counseling and germline testing. The wide variability across studies highlights the need for standardized genetic testing approaches. These findings support routine referral for genetic counseling and panel testing in patients with NENs to guide management and familial risk assessment.

622 Background: Colorectal small and large cell neuroendocrine carcinoma (SCNEC and LCNEC) comprise <1% of colorectal cancers and have poor prognosis. Detailed survival information is limited due to rarity. We analyzed survival outcomes using Survival, Epidemiology, and End Result (SEER) database (2000-2022) and compared with NETs and adenocarcinoma (AC). Methods: All patients with SCNEC, LCNEC, NETs or AC with colorectal primaries were extracted. AJCC stage was calculated with 8 th ed. TNM classification. Kaplan-Meier estimator, log-rank test, and Cox regression (including AJCC stage, surgery, radiation, and chemotherapy variables) were used to analyze survival outcomes. Results: Comparing colon and rectal primaries, the only significant mOS difference was in stage IV SCNEC (2 vs 7 months, p<0.0001). Comparing LCNEC and SCNEC, the only significant mOS difference was in stage IV colon SCNEC and LCNEC (2 vs 5 months, p<0.0001). Stage III and IV colorectal SCNEC and LCNEC had significantly shorter mOS than stage III and IV AC and NETs. In multivariate Cox regressions, surgery and chemotherapy were associated with significantly improved survival for both SCNEC and LCNEC at both primaries (p<0.001), while radiation was never significant. Conclusions: Most colorectal SCNEC and LCNEC patients present with stage IV disease. Stage IV colon SCNEC had significantly shorter mOS than both stage IV colon LCNEC and stage IV rectal SCNEC. Further research should explore early diagnosis and effective therapies for this rare, aggressive malignancy. Median overall survival (months) Colon SCNEC (n/mOS) Colon LCNEC (n/mOS) Colon NETs (n/mOS) Colon AC (n/mOS) SCNEC vs NETs in colon: P-value LCNEC vs NETs in colon: P-value SCNEC vs AC in colon: P-value LCNEC vs AC in colon: P-value SCNEC vs LCNEC in colon: P-value Rectal SCNEC (n/mOS) Rectal LCNEC (n/mOS) Rectal NETs (n/mOS) Rectal AC (n/mOS) SCNEC vs NETs in rectum: P-value LCNEC vs NETs in rectum: P-value SCNEC vs AC in rectum P-value LCNEC vs AC in rectum SCNEC vs LCNEC in rectum: P-value Colon SCNEC vs rectal SCNEC P-value Colon LCNEC vs rectal LCNEC: P-value Stage I 19/32 17/122 4496/NA 114,213/144 <0.0001 <0.0001 <0.0001 0.34 0.25 27/23 10/28 5185/NA 54,702/160 <0.0001 <0.0001 <0.0001 0.00047 0.88 0.99 0.24 Stage II 17/38 30/49 259/NA 121,757/106 0.0015 <0.0001 0.4 0.0068 0.65 17/16 3/NA 33/NA 38,417/106 <0.0001 0.57 <0.0001 0.87 0.3 0.065 0.55 Stage III 40/14 107/13 582/184 104,793/82 <0.0001 <0.0001 <0.0001 <0.0001 0.48 50/19 37/17 103/102 46,687/107 <0.0001 <0.0001 <0.0001 <0.0001 0.45 0.48 0.47 Stage IV 245/2 217/5 393/49 83,542/13 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 260/7 57/6 158/36 36,652/17 <0.0001 <0.0001 <0.0001 <0.0001 0.25 <0.0001 0.95

619 Background: Well-differentiated G3 GEP-NETs are rare and heterogeneous diseases, limiting phase III trials and definition of clear standards of care. Building upon our preliminary cohort of 76 patients (pts), we present an updated and expanded retrospective analysis across three Mayo Clinic tertiary centers. Methods: We included pts with histologically confirmed well-differentiated G3 GEP-NETs diagnosed since 2017 (new WHO classification) from the three Mayo Clinic sites (Rochester, Phoenix, Jacksonville). Endpoints were ORR, DCR, PFS, and OS across treatment lines. PFS/OS were estimated by Kaplan-Meier. OS was defined from treatment start. Multivariate Cox regression was used to evaluate the association of clinic-pathologic features (age, sex, tumor functionality, Ki-67, primary tumor site, stage at diagnosis, presence of liver metastasis, number of metastatic sites at diagnosis) with OS (p<0.05). Results: 111 pts (median age 62 y, range 22–83). Primary sites were pancreas (58%), small bowel (19%), unknown (9%), and rectum (5%). Most tumors were G3 at diagnosis (88%); the