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4183 Background: High grade neuroendocrine neoplasms (HG-NENs) are treated with platinum doublets mirroring guidelines for small cell lung cancer (SCLC) but recurrences are common and salvage options are limited in efficacy. Cabozantinib (CABO), an inhibitor of VEGFR, MET, and TAM kinases (TYRO3, AXL, and MER) was approved by the FDA for treatment of well differentiated (WD) NENs of both pancreatic and extrapancreatic origins based on the CABINET study (Chan, NEJM 2025). However, its efficacy in the whole spectrum of HG-NEN patients including poorly differentiated disease (PDD) has not been prospectively explored. Methods: This was a single institution, Phase II study of CABO in patients with HG-NENs who had progressed on at least one prior treatment. Key inclusion/exclusion criteria were NENs of any origin except SCLC, high grade by Ki-67 of > 20% or histology consensus, ECOG of < = 1, appropriate hematological parameters and no history of bleeding or active cardiac disease. CABO was given orally starting at 60 mg po daily in 3-week cycles. The primary endpoint of this study was overall response rate (ORR). Secondary endpoints included progression free survival (PFS) and overall survival (OS). A Simon optimal 2-stage design tested the null hypothesis that the true ORR is < = 1% at the type I error rate of 5%, resulting in projected enrollment of up to 32 total patients. Toxicities were graded according to CTCAE v5.0 and response was evaluated according to RECIST v1. Results: All patients have been accrued, with 4/32 patients still on treatment. Median age at diagnosis was 62 years and male to female ratio was 1.46. Origin of tumor was GI in 68.8% of the cases, the rest being thoracic (6.3%), prostate (6.3%) cervical (6.3%) head/neck (3.1%) and unknown (9.4%). Median Ki-67 was 55%, 11 patients had Ki-67 > 70%. Histology was WD-HG in 40% of patients and PDD in 60%. Two patients had mixed PDD/other components (MiNEN). Median PFS in evaluable patients was 4.01 months [95% CI 1.61 to 9.30] and mOS was 9.89 mo [95% CI 6.73 to 18.96]. Three patients so far (9.3%) have had partial response as best response (PDD-colon, WD-pancreas and PDD-cervical) while 19/32 (59.4%) patients have had stable disease as best response so far (disease control rate 68.8%). Five (15.6%) patients have received more than 10 treatment cycles. The three longest treated patients had WD-pancreas (23 and 17 cycles) and PDD-unknown (12 cycles). One patient had eventual resection of a metastatic site and is currently without evidence of disease. Three patients withdrew from the trial because of toxicities (shortness of breath, GI bleeding, thromboembolism). Twenty-six patients have expired. Conclusions: CABO monotherapy showed efficacy in some HG-NEN patients with not just WD but also the very aggressive PDD histology. No new side effects to the ones previously described for this agent were noted. Supported by Exelixis and a Siteman investment program grant. Clinical trial information: NCT04412629 .

4219 Background: Pancreatic ductal adenocarcinoma (PDAC) remains a notoriously difficult-to-treat malignancy, with limited therapy options for patients with advanced disease. While KRAS mutations are the dominant oncogenic driver in PDAC, next-generation sequencing has enabled the identification of rare, targetable alterations such as the BRAF V600E mutation, which occurs in approximately 2-3% of cases. BRAF mutant cell lines are responsive to MEK and RAF inhibitors. This study evaluates the efficacy of the combination of encorafenib and binimetinib as ≥ 2nd line therapy in this specific molecular subgroup of pancreatic cancer patients. Methods: This study used a planned two-stage design. Seven patients were pre-registered; one did not meet eligibility criteria and was excluded. Six patients were enrolled in Stage 1, which required an objective response (OR) in 40% of patients to proceed to Stage 2. Stage 2 was planned to enroll an additional 16 patients, contingent on meeting this efficacy threshold. Enrolled patients received treatment in 28-day cycles until disease progression or for a maximum of 36 cycles. Patients self-administered encorafenib (450 mg orally once daily) and binimetinib (45 mg orally twice daily) starting on Day 1 of each cycle. Objective responses were assessed using RECIST version 1.1 over 24 weeks. Results: The median number of cycles was 8. The objective response rate at 24 weeks was 33.33%. The overall objective response rate was 50%. The median time to response for progression-free survival, overall survival, duration of response, and time to response was 7.1, 15.0, 9.9, and 3.9 months respectively, with 95% CI in all categories. 50% of patients experienced at least one Grade ≥3 adverse event, including anemia, thromboembolic events, and acute kidney injury. Conclusions: The six BRAF-V600E-mutated PDAC patients in our cohort demonstrated meaningful antitumor activity with a manageable safety profile after treatment with encorafenib and binimetinib. Although the study was prematurely terminated due to limited accrual, observed objective responses and survival outcomes suggest that dual RAF/MEK inhibition may represent a feasible therapeutic strategy in this rare molecular subgroup. Larger studies are warranted to further define the efficacy and safety of this treatment combination in BRAF-V600E-mutated pancreatic cancer. Clinical trial information: NCI-2020-02972 .

