Sequential treatment with surufatinib combined with gemcitabine and nab-paclitaxel (AG) or AG alone as first-line therapy for locally advanced or metastatic pancreatic ductal adenocarcinoma (mPDAC) after 6 weeks of AG induction therapy: A two-cohort, exploratory phase II study

Background: PDAC is an extremely aggressive malignancy with limited therapeutic options. Despite current first-line therapies like AG, the 5-year survival rate remains below 5%. Surufatinib (S) is a novel tyrosine kinase inhibitor that selectively targets VEGFR1-3, FGFR1, and CSF-1R. This study aimed to evaluate the efficacy and safety of S plus AG or AG alone as first-line treatment for patients with mPDAC. Methods: This exploratory, phase II trial (NCT05969171) enrolled two cohorts. Eligible patients (pts) with 18-75 years, histologically confirmed mPDAC, with no disease progression after 6 weeks of AG induction therapy (pts with increased SD were also excluded) were assigned to cohort 1 (S 250 mg qd, po, q3w plus AG: nab-paclitaxel 1000mg/m 2 , iv, d1, d8; gemcitabine 1000mg/m 2 , iv, d1, d8, q3w) or cohort 2 (AG alone, q3w). The Primary endpoint was PFS. Secondary endpoints included ORR, DCR, OS, and safety. Results: As of December 31, 2025, 26 pts were enrolled in cohort 1 (median age 61.0 years; 57.7% male; 50% had ≥1 metastatic organ; median CA19-9 206.0 U/mL) and 26 pts in cohort 2 (median age 60.0 years; 65.4% male; 38.4% had >1 metastatic organs; median CA19-9 438.5 U/mL). In cohort 1, 6 pts (23.1%) achieved PR following 6 weeks of AG therapy, and an additional 14 pts achieved PR during S plus AG treatment, resulting in an ORR of 76.9%. The median PFS (time from initiation of AG treatment to PD or death) was 13.96 months (95% CI: 5.6-22.3). Subgroup analysis revealed longer mPFS in pts without metastatic organ compared to those with ≥1 metastatic organ (not reached vs. 8.64 months, p=0.081) and in pts with a ≥90% reduction in CA19-9 versus those with a <90% reduction (not reached vs. 9.26 months, p=0.046). In cohort 2, 8 pts (30.8%) achieved PR during AG therapy, and 10 additional pts achieved PR with continued AG treatment, yielding an ORR of 69.2%. The median PFS was 10.68 months (95% CI: 9.3-12.1). Consistent with cohort 1, subgroup analysis showed prolonged PFS in pts with ≤1 metastatic organ versus those with >1 metastatic organs (12.52 vs. 6.64 months, p=0.0083) and in pts with a ≥70% reduction in CA19-9 versus those with a <70% reduction (11.6 vs. 8.34 months, p=0.072). Median OS was not reached in either cohort. Common TEAEs of grade ≥3 in cohort 1 were alopecia (80.8%), neutropenia (42.3%), and leukopenia (30.8%); in cohort 2, these were alopecia (76.9%), leukopenia (34.6%), and neutropenia (26.9%). Conclusions: Induction therapy with 6 weeks of AG followed by sequential surufatinib plus AG demonstrated promising efficacy with a manageable safety profile as first-line treatment for mPDAC. This therapeutic strategy may be particularly beneficial for patients without metastatic organs or those who achieve a ≥90% reduction in CA19-9 during treatment.