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4006 Background: Elraglusib (9-ING-41) is a first-in-class inhibitor of GSK-3ß, which may mediate drug resistance, EMT, and damaged DNA and tumor immune response in advanced cancer. In pancreatic cancer models in mice, elraglusib combined with chemotherapy enhanced anti-tumor effects and survival. In a single-arm clinical study, elraglusib/GnP showed antitumor activity and prolonged survival in pts with mPDAC. Methods: Pts with previously untreated mPDAC were randomized 2:1 to GnP plus elraglusib 9.3 mg/kg IV once weekly or GnP in an open-label phase 2 study. The primary endpoint was 1-yr OS in the primary analysis set. Upon study completion, mOS will be the primary endpoint once survival distributions are compared after the 12-month follow-up using log-rank analysis. Secondary endpoints included DCR, ORR, mPFS, and TEAEs/TRAEs. The planned sample size was 207 evaluable pts (130 for elraglusib/GnP and 77 for GnP), assuming 1-yr OS of 55% with elraglusib/GnP and 35% with GnP to achieve 80% power with a chi-square test at a 2-sided 5% α. For OS, nonparametric log-rank test was used with statistical significance at p-value < 0.048. Cytokine/chemokine correlative biomarker assays were performed. The study completed enrollment in February 2024. Results: As of November 15, 2024 (preliminary data cut-off date), the primary analysis set included 155 pts in the elraglusib/GnP arm and 78 pts in the GnP arm, with 52.8% males and 57.5% ECOG PS 1. Median (range) CA 19-9 levels were 1568 U/mL (1 to 381,904 U/mL) in the elraglusib/GnP arm and 1590 U/mL (2 to 501,000 IU/mL) in the GnP arm. The 1-yr OS rate was 43.6% with elraglusib/GnP vs 22.5% with GnP (z-test p = 0.002); the mOS was 9.3 mo with elraglusib/GnP vs 7.2 mo with GnP (HR, 0.63; log rank p = 0.016; see Table). 38.1% of pts on elraglusib/GnP and 19.2% on GnP are censored, with the majority at > 10 months OS. Several biomarkers appear to be predictive for OS including IFNβ and PD-L1. The most common TRAE with elraglusib/GnP was grade 1-2 transient visual impairment in > 60% of patients (vs 9% with GnP). Grade ≥3 TEAEs occurred in 89.7% of pts on elraglusib/GnP and 80.8% on GnP. Most common grade ≥3 TEAEs with elraglusib/GnP (vs GnP) were neutropenia 51.6% (vs 29.5%), anemia 24.5% (vs 29.5%), and fatigue 16.1% (vs 5.1%). Conclusions: The preliminary results showed a statistically significant benefit for 1-yr OS and mOS and favorable trends for ORR and DCR with elraglusib/GnP over GnP, with manageable safety profile. The mOS for GnP is lower relative to MPACT and NAPOLI-3 but comparable to recent real-world meta-analyses, explained by advanced disease burden and higher mortality rate in the first 4 months in our study. Topline analysis (April 2025) and correlative biomarker analysis predictive for OS will be presented. Clinical trial information: NCT03678883 . Preliminary efficacy results. Elraglusib/GnPn=155 GnPn=78 1-year OS, %z-test p=0.002 43.6 22.5 mOS, moHR=0.63; log-rank p=0.016 9.3 7.2 Events, n (%) 96 (61.9) 63 (80.8) mPFS, moHR=0.91; p=NS 5.6 4.9 Events, n (%) 128 (82.6) 70 (89.7) DCR, % 42.6 33.3 ORR, n (%) 43 (27.7) 16 (20.5)

9009 Background: International Medical Graduates (IMGs) are a vital component of the US oncology workforce, representing nearly half of practicing medical oncologists. However, systemic barriers may influence their career trajectories differently. Understanding these challenges is essential for addressing workforce disparities and optimizing cancer care delivery across diverse geographic regions. Methods: We conducted a cross-sectional study of 13,497 medical oncologists using the 2024 Dec CMS Provider Dataset linked with the 2023 Rural-Urban Continuum Codes (RUCC). Medical oncologists were identified by their self-reported primary specialties, including Hematology/Oncology, Medical Oncology, and Hematopoietic Cell Transplant. Physicians were categorized by graduation origin (based on their self-reported medical school), career stage (early: 0–10 years, mid: 11–30 years, late: >30 years post-medical school graduation). The primary outcomes included practice at Main Campus of NCI Designated Cancer Centers (as an indicator of academic practice) and the geographical location of their practice (Metro, Non-Metro, Mixed). We employed chi-squared tests for statistical comparisons and performed stratified analyses by career stage to evaluate transition patterns over time. Results: 6920 IMGs constituted 48.7% of the oncology workforce, with similar gender distributions between IMG and non-IMG oncologists (37.9% vs 36.5% female, p=0.068). Notably, early career oncologists were less likely to be IMGs (IMG vs non-IMGs: 8.2% vs 12.5%, p<0.001). Compared to Non-IMGs, IMG oncologists are less likely to practice at main campuses of NCI Center (19.9% vs. 27.7%, p<0.001), especially as their career advances (all p<0.01). (Table). IMGs had higher representation in non-metropolitan areas than non-IMGs (11.4% vs 9.1%, p<0.001), particularly in late-career stages (14.7% vs 12.3%, p=0.033), indicating their unique role in serving underserved regions. (Table). Conclusions: Our findings reveal that, IMGs are less likely to practice at main campuses of NCI-Cancer Center than their non-IMG colleagues. Meanwhile, IMG oncologists are disproportionately serving rural communities. Supporting IMG pathways in oncology is critical to ensure a balanced cancer care delivery across the United States. Practice setting distribution and academic affiliation among international medical graduates (IMGs) and US graduates (USGs) by career stage. IMG (N=6,577) Non-IMG (N=6,920) IMG (N=6,577) Non-IMG (N=6,920) NCI Center Other NCI Center Other Metro Non-Metro/Mixed Metro Non-Metro/Mixed Total 19.9% 80.1% 27.7% 72.3% 88.6% 11.4% 90.9% 9.1% Career Stage Early (0-10y) 29.1% 70.9% 36.1% 63.9% 91.1% 8.9% 95.4% 4.6% Mid (11-30y) 21.3% 78.7% 28.8% 71.2% 90.1% 9.9% 91.6% 8.4% Senior (30+y) 15.0% 85.0% 22.0% 78.0% 85.3% 14.7% 87.7% 12.3%

4119 Background: TP53 mutations are frequent genetic alterations in cancers and also prevalent in biliary tract cancer (BTC). In non-small cell lung cancer, TP53 mutations have been reported to enhance immune checkpoint inhibitor (ICI) efficacy and improve outcomes. However, their impact on BTC remains unclear. This study investigated the clinico-molecular characteristics, prognosis, and ICI efficacy in TP53 -mutated BTC. Methods: Patient data were collected from the SCRUM-Japan GOZILA and MONSTAR-SCREEN-1/2 databases (Japan) and the Duke university and Mayo clinic databases (U.S.), which included patients receiving first-line ICI therapy. Comparisons between TP53 wild-type (WT) and mutation groups were performed in the Japanese cohort. Subsequently, analyses were expanded to include U.S. patients, focusing on comparisons between non-ICI and ICI groups. Tumor Immune Dysfunction and Exclusion (TIDE) scores were calculated using MONSTAR-SCREEN-2 whole transcriptome sequencing (WTS) data to evaluate ICI responsiveness, and gene set enrichment analysis (GSEA) explored pathways associated with TP53 mutations. Results: In the Japanese cohort (n=594), TP53 mutations were identified in 311 patients (52.4%). KRAS , ERBB2 , CDKN2A , and SMAD4 alterations were more frequent in the TP53 mutation group, while IDH1, BAP1 , and FGFR2 fusions were more common in the WT group. Multivariable analysis showed TP53 mutations were independent prognostic factors for poor outcomes (progression-free survival [PFS]: HR 1.37, 95% CI: 1.11–1.69, P=0.003; overall survival [OS]: HR 1.36, 95% CI: 1.06–1.75, P=0.017). Incorporating the U.S. cohort (n=625; non-ICI: 548; ICI: 77), no significant differences in overall response rate (ORR) or disease control rate (DCR) were observed in the non-ICI group between the groups. However, in the ICI group, TP53 mutations tended to show higher ORR (21.1% vs. 38.5%, P=0.16) and DCR (47.4% vs. 66.7%, P=0.14). In the non-ICI group, TP53 mutations were associated with worse PFS (HR 1.46, median PFS: 7.4 vs. 5.3 months, P<0.001), whereas, in the ICI group, no significant difference was observed; however, a trend toward better PFS was seen in the TP53 mutation group (median PFS: 5.0 vs. 6.4 months, P=0.163). TIDE scores were significantly lower in the TP53 mutation group, indicating higher ICI responsiveness. GSEA revealed enrichment of oxidative phosphorylation and hypoxia pathways. Conclusions: TP53 mutations are independent prognostic factors for poor outcomes in BTC. However, patients with TP53 mutations may derive greater benefits from ICIs, underscoring the importance of tailored therapeutic strategies in TP53- mutated BTC.

e15527 Background: Fruquintinib, regorafenib, and trifluridine-tipiracil (TAS-102) alone or in combination with bevacizumab (bev) are approved for use in treatment of metastatic colorectal cancer (mCRC) following progression on or intolerance to fluoropyrimidine-based therapy with irinotecan, oxaliplatin, and targeted agents if indicated. All three medications have established overall survival (OS) benefit when used third line or later; however, there is a paucity of literature and guideline recommendations regarding optimal sequencing of these agents. The aim of this study was to investigate OS in patients (pts) with mCRC based on the sequencing of these three “late-line” treatments. Methods: This retrospective, multi-site cohort study evaluated OS in pts with mCRC who received fruquintinib possibly sequenced with regorafenib and/or TAS-102 +/- bev between 11/01/2023 and 11/19/2024. Pts prescribed fruquintinib (N = 64) were identified utilizing SlicerDicer within EPIC. Pts were excluded from final analysis for incomplete information, non-mCRC diagnosis, or failure to initiate fruquintinib (N = 21). OS was defined as the time from initiation of first late-line therapy to death from any cause. Cox regression models were utilized for multivariable adjustment. P-values were calculated using Chi-Square for categorical variables and Kruskal-Wallis for continuous variables. Results: Forty-three pts were included in the final analysis. The median age at initiation of first late-line therapy was 56 years old. Most pts had left-sided primary tumors (60.5%) and liver metastases (79.1%). RAS and BRAF V600E mutations occurred in 65.1% and 4.7% of pts, respectively, and 83.7% of pts had received prior bev therapy. All pts were pMMR/MSI-S. TAS-102 +/- bev was the most common first late-line agent utilized (72.1%), and fruquintinib the most common second late-line agent (73%). Regorafenib was prescribed in only 12 pts (27.9%) and used primarily as a second or third late-line option. OS was not statistically different based on initial late-line therapy chosen (median OS 19.2 months for TAS-102 +/- bev and not estimable for fruquintinib and regorafenib, p = 0.058). This result was maintained on multivariate analysis after adjusting for age, liver metastases, and RAS mutation status. However, fruquintinib sequenced after TAS-102 +/- bev demonstrated improved OS (median 20.5 months) compared to fruquintinib as first or last late-line therapy (median not estimable vs. 15.8 months, p = 0.049). Conclusions: Fruquintinib sequenced after TAS-102 +/- bev may confer an OS advantage in the treatment of mCRC. However, prospective studies evaluating sequencing strategies representative of standard prescribing patterns are still needed to firmly establish optimal sequencing of fruquintinib, regorafenib, and TAS-102-based therapy.

Abstract Background Optimal treatment for resectable gastric and gastroesophageal junction (GEJ) adenocarcinoma remains unclear due to limited head-to-head comparisons among chemotherapy and chemoradiation regimens. This network meta-analysis aimed to determine the relative efficacy of available multimodality treatment regimens in these patients. Methods MEDLINE, EMBASE, Scopus, Web of Science, and CENTRAL were searched till September 20, 2024. Phase 3 randomized trials evaluating perioperative/neoadjuvant systemic therapy ± radiation in resectable gastric/GEJ adenocarcinoma were included. Primary outcomes were disease-free survival (DFS) and overall survival (OS). Frequentist network meta-analysis was conducted to compare hazard ratios (HRs) and 95% confidence intervals (CIs). Results Fifteen trials (8072 patients) were analyzed. pFLOT (perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel) ranked highest for DFS in the overall population (P-score 91%), achieving significant improvements compared to 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. pFLOT significantly outperformed surgery alone (0.57, 0.45-0.72) and nCROSS (0.73, 0.60-0.89). Based on the limited data available, 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 (cisplatin and fluorouracil/capecitabine) was not superior to pFLOT (DFS: 1.10, 0.71-1.69; OS: 1.09, 0.69-1.72). Conclusions pFLOT demonstrated superior efficacy in resectable gastric/GEJ adenocarcinoma, outperforming surgery alone, nCROSS, and alternative perioperative regimens. The additive role of immunotherapy requires further investigation to optimize patient selection and outcomes.

AbstractStandard of care first‐line systemic treatment for advanced biliary tract cancer includes chemo‐immunotherapy with gemcitabine, cisplatin, and durvalumab, followed by maintenance durvalumab monotherapy. The present work aims to investigate the differences in baseline clinical and molecular characteristics between patients with early progression during chemo‐immunotherapy and those who reach durvalumab maintenance therapy. The study population included patients with unresectable, locally advanced, or metastatic BTC who received treatment at 38 clinical Institutions in 12 countries from July 2021 to December 2023. The primary objective of the study was to investigate whether baseline clinical and molecular characteristics differed between patients with early progression during chemo‐immunotherapy versus those reaching durvalumab maintenance therapy. Four hundred forty‐eight patients were included in this study. Two hundred twenty‐seven patients (50.7%) received maintenance with durvalumab monotherapy, whereas 221 (49.3%) did not receive maintenance therapy due to PD during first‐line chemo‐immunotherapy before completing 8 cycles. Results show that patients who received maintenance were more likely to be older (≥70 years), have an ECOG = 0, locally advanced disease, and a neutrophil‐to‐lymphocyte ratio (NLR) <3. A higher proportion of patients with BAP1 mutations received maintenance, while TP53 mutations were more common in those who progressed early. According to the present analysis, a substantial proportion of patients (50.7%) with advanced BTC who were treated with chemotherapy plus durvalumab proceeded to receive maintenance therapy with durvalumab monotherapy, with a median treatment duration of 4.4 cycles. Patients ≥70 years, with ECOG PS 0, with locally advanced disease, and with NLR <3 had a higher likelihood of receiving maintenance therapy.

Abstract Background: Pancreatic ductal adenocarcinoma (PDA) is a disease with guarded prognosis with a 5-year overall survival (OS) of 3.1% in patients with metastatic disease. The need for innovative treatments for this lethal disease is paramount. TTFields is a novel treatment modality that employs low intensity, alternating, and intermediate frequency electrical fields that abrogates cancer cell proliferation through different mechanisms. These include inhibition of mitosis, disruption of cancer cell membranes, metabolomic dysregulation of cancer cells, and immunogenic activation of the tumor microenvironment (TME). TTFields are approved in glioblastoma multiforme, non-small cell lung cancer and malignant mesothelioma. The PANOVA trial demonstrated promising efficacy for TTFields plus chemotherapy in patients with PDA. A trial of GCN in patients with PDA demonstrated exceptional efficacy in patients with metastatic disease. Here in, we present our ongoing clinical trial investigating the safety and efficacy of TTFields plus GCN in patients with PDA (NCT04605913). Methods: This a phase I/II trial with an initial safety run-in phase followed by the phase II portion. The primary objective of the trial is to determine the safety (CTCAE v 5.0) of GCN plus TTFields. Secondary objectives include determining the 6-month progression free survival (PFS) rate, overall response rate (ORR, RECIST v1.1), 12-month survival rate, OS, and QOL (EORTC QLQ-C30, version 3.0.2.3). Inclusion criteria include PDA with liver metastasis (patients can have additional sites of metastasis), ECOG 0-1, measurable disease, and ability to operate the Novo TTF-100L (P)/Novo TTF-200T system. Treatment consisted of TTFields (150 kHz 18 hours/day) and GCN (G: 1000 mg/m2, C 30 mg/m2, and N: 150 mg/m2 every 2 weeks, 28 days cycle), followed by a maintenance phase after 6 months (G: 1000 mg/m2 every 2 weeks) plus TTFields until progression. Six patients were to be enrolled in the phase I portion and if ≤1/6 patients experienced a dose limiting toxicity (DLT, treatment emergent adverse event, or skin toxicity of Gr4), the plan would be to move to a phase II trial enrolling 34 more patients. If 2/6 patients experienced a DLT, 6 patients would be enrolled in dose level -1 (GCN plus TTFields for 9 hours/day followed by the maintenance treatment) and if tolerated the phase II portion would start with dose level -1 regimen. The phase I portion was completed without any DLTs and the trial is currently enrolling to the phase II portion. The total number of patients (40) was powered to the 6-months PFS rate and ORR (estimated using the lower bound of exact one-sided 90% confidence intervals). The goal is to "reject" a 6-month PFS rate of 66% and an ORR of 71% (based on previous GCN trial). Time-to-event endpoints will be assessed using the Kaplan-Meier method. Citation Format: Hani M. Babiker, Jason Starr, Jeremy Jones, Conor O’Donnell, Robert Jones, Jacqueline Boni, Lashundra Stewart, Josh Cameron, Oudom Kour, Kabir Mody, Robert R. McWilliams, Daniel H. Ahn, Tanios Bekaii-Saab, Mitesh J. Borad, Umair Majeed. A phase I/II pilot trial, single arm, open label, of gemcitabine, cisplatin, protein-bound paclitaxel (GCN) combined with Tumor Treatment Fields (TTFields) in patient with metastatic pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT190.

PURPOSE This study aimed to investigate the clinicomolecular profiles and the efficacy of human epidermal growth factor receptor 2 (HER2)-targeted therapy in HER2 -amplified biliary tract cancer (BTC). METHODS This study was an international collaboration that used combined data from the prospective SCRUM-Japan GOZILA and MONSTAR-SCREEN in Japan and retrospective reviews in the United States; patients with advanced BTC who had received systemic therapy were included. The clinicomolecular profiles were evaluated in an exploratory cohort, whereas the efficacy of HER2-targeted therapy was assessed in a biomarker-selected cohort. RESULTS Of the 439 patients in the exploratory cohort, 43 (10%) had HER2 amplification. The frequencies of coalterations were higher in patients with HER2 amplification versus patients without HER2 amplification including HER2 mutations (26% v 5%, P < .001), TP53 mutations (84% v 61%, P = .003), and BRAF amplification (9% v 2%, P = .030). There were no KRAS mutations identified in patients with HER2- amplified BTC. No significant difference in overall survival (OS) was observed between patients with and without HER2 amplification (median, 17.7 v 16.9 months; hazard ratio [HR], 0.95 [95% CI, 0.65 to 1.40]). Of the 60 patients with HER2 -amplified BTC in the biomarker-selected cohort (43 from Japan and 17 from the United States), the OS was significantly longer in 29 patients who received HER2-targeted therapy than in those who did not receive HER2-targeted therapy (median, 24.3 v 12.1 months; HR, 0.39 [95% CI, 0.23 to 0.82]). Multivariate analysis identified HER2-targeted therapy as an independent prognostic factor for OS (HR, 0.29 [95% CI, 0.14 to 0.58]; P < .001). CONCLUSION HER2 amplification was found in 10% of advanced BTC and was not identified as an independent prognostic factor for OS. Patients with HER2 -amplified BTC derive significant benefit from HER2-targeted therapy.