remainder evolved from prior G1/G2. Ki-67 was 20–55% in 83% of cases. Most were nonfunctional (70%); functional subtypes included carcinoid (13%) and gastrinoma (8%). Median plasma 5-HIAA was 38.5 ng/ml (5–1394). Advanced disease was present in 85%. Common metastatic sites included liver (85%), lymph nodes (32%), bone (26%), peritoneum (10%), and lung (9%). Median number of metastatic sites was 1 (range 0–5). Median number of systemic treatment lines was 2 (range 0–8). The most frequent regimens and outcomes are shown in the Table. Insulin-secreting tumors (HR 2.16, 95% CI 1.33–25.73, p=0.019) and ≥2 metastatic sites (HR 2.13, 95% CI 1.05–4.31, p=0.035) were associated with inferior OS. Conclusions: This represents one of the largest real-world datasets of well-differentiated G3 GEP-NETs and provides a deeper evaluation of treatment strategies and prognostic factors. CAPTEM, SSAs, and PRRT with Lu-177 emerged as the most commonly used therapies, with PRRT showing the most favorable outcomes. Insulin secretion and higher metastatic burden were confirmed as adverse prognostic factors. CAPTEM SSAs PRRT Lu-177 Carboplatin plus etoposide FOLFOX Everolimus Sunitinib N of pts (%) 64 (58) 44 (40) 37 (33) 24 (19) 18 (13) 11 (10) 8 (7) Line of therapy (%) First 36 (56.3) 27 (61.4) 5 (13.5) 13 (59.2) 5 (7.2) 1 (9.0) 1 (12.5) Second 15 (23.4) 13 (29.5) 13 (35.2) 3 (13.6) 5 (35.7) 3 (27.3) 2 (37.5) Third or higher 13 (20.3) 4 (9.1) 19 (51.3) 6 (27.2) 8 (57.1) 7 (63.7) 5 (62.5) DCR (%) 60.9 56.8 75.0 52.2 71.4 45.5 37.5 ORR (%) 34.4 13.6 44.4 30.4 35.7 18.2 12.5 mPFS (95% CI) 8.0 (5.3-10.6) 6.2 (2.8-9.5) 11.2 (9.1-13.3) 7.3 (2.8-11.8) 4.4 (2.4-6.4) 3.9 (2.2-5.6) 3.9 (1.54-6.26) mOS (95% CI) 40.1 (23.0-57.2) 50 (22.6-77.4) 76.1 (16.3-135.8) 33.0 (21.0-45.0) 21.1 (15.0-27.2) NE NE

561 Background: For patients with aHCC, second-line treatment options are not well established. The primary aim of this study was to evaluate the efficacy of Futi, an FGFR 1-4 inhibitor, in combination with Pem as a second line therapy in patients with FGF19-expressing aHCC. Methods: Patients aged ≥ 18 years, with histological/cytological diagnosis or radiological diagnosis of HCC, Child-Pugh (CP) class A-B7, Barcelona Clinic Liver Cancer (BCLC) A, B or C, ECOG performance status of 0-2, and FGF19+, by in-situ hybridization or immunohistochemistry, received Futi 20 mg once daily plus i.v. Pem 200mg every 3 weeks. The primary endpoint was progression-free survival at 6 months (PFS6). Secondary endpoints include overall survival (OS). The study was designed to enroll 22 evaluable patients to detect PFS6 from 25% (historical control) to 47%, assuming a 1-sided alpha of 0.1 with 80% power. All patients provided written consent. Eligible patients with consent who started treatment are considered evaluable. Results: The study was closed to enrollment early at the request of funding agency due to poor accrual. Between 8/2021 and 3/2024, 14 patients enrolled with 1 patient withdrawing consent before beginning protocol treatment. Among 13 evaluable patients, median age was 72 (range: 60-87) years, 7 (53.8%) were male, 12 CP A (92.3%), 7 BCLC C (53.8%), with 7 (53.8%) having received prior liver directed therapy. Median PFS was 15 weeks (95% confidence interval [CI]: 9.0-Not Estimable) and PFS6 was 23.1% (95% CI: 8.6%, 62.3%). Objective response rate was 0% (95% CI: 0%, 24.71%) and stable disease occurred in 7 (53.9%) of patients. Median OS was 55.7 weeks (95% CI: 47.3-NE). Nine (69.2%) patients experienced at least 1 grade 3+ adverse event (AE), and 2 (15.4%) patients experienced at least a grade 4+ AE. One patient had a grade 5 AE unrelated to study treatment (acute kidney injury). Most commonly reported AEs (occurring in more than 31% of patients) were hyperphosphatemia (76.9%), fatigue (69.3%), diarrhea (61.6%), AST (53.9%) and ALT (46.2%), dry eye (38.5%), nail changes (38.5%), rash-maculo-papular (38.5%), and mucositis oral (38.5%). Conclusions: This prospective study evaluated the use of a targeted treatment in combination with immunotherapy following first line immune-based therapy. This combination had modest activity as a second line therapy for patients with aHCC but did not meet the primary endpoint. The safety profile was acceptable and consistent with prior reports. An optimal second-line regimen remains a critical need. Clinical trial information: NCT04828486 .

