Ji, Yan

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)

TPS4196 Background: Advanced BTC patients have poor prognosis. Up to 40% of BTCs have KRAS mutations and are associated with worse overall survival (OS). With a median OS of 7.7 months in KRAS wild-type compared to 1.7 months in KRAS mutated disease, these alterations are independent poor prognostic factors in BTC. Gemcitabine and cisplatin (GC) with or without immunotherapy are often used as 1st-line therapies. However, there is a lack of data on best 2nd-line regimens. mFOLFOX6 (5-fluorouracil [5-FU], leucovorin [LV], oxaliplatin) or liposomal irinotecan+5-FU+LV are options when no biomarkers are found (e.g., MSI-H, BRAFV600E, FGFR-fusions, IDH1-mutation, HER2-overexpression). Prior studies do not demonstrate benefit with MEK inhibitors (MEKi), but none of the studies had biomarker selection. Pre-clinical studies in BTC cell lines suggest synergy between MEKi and 5-FU. Thymidylate synthase (TS )levels induced by 5-FU are downregulated by addition of binimetinib. Early clinical studies show safety and tolerance of this combination. In this study, we will evaluate if the combination of mFOLFOX6+binimetinib improves OS for patients with BTC and MAPK mutations compared to mFOLFOX6 alone in 2nd-line therapy. Methods: EAY191-A6 is a treatment study arm of the NCI ComboMATCH master registration trial EAY191. The A6 trial has a randomized phase II design, enrolling a maximum of 66 patients. Patients with any MAPK pathway mutations except those with available therapies will be eligible. Patient must first enroll to the EAY191 master trial. Local molecular results may be used for enrollment. Submission of tissue at baseline is mandatory. Eligible patients will be randomized 1:1 to mFOLFOX6 vs mFOLFOX6 + binimetinib (45 mg oral twice a day every 14 days). Stratification factors include location and stage of disease. Primary efficacy analysis will compare OS in the intent-to-treat population. If the observed hazard ratio (HR) of experimental arm vs standard of care is < 0.545 (corresponding to an observed increase in OS by 5 months or longer), experimental treatment will be considered superior. An interim futility analysis at 50% of expected events will be conducted. If the observed HR is ≥ 1, experimental treatment will not be considered superior, and accrual maybe suspended. Secondary endpoints include progression-free survival, objective response rate, duration of response, disease control rate and toxicity of treatments. Exploratory objectives include prognostic modeling, correlations of genomic alterations with response or resistance and use of machine learning for outcome prediction. This study is active and open to accrual. Clinical trial information: NCT05564403 .

Transforming growth factor β (TGF-β) is critical for the development and maintenance of epithelial structures. Because receptor localization and trafficking affect the cellular and organismal response to TGF-β, the present study was designed to address how such homeostatic control is regulated. To that end, we identify a new role for the mammalian retromer complex in maintaining basolateral plasma membrane expression of the type II TGF-β receptor (TβRII). Retromer and TβRII associate in the presence or absence of TGF-β ligand. After retromer knockdown, although TβRII internalization and trafficking to a Rab5-positive compartment occur as in wild-type cells, receptor recycling is inhibited. This results in TβRII mislocalization from the basolateral to both the basolateral and apical plasma membranes independent of Golgi transit and the Rab11-positive apical recycling endosome. The data support a model in which, after initial basolateral TβRII delivery, steady-state polarized TβRII expression is maintained by retromer/TβRII binding and delivery to the common recycling endosome.