Surufatinib plus KN046 and chemotherapy as first-line treatment for advanced pancreatic ductal adenocarcinoma: Updated results and biomarker analysis from a phase 1b/2 trial.

4198 Background: In China, gemcitabine (G) and nab-paclitaxel (nP) remain the standard first-line (1L) therapy for patients (pts) with advanced pancreatic ductal adenocarcinoma (PDAC). Our previous report (Wang W, et al; 2025 ASCO) showed that the add-on of surufatinib (S, multi-kinase inhibitor) and KN046 (K, bi-specific PD-L1/CTLA-4 antibody) to GnP chemotherapy provided enhanced anti-tumor activity in advanced PDAC. Here we present the updated results and findings from a biomarker analysis. Methods: In this single-arm, phase 1b/2 trial (NCT05832892), eligible pts with treatment-naïve advanced PDAC received oral S (200~250 mg, once daily), intravenous K (5 mg/kg, on day 1) and GnP (G 1000 mg/m 2 , nP 125 mg/m 2 , on days 1 & 8) at 21-day cycles till disease progression or intolerable toxicity. The primary efficacy endpoint was ORR per RECIST 1.1; secondary endpoints included DCR, PFS, OS and safety; efficacy-predictive biomarkers were exploratory endpoints. Results: Overall, 31 pts were enrolled with a median age of 56 years (range 40–74) and a predominant male gender (74.2%). Distant metastasis was present in 28 (90.3%) pts and 24 (77.4%) had liver metastasis (LM) at baseline. Best overall responses included 4 CR, 18 PR, and 6 SD. The ORR was 71.0% (95% CI 52.0–85.8) and DCR was 90.3% (95% CI 74.2–98.0). As of Dec 25, 2025, with a median follow-up of 15.9 months, median PFS was 8.2 months (95% CI 6.1–not estimable [NE]). Median OS was 18.0 months (95% CI 13.8–NE) with a 12-month OS rate of 68.2% (95% CI 50.8–91.6). Baseline LM was correlated to significantly worse PFS (8.0 vs NE months, log-rank P = 0.02), though no significant impact on ORR (73.9% vs 62.5%, P = 0.66), DCR (91.3% vs 87.5%, P = 1.00) or OS (13.8 vs NE, log-rank P = 0.12) was observed. Among the 27 pts who received ≥4 cycles of treatment, 22 (81.5%) and 19 (70.4%) experienced a decline in CA199 and CA125 from baseline, respectively, while fewer (37.0%) had CEA declined. A ≥50% decline in CA199 was correlated to significantly improved PFS (10.3 vs 8.1 months, log-rank P = 0.01) and a trend towards improved OS (NE vs 11.1 months, log-rank P = 0.11), as compared to a milder decrease or increase in CA199; Such correlation was not observed for CA125 or CEA. Treatment-related adverse events (TRAEs) occurred in 29 (93.5%) pts, of whom 14 (45.2%) experienced Grade ≥3 events, with hypertension (12.9%), neutropenia (12.9%), and thrombocytopenia (9.7%) being the most frequently observed. No treatment-related serious adverse events or deaths occurred. Conclusions: S plus K and GnP demonstrated consistently encouraging efficacy and manageable safety in 1L treatment of advanced PDAC. Early and sharp decline in CA199 may predict more favorable survival benefit. Analyses in genetic profile and its impact on clinical outcome will be carried out in future, and investigations in larger population are warranted. Clinical trial information: NCT05832892 .