103 Background: Clinicians spend significant time extracting and synthesizing information to risk-stratify and make adjuvant chemotherapy (AC) recommendations for CRC. By automating parts of this process, LLMs could help reduce documentation burden and variability in decision-making. Methods: We selected 144 stage III, pMMR CRC patients treated at Mayo Clinic (2017–2021). HIPAA-compliant Gemini-2.0-Flash-001 and GPT-4o extracted clinical variables (age, neuropathy grade, pathological stage) from EHRs and generated AC recommendations. Two approaches were compared: (1) a rule-based algorithm with nested if/else statements translating variables into NCCN-based recommendations, and (2) a dynamic LLM agent generating recommendations using a structured prompt informed by NCCN guidelines. Concordance with treating physicians was assessed, with disagreements reviewed by a blinded GI oncologist. Results: The dataset included 144 patients with median age 67 (IQR 66–68), 48.6% female. The LLM pipeline extracted neuropathy grade with 100% accuracy and pathological T/N stages with 99.3% accuracy. Concordance with physician recommendations was 93.1% for the rule-based algorithm and 62.5% for the LLM agent. In discordant cases, blinded adjudication by a GI oncologist favored the algorithm and LLM agent over physicians in most cases (Table 1). Conclusions: This exploratory work shows LLM agents can reliably extract variables and generate evidence-based treatment recommendations for stage III CRC. The high rate of expert preference for LLM recommendations in discordant cases is intriguing but limited by small sample size and possible adjudicator bias. Discordant physician recommendations reflect the complexity of decision-making, including patient preferences, performance status, comorbidities, and subtle findings not fully captured in EHRs. Rather than replacing judgment, we envision LLMs as decision support tools—analogous to an advanced trainee reviewing charts and presenting evidence-based recommendations to the attending physician with ultimate authority. Larger multi-institutional studies with multiple adjudicators are needed to validate these findings and clarify AI’s role in oncology. Patient characteristics, LLM extraction accuracy, and concordance with physician recommendations. Metric Result Total patients 144 Median age (IQR) 67 (66-68) Female (%) 48.6% LLM extraction accuracy – Neuropathy grade 100% LLM extraction accuracy – Pathological T and N stages 99.3% Primary Concordance – Rule-based algorithm vs. physician 93.1% Adjudicator preference of rule-based algorithm over treating physician for discordant cases 100% Concordance – LLM agent vs. physician 62.5% Adjudicator preference of LLM agent over treating physician for discordant cases 82.0%

Abstract Introduction: Lutetium-177 DOTATATE peptide receptor radionuclide therapy (PRRT) is an effective treatment for gastroenteropancreatic neuroendocrine tumors (GEP-NETs). While generally well tolerated, PRRT can result in hematologic toxicity ranging from mild cytopenias to therapy-related myeloid neoplasms (t-MNs). Understanding the incidence, severity, and clinical consequences of hematologic toxicity is essential for optimizing treatment decisions and establishing effective monitoring strategies. This study aimed to characterize hematologic toxicity patterns, severity, and recovery profiles in GEP-NET patients treated with Lutetium-177 DOTATATE PRRT and to determine the frequency of cytopenia-related treatment discontinuation. Methods: We conducted a retrospective analysis of 160 consecutive GEP-NET patients who underwent PRRT. Hematologic parameters (hemoglobin, white blood cell count, absolute neutrophil count, platelet count, and lymphocyte count) were assessed at baseline, mid-treatment (post-cycle 2), and post-treatment (post-cycle 4). Cytopenias were graded using Common Terminology Criteria for Adverse Events version 4.03 and categorized as never (grade &lt;2 throughout), transient (grade ≥2 mid-treatment, resolving post-treatment), persistent (grade ≥2 at both timepoints), or late-onset (grade &lt;2 mid-treatment, grade ≥2 post-treatment). Treatment completion rates and discontinuation reasons were documented. Results: Overall, 73% of patients (117/160) completed all planned PRRT cycles. Among the 43 patients who discontinued treatment early, only 4 (2.5% of total cohort) discontinued specifically due to cytopenia, while the remainder discontinued for other reasons. Post-treatment grade ≥2 cytopenias were uncommon: lymphocytes (4.4%), hemoglobin (2.5%), neutrophils (1.9%), white blood cells (1.3%), and platelets (1.3%). The majority of patients (≥85%) never experienced grade ≥2 cytopenia throughout treatment. When cytopenias occurred, they were predominantly transient (8-10% of patients) with complete recovery by treatment completion. Persistent cytopenias were rare (&lt;5% across all cell lines), while late-onset cytopenia occurred most frequently with neutrophils (14%). Conclusion: Lutetium-177 DOTATATE PRRT demonstrates an excellent hematologic safety profile in GEP-NET patients. Severe cytopenias are uncommon, predominantly transient, and rarely necessitate treatment discontinuation. These findings support the continued use of PRRT in appropriate candidates, with cytopenia-related discontinuation occurring in fewer than 3% of cases. Long-term follow-up remains essential to monitor delayed hematologic effects, including t-MNs. Future research should evaluate baseline predictors such as prior chemotherapy, renal function, and marrow reserve to identify patients at higher risk who may benefit from closer hematologic surveillance.

Abstract Background: [212Pb]VMT-a-NET is an alpha therapy agent targeting somatostatin receptor subtype 2 (SSTR2)-expressing tumors. Neuroendocrine tumors (NETs) generally express SSTR2 on their cell surface. Here, we report the results of a prospective, open-label, Phase I/IIa clinical trial evaluating the safety, tolerability, pharmacokinetics, and preliminary efficacy of [212Pb]VMT-a-NET [NCT05636618]. Methods: The study design follows a Bayesian dose-finding algorithm. Main inclusion criteria include histologically proven well-differentiated unresectable or metastatic NETs, radiological evidence of progression on at least one prior line of systemic therapy, demonstration of lesional SSTR2 expression on an FDA-approved SSTR PET. Main exclusion criteria include: prior treatment with systemic PRRT-based therapies. In the dose finding phase, participants can receive up to four cycles of [212Pb]VMT-a-NET at the assigned dose level. Participants are followed for dose-limiting toxicity (DLT) observation up to 42 days after the first cycle. Efficacy is evaluated by investigators according to RECIST criteria v1.1. Here we report safety and preliminary efficacy data of participants enrolled in cohorts 1 and 2 at 92.5 MBq [2.5 mCi] and 185 MBq [5 mCi], respectively. Results: As of 30-Apr-2025 (data cut-off – DCO), a total of 42 participants were enrolled into the study. Nine of them were followed for DLT observation; thirty-three (33) additional participants were subsequently enrolled into cohort 2 to further evaluate safety and efficacy at the selected dose. For data analysis purposes, participants were divided into two different groups: a safety group and an efficacy group. The safety group included all participants enrolled by the DCO (n=42), while the efficacy group included only nine participants enrolled in cohort 1 (n=2) and cohort 2 (n=7) for DLT observation. Median follow up time for participants included in the safety group was 14 weeks (range:0,77); median follow up time for participants included in the efficacy group was 56 weeks (range: 6,77). In the safety group (n=42) we did not observe any DLTs, any grade 4 or 5 adverse events (AEs), any treatment-related discontinuations, any serious renal complications or myelosuppression, or any dysphagia. In the efficacy group (n=9) seven out of nine participants were with no progression as of the DCO, and four out of the seven participants enrolled in cohort 2 achieved a partial response (PR). Three PRs were confirmed, while one was pending confirmation at the time of DCO. Cohort 3, at a dose level of 222 MBq [6 mCi], has recently been opened for enrollment. Safety data for all treated participants and efficacy results for a mature subset will be presented at the congress. Conclusions: [212Pb]VMT-a-NET showed a favorable safety profile and promising clinical benefit for patients with advanced SSTR2-expressing NETs treated at the dose level of 185 MBq (5 mCi). The study is ongoing with cohort 3 currently open for enrollment. Citation Format: Vikas Prasad, Richard Wahl, Lilja Solnes, Savitha Balaraman, Gregory Sibley, Lowell Anthony, Brandon Mancini, Jason Starr, Vineeth Sukrithan, Chih-Yi Liao, Samuel Mehr, Lucia Baratto, Wenjing Yang, Alaa Hanna, Stephen Keefe, Markus Puhlmann, Thorvadur Halfdanarson. [212Pb]VMT-a-NET for somatostatin receptor subtype 2 (SSTR2)-expressing tumors: safety and preliminary efficacy results in patients with advanced neuroendocrine tumors (NETs) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C095 .

426 Background: Testing for DPYD gene variations prior to administration of fluoropyrimidines ([FP] e.g. 5-FU or capecitabine) can determine if patients are at risk of significant toxicity and may benefit from dose reduction or elimination of chemotherapy. Barriers to testing include lack of recommendations in US guidelines for routine DPYD testing, absence of insurance coverage, and limitations in provider support. We designed an electronic health record (EHR)-based intervention to support shared decision-making (SDM) between providers and patients regarding DPYD testing. Methods: We built an EHR alert identifying all patients initiating FP without DPYD testing. The alert fired to remind providers upon signing FP. Clinical decision support (CDS) was included in the alert to help with DPYD testing selection along with an educational note template containing the incidence of DPYD deficiency, rationale for testing, test costs, and turnaround time. Interactions with the EHR were recorded to determine why providers declined ordering pharmacogenomic testing. Testing rates and results for patients initiating FP were collected from the EHR. Finally, providers were surveyed to determine the impact of the alert on conversations with patients as well as the utility of the embedded CDS and educational note template. Results: Within the first 8 months after alert activation, 34 patients completed DPYD testing of 444 starting FP (testing rate of 7.7%) vs the baseline testing rate in the 3 months prior to alert go-live of 6.8% (p = 0.86 via chi-squared analysis, two-tailed). Of the 34 patients, 5 were intermediate DPYD metabolizers. Reasons for alert dismissal per provider selection were: “Patient already tolerated prior fluoropyrimidines” (15.7%), “Patient declines” (12.9%), “Will order separately” (5.7%), “Not discussed as not appropriate” (5.3%), and “Not discussed, deferred” (60.4%). Thirty-nine providers (n = 77 eligible) responded to the survey; 22 prescribed FP in their practice and had encountered the alert. 21 (95.5%) of these reported the alert was “Very Useful” or “Somewhat Useful” and 18 (81.8%) used the DPYD testing options available in the alert. Sixteen (72.7%) discussed DPYD testing more frequently with patients as a result of the alert. Barriers to DPYD testing were “Concerned about the impact of lowering FP dosing” and “Lack of knowledge about DPYD testing”, while “Cost of DPYD testing” was scored lowest. Conclusions: Utilizing an EHR alert with embedded CDS had a positive impact on provider awareness and led to more discussions regarding DPYD pharmacogenomic testing with patients in line with current FDA recommendations. Limitations in provider knowledge regarding DPYD testing and concerns about lowering chemotherapy doses posed barriers to ordering testing. Further interventions including additional education are required.