Background: This prospective, randomized controlled phase 1b/2 clinical study was designed to explore the efficacy and safety of surufatinib combined with camrelizumab, nab-paclitaxel and S-1 as first-line treatment compared with nab-paclitaxel and gemcitabine (AG) in mPDAC. Preliminary data was reported (Guanghai Dai, 2023 ASCO, 4142). Here we presented the updated data as more patients (pts) were recruited. Methods: In phase 1b, pts with mPDAC received surufatinib (200mg to 300mg, qd po), camrelizumab (200mg, I.V., D1, Q3W), nab-paclitaxel (125mg/m², I.V., D1, D8, Q3W), and S-1 (40mg bid, D1-14, Q3W). Phase 2 is a prospective, open-label, randomized (1:1) trial comparing NASCA with AG in the first-line setting. The primary objective was the RP2D and overall response rate (ORR) per RECIST v1.1. Tumor tissue samples were collected at diagnosis and were subjected to mIHC to evaluate tumor immune microenvironment. Results: From Aug 2021 to Jun 2023, 49 pts were enrolled. As previously reported, 6 pts were enrolled in phase 1b and RP2D was determined as surufatinib 200mg. Of the 49 pts, 48 were evaluable for efficacy (28 in NASCA and 20 in AG group). ORR was 53.6% (15/28) (95% CI: 35.8-70.5) in pts receiving NASCA (pts in phase 1b included) and 15.0% (3/20) (95% CI: 5.2-36.0) in AG group. In NASCA group, pts with liver metastases exhibited higher ORR than those without liver metastases (71.4% vs 35.7%, p=0.13). Median progression-free survival and overall survival was 9.17m (95% CI: 5.5-NA) and 15.57m (95% CI: 9.27-NA) in NASCA group, 6.3m (95% CI: 4.87-NA) and 8.63m (95% CI: 7.90-NA) in AG group at the median follow-up of 13.7m. The most frequent adverse events (AEs) of all-grade in NASCA were neutropenia (57.1%), hepatotoxicity (42.9%), and neuropathy (39.3%). Immune-related AEs were observed in 5 pts with grade 3 hepatotoxicity in 4 pts and grade 2 enteritis in 1 pt. Safety was comparable in two groups except for hepatotoxicity and diarrhea. Using mIHC, the tissue of 13 pts treated with NASCA were stained for multiple markers of immune cells. CD3⁺ T cells infiltrated the tumor core at the highest level, followed by CD68⁺CD163^- (M1) macrophages, and FOXP3⁺ T cells. Majority of immune cells and ICI biomarkers were expressed at higher proportion in the stroma. Pts with liver metastases displayed elevated tumoral FOXP3⁺ T cells (p=0.031), PD-L1⁺CD68⁺ macrophages (p=0.014), and decreased infiltration of stromal CD8⁺ T cells (p=0.064) than pts without liver metