Mahalingam, Devalingam

4213 Background: Elraglusib (9-ING-41), a glycogen synthase kinase-3β (GSK-3β) inhibitor, has multimodal antitumor activity. In the international, open-label, randomized phase 2 1801 Part 3B study, elraglusib plus gemcitabine/nab-paclitaxel (GnP) was evaluated in previously untreated metastatic pancreatic ductal adenocarcinoma (mPDAC), with patients randomized 2:1 to weekly elraglusib/GnP or GnP alone. Primary endpoints were median overall survival (mOS) and 1-year survival. The GnP control arm demonstrated shorter mOS than contemporary randomized trials (7.2 months vs 9.2 months in NAPOLI-3 and 9.7 months in PASS-01), driven by higher early mortality (0–2 months: 23.1% vs 10.1% in NAPOLI-3). Given balanced randomization, similar early mortality was inferred in the elraglusib/GnP arm, prompting post-hoc analyses to contextualize efficacy and identify factors associated with early death. Methods: Efficacy and safety were summarized descriptively. Time-to-event endpoints were analyzed using Kaplan–Meier estimates, log-rank testing, and Cox proportional hazards models. Response rates were compared using the Cochran–Mantel–Haenszel test. Post-hoc subgroup, sensitivity, and machine-learning–based multivariate analyses explored clinical, demographic, and biomarker correlates of survival and early mortality. Results: In the full randomized population (elraglusib/GnP n=155; GnP n=78), elraglusib/GnP improved mOS by 2.9 months versus GnP (10.1 vs 7.2 months; HR 0.62; 95% CI 0.46–0.84; p=0.01), with 1-year survival rates of 44.1% versus 22.3%. Among patients receiving ≥1 full treatment cycle, mOS was 12.5 months with elraglusib/GnP and 8.5 months with GnP, comparable to contemporary registrational trials. Across multiple post-hoc sensitivity analyses—including evaluable patients, those matched to NAPOLI-3 baseline tumor burden, patients treated in the EU (early mortality 4%), and those achieving ≥20% CA19-9 decline within the first 1–2 cycles—elraglusib/GnP consistently demonstrated a ≥4-month OS advantage. Early death was associated with low baseline albumin (<3 g/dL), high CA19-9 (>800 U/mL), high tumor burden, and KRAS, TP53, and CDKN2A co-mutations. Conclusions: The elevated early mortality in the GnP control arm reflects enrollment of a heterogeneous, real-world mPDAC population with less restrictive eligibility than recent registrational trials. Post-hoc analyses identify key clinical and molecular drivers of early death and confirm a consistent survival benefit with elraglusib/GnP. These hypothesis-generating findings directly inform eligibility criteria, stratification, and endpoint assumptions for the planned phase 3 trial. Clinical trial information: NCT03678883 .

4013 Background: Pancreatic ductal adenocarcinoma (PDAC) is driven predominantly by oncogenic KRAS signaling, yet prior attempts to target the MAPK pathway have been limited by toxicity and emergence of resistance. Atebimetinib is a next-generation, deep cyclic inhibitor (DCI) of MEK designed to achieve pulsatile pathway inhibition with improved tolerability. We report a Phase 2a cohort evaluating atebimetinib in combination with modified gemcitabine/nab-paclitaxel (mGnP) in the first-line treatment of advanced or metastatic PDAC (NCT05585320). Methods: In this multicenter, open-label, nonrandomized Phase 2a study, patients with previously untreated advanced or metastatic PDAC were eligible for participation and were treated with orally administered atebimetinib daily in combination with mGnP (modification: every other week dosing). The primary endpoint was objective response rate (ORR) per investigator assessment using RECIST 1.1 criteria in response-evaluable patients. The cohort was powered (~80%, one sided alpha 0.05) using an optimal Simon’s 2-stage design. Results: Fifty-five patients were enrolled and treated with 320 mg atebimetinib daily + mGnP. ECOG performance status was 0-1 (100%); median age was 68 years (range 42-85 years), 62% were ≥65 years, and 55% were male. No grade 5 treatment-related adverse events (AE) were observed. No AE related to atebimetinib were higher than grade 3. Grade 3 AE related to atebimetinib occurred in 29% of participants, with the most frequent being rash (5%), ALT increased (5%), and AST increased (5%). Among the 50 response-evaluable patients, best overall response (BOR) achieved were 21 PR, 21 SD, 7 PD, 1 NE. The ORR was 42%, and DCR was 84%. With a median follow-up of 10.4 months (data cutoff Jan 7, 2026), 6- and 9-month OS rates were 88% and 79%, respectively; median PFS was 8.3 months and median OS was not reached. Conclusions: Atebimetinib in combination with mGnP demonstrated favorable safety and promising efficacy compared to historic standard-of-care (SoC) GnP. 1 A phase 3 registrational trial is planned to start in mid-2026 for evaluation of atebimetinib + mGnP versus SoC GnP. 1. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med . 2013;369(18):1691-1703. doi:10.1056/NEJMoa1304369 (PMID: 24131140). Clinical trial information: NCT05585320 .