4178 Background: In the CABINET trial, CABO significantly prolonged progression-free survival (PFS) compared to placebo (PB) in patients (pts) with advanced, previously treated extrapancreatic NET (epNET) or pancreatic NET (pNET) (Chan et al., NEJM, 2025). Here we report outcomes according to functional status based on NET hormone secretion. Methods: Pts with locally advanced or metastatic epNET or pNET were randomized 2:1 in separate cohorts to receive CABO 60 mg daily vs PB. Eligibility included progression by RECIST within 12 months (mo) before registration, ≥ 1 prior systemic therapy not including somatostatin analogs (SSA). Pts with functional NET due to hormone secretion and non-functional NET were included. In this post hoc subgroup analysis, we analyzed PFS by blinded independent central review and adverse events for pts receiving CABO vs PB based on functional status. Cox regression models were used with stratification on primary tumor site (epNET vs pNET). Subset analyses to evaluate treatment arm differences were conducted in pts with functional and non-functional tumors. Due to small numbers, separate results for those with unknown functional status are not included. Results: Of the total 298 pts enrolled in both cohorts, 74 had a functional NET (CABO, n = 47; PB, n = 27); 179 had a non-functional NET (CABO, n = 123; PB, n = 56); 45 had unknown functional status (CABO, n = 28; PB, n = 17). For functional NET, primary tumor sites were GI tract (n = 50; 68%), pancreas (n = 15; 20%), unknown (n = 4; 5%), lung (n = 3; 4%), and thymus (n = 2; 3%). Secreted hormones that were reported included serotonin (55%), somatostatin (18%), gastrin (16%), glucagon (4%), insulin (4%), ACTH (1%), and vasoactive intestinal peptide (1%). For non-functional NET, primary tumor sites were pancreas (n = 75; 42%), GI tract (n = 42; 23%), lung (n = 30; 17%), unknown (n = 17; 9%), thymus (n = 8; 4%), and other (n = 7; 4%). Concurrent SSA was received by 91% and 53% of pts with functional and non-functional NET, respectively. In both subgroups, CABO was associated with improved PFS compared to PB (for functional NET: stratified hazard ratio [sHR], 0.40; 95% confidence interval [CI]: 0.20-0.82, P = 0.012; for non-functional NET: sHR, 0.26; 95% CI: 0.17-0.41, P < 0.001). The most frequent grade 3/4 adverse events (AEs) attributed to CABO vs PB in pts with functional NET included hypertension (21% vs 11%), diarrhea (9% vs 11%), and fatigue (2% vs 15%); in pts with non-functional NET, grade 3/4 AEs included hypertension (21% vs 4%) and fatigue (18% vs 4%). Conclusions: Subset analyses of the CABINET trial suggest that CABO is an effective treatment option for pts with functional and non-functional epNET or pNET. Efficacy and safety results for pts with functional or non-functional NET treated with CABO are consistent with results for the entire trial. Clinical trial information: NCT03375320 .

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 .

4173 Background: [ 212 Pb]VMT-α-NET is an alpha-particle radiation-delivering agent targeted to somatostatin receptor type 2 (SSTR2)-expressing tumors. Here, we present safety and efficacy results from the dose-finding phase 1/2a clinical trial (NCT05636618). Methods: This phase 1/2a dose-escalation study uses a Bayesian algorithm to identify an optimal dose of [ 212 Pb]VMT-α-NET for participants with advanced, well-differentiated NETs expressing SSTR2. Eligible participants must have unresectable or metastatic disease, documented radiologic progression following at least one prior systemic treatment, and evidence of SSTR2 expression (Krenning Score ³2) in ≥1 lesion confirmed on an FDA-approved somatostatin receptor PET scan. Patients previously treated with systemic peptide receptor radionuclide therapy (PRRT) are excluded from enrollment. During the dose-finding phase, participants may receive up to four administrations of [ 212 Pb]VMT-α-NET at their assigned dose level, and they are monitored for dose-limiting toxicities (DLTs) for 42 days and safety throughout the study. Efficacy is evaluated by investigators according to RECIST criteria v1.1. Dosimetry is included as a supportive analysis. Results: As of the 10-Dec-2025 data cut-off (DCO), 56 participants had been enrolled across Cohorts 1, 2, and 3 and received at least one dose of [ 212 Pb]VMT-α-NET: 2 participants in Cohort 1 (2.5 mCi), 46 in Cohort 2 (5 mCi), and 8 in Cohort 3 (6 mCi). No dose-limiting toxicities, grade 5 adverse events, treatment-related discontinuations, serious renal events, dysphagia, or clinically meaningful treatment-related myelosuppression were observed. The median follow-up for all treated participants was 40 weeks (range 6–97). Efficacy has been summarized in this abstract for 25 participants (2 in Cohort 1 and 23 in Cohort 2). Nineteen of these 25 participants remained progression-free at the time of the DCO, with a median efficacy follow-up of 49 weeks (range 6–97). In Cohort 2, investigators observed RECIST v1.1 objective responses in 9 of 23 participants (39%), including 8 confirmed responses. Both participants in Cohort 1 continued to exhibit stable disease after two years of follow-up. Updated safety for all participants and updated efficacy for participants with sufficient maturity beyond the 25 summarized here will be presented at the congress. Conclusions: Treatment with [ 212 Pb]VMT-α-NET continues to demonstrate a favorable safety profile across all treated participants (n = 56) and shows signs of sustained efficacy at the 2.5 mCi and 5 mCi dose levels. The therapy has been well-tolerated with no observed dose-limiting toxicities or serious treatment-related adverse outcomes. Based on these encouraging safety and efficacy findings, the study is ongoing, and enrollment into Cohort 3 (6 mCi) remains active. Clinical trial information: NCT05636618 .

4163 Background: Standard first-line systemic therapy for hepatocellular carcinoma involves immune checkpoint inhibitors, including A+B and the STRIDE regimen consisting of D+T. However, there is limited data comparing outcomes of patients receiving these two regimens. We aimed to compare the survival and safety profiles of patients receiving A+B versus D+T as first-line systemic therapy for advanced HCC in a propensity score matched analysis. Methods: We performed a retrospective cohort study using data from TriNetX, a healthcare database of over 150 million patients in the United States. We identified adult patients with a history of HCC and included those who received A+B or D+T as first line treatment. Propensity score matching (PSM) was conducted, matching for patient demographics (age, sex, race), clinical history (alcohol use, ascites, esophageal varices, viral hepatitis), and laboratory parameters [platelets, albumin, bilirubin, INR, alpha-1-fetoprotein (AFP)]. Median overall survival (mOS) and relevant patient safety events were compared between those who received A+B or D+T. Results: We identified 2,762 patients who had HCC who were treated with A+B or D+T, of which 2,030 patients received A+B and 723 patients received D+T. Compared to patients in the A+B cohort, those who received D+T were more often older (68.5 vs 66.9 years, standardized mean difference (SMD) = 0.17), had lower platelet counts (186.4 vs 198.6, SMD = 0.11), had higher prevalence of ascites (33.1% vs 20.3%, SMD = 0.29), and alcohol use (23.8% vs 18.8%, SMD = 0.12). After PSM, 723 patients were included in survival analyses, with all variables adequately balanced except for albumin, which was higher in the A+B group (3.6 vs 3.5, SMD = 0.19). At 90 days after starting therapy, D+T was associated with higher incidence of immune-mediated colitis [5.3% vs 2.6%, odds ratio (OR) 2.1; 95% confidence interval (CI), 1.2-3.7], and a higher risk of hospitalization [35.4% vs 27.9%, OR 1.4; 95% CI, 1.1-1.8]. At 6 months, the risk of hypertension and proteinuria was higher in the A+B cohort [21.9% vs 13.7%, OR 0.57; 95% CI, 0.34-0.95], which persisted at 1 year [28.1% vs 16.5%, OR 0.51; 95% CI, 0.32-0.81]. There was no significant difference in mOS between those receiving A+B or D+T [18.3 months vs 22.8 months, hazard ratio (HR) 0.94; 95% CI, 0.79-1.1]. Conclusions: In patients with advanced HCC who received A+B or D+T as first-line systemic therapy, we found that A+B was associated with higher risk of hypertension and proteinuria, while D+T was associated with a higher risk of immune-mediated colitis and hospitalization. No significant difference in mOS was observed between the cohorts. These findings suggest that safety profiles, rather than survival differences, may be used to guide optimal first-line treatment regimens. Prospective studies are warranted to further assess differences in patient outcomes.

4157 Background: IDH1/2 mutations occur in ~25% of cholangiocarcinomas (CCAs). Preclinical studies suggest synergy between PARP inhibition and PD-L1 blockade. We previously conducted a phase II trial of olaparib plus durvalumab in advanced IDH -mutant CCA. We report matched baseline tissue and serial cell-free DNA (cfDNA)-based correlative analysis of pts samples. The primary objective was to develop a cfDNA methylome signature as a non-invasive biomarker. Methods: This single-arm, open-label phase II study (NCT03991832) enrolled patients with unresectable/metastatic IDH -mutant CCA and ≤2 prior lines of systemic therapy. Patients received olaparib 300 mg orally twice daily and durvalumab 1500 mg IV every 4 weeks. Blood samples were collected at baseline and monthly while on treatment for planned correlatives to examine R2HG, S2HG, and artemin levels using HPLC (High-Performance Liquid Chromatography). Cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) was performed on pts cfDNA samples and case-matched IDH -wildtype pts. Formalin-fixed, paraffin-embedded blocks of baseline tumor biopsies were used for multispectral fluorescent IHC (FL-IHC) using a 6-marker panel composed of pan-cytokeratin, CD4, CD8, CD163, PD-L1, and CD68. Results: Ten patients were enrolled (median age 63.5 y; 50% female; 90% received prior platinum). Median treatment duration was 1.95 mo (range 1.8–13.5). No complete or partial responses were observed. DCR was 30% (3 patients with stable disease); one patient remained on therapy for 13.5 mo before progression. Median PFS was 1.97 mo (95% CI 1.73–3.93). HPLC from baseline plasma showed lower baseline artemin levels correlated with stable disease (p=0.038), while R2HG/S2HG ratios showed no association with outcome. FL-IHC showed enriched immune cell populations, specifically CD4 + T cells (p=0.0032) and a trend for CD68 + macrophages (p=0.062), in the tumor stroma compared with tumor core. 54 plasma samples (from 8 patients) were profiled with cfMeDIP-seq along with 8 IDH -wildtype controls. Using top 100 differentially methylated regions, the circulating tumour DNA methylome exhibited a highly specific signature, accurately discriminating IDH -mutant and IDH -wildtype CCA regardless of treatment status. The specific differentially methylated gene pathways between groups were comprehensively examined in both on-treatment and baseline plasma samples. Conclusions: Advanced IDH -mutant CCA harbors an immune-excluded phenotype, which may underlie primary resistance to immunotherapy. Plasma cfDNA methylome signature can accurately discriminate CCA with IDH mutations. Clinical trial information: NCT03991832 .

4122 Background: BTCs are rare and aggressive malignancies. The first-line standard of care regimen for advanced BTC (aBTC) is gemcitabine (GEM), cisplatin, and an immune checkpoint inhibitor. Although FOLFOX is a preferred second-line treatment, it is limited by neuropathy. Nal-IRI contains IRI free base in liposome nanoparticles, which shelter IRI from conversion to its active metabolite (SN-38) and increase intratumoral SN-38 compared with IRI alone. The NAPOLI-1 trial of FU/LV/nal-IRI vs. FU/LV in second-line advanced pancreatic adenocarcinoma showed an overall survival (OS) benefit. The NIFTY trial (South Korea) demonstrated median OS (mOS) benefit of FU/LV/nal-IRI over FU/LV in a second-line aBTC population (8.6 vs. 5.3 months [mo], HR 0.68, 95% CI 0.48-0.95); however, the NALIRICC trial (Germany) did not (6.9 vs. 8.2 mo, HR 1.08, 95% CI 0.68-1.72). We sought to characterize second-line FU/LV/nal-IRI efficacy in US patients (pts) with second-line aBTC. Methods: This was a single-arm, open-label, multicenter phase II study of pts with aBTC previously treated with GEM/platinum chemotherapy. Pts received nal-IRI 70 mg/m 2 IV over 90 minutes, LV 400 mg/m 2 IV over 30 minutes every 14 days, and FU 2400 mg/m 2 IV over 46 hours every 14 days. The primary objective was to determine progression-free survival rate at 4 mo (PFS 4mo ) using RECIST v. 1.1 criteria. Median PFS reported for pts receiving second-line 5-FU doublet chemotherapy was 3 mo with a PFS of 30%. FU/LV/nal-IRI was of interest if it could increase the PFS 4mo to 50% or higher. Using a one-sided α of 0.05 and 80% power, 17 of 39 evaluable pts had to be progression-free at 4 mo to detect a difference in PFS 4mo between 30% and 50%. Results: Forty-eight pts were enrolled: median age 64.5 years; 69% women; 27% gallbladder primary; 54% intra- and 19% extrahepatic. Ten pts came off study due to toxicity without disease progression before 4 mo on study and were replaced to evaluate the PFS 4mo endpoint. Of 38 evaluable pts, 18 pts (PFS 4mo 47%) were alive and progression-free at 4 mo, meeting the primary endpoint. With a median follow-up of 7.1 mo, median time to disease progression or study discontinuation due to toxicity for all pts was 2.3 mo (95% CI 1.8-4.6, PFS 4mo 38%), and for pts evaluable for the primary endpoint, median PFS was 3.5 mo (95% CI 1.8-5.5). Five pts (10%) had PFS beyond 12 mo. mOS for all pts was 7.9 mo (95% CI 5.7-11.7). Of 41 evaluable pts, the response rate was 2% (1 PR), and the disease control rate was 54%. Adverse events (AEs) were consistent with known toxicities from the FU/LV/nal-IRI regimen. Conclusions: FU/LV/nal-IRI is an effective second-line regimen for aBTC in US pts. There was significant early toxicity as 21% of pts came off study due to AEs before 4 mo. Correlative studies, including longitudinal analyses of circulating tumor DNA using banked blood specimens, are planned (NCT04005339). Clinical trial information: NCT04005339 .

4017 Background: First-line mCCA treatment is chemotherapy and immunotherapy. Based on the phase 2 FIGHT-202 trial, pemigatinib was the first FGFR1-3 inhibitor approved in second line and beyond for mCCA with FGFR2 rearrangement. Results from the phase 3, randomized, global FIGHT-302 trial evaluating pemigatinib as first-line therapy are reported here (NCT03656536). Methods: Patients (pts) aged ≥18 y with previously untreated mCCA with FGFR2 rearrangement were randomized 1:1 to receive oral pemigatinib (13.5 mg once daily q21) or intravenous chemotherapy (1000 mg/m 2 gemcitabine + 25 mg/m 2 cisplatin d1,8 q21 ≤8 cycles) stratified by previous receipt of 1 chemotherapy cycle, geographic region, and tumor burden. Pemigatinib crossover was allowed for control arm pts progressing on chemotherapy. Primary end point was progression-free survival (PFS). Secondary efficacy, safety, and exploratory end points were also analyzed. Results: After prescreening >4000 pts, only 196 had FGFR2 rearrangement and were screened; 167 were randomized to receive pemigatinib (n=83) or chemotherapy (n=84) before closing the study early due to slow accrual. Baseline characteristics and demographics were similar between arms. Median PFS (mPFS) with pemigatinib versus chemotherapy was 8.3 versus 6.8 mo, respectively (hazard ratio [95% CI], 0.58 [0.39-0.87]; nominal P =.0078); secondary efficacy endpoints generally supported primary results (Table). Median OS was similar, although these results are confounded by FGFR inhibitor administration as second-line treatment. In the crossover group (n=42, second-line pemigatinib), mPFS was 8.1 mo. Safety was consistent with previous results (Table). Exploratory analyses of genetic co-alterations associated with treatment response will be presented. Conclusions: FIGHT-302 was the first phase 3 trial of a targeted therapy for untreated mCCA. Pemigatinb demonstrated superior activity and prolonged mPFS compared with first-line chemotherapy. The results confirm the current management paradigm of pemigatinib administration after disease progression on chemotherapy. Clinical trial information: NCT03656536 . Pemigatinib Gemcitabine + cisplatin mPFS (95% CI), mo a 8.3 (6.5-12.2) 6.8 (6.1-8.3) Objective response rate, n/N (%) a 39/83 (47) 13/84 (15.5) Median duration of response (95% CI), mo a 14.2 (8.7-24.7) 6.3 (4.3-not estimable) Median overall survival (95% CI) a,b , mo 24.4 (18.6-35.9) 25.0 (18.7-34.2) Treatment related TEAEs, n/N c (%) 80/83 (96) 70/73 (96) Serious TEAEs, n/N (%) c,d 23/83 (28) 17/73 (23) Grade ≥3 TEAEs, n/N (%) c 65/83 (78) 49/73 (67) TEAEs leading to treatment discontinuation, n/N (%) c 5/83 (6) 8/73 (11) Fatal TEAE, n/N (%) c,d 3/83 (4) 0 a All randomized pts. b Interpretation limited by second-line treatment with FGFR inhibitor in gemcitabine + cisplatin arm. c Pts who received ≥1 study dose. d None deemed treatment related.

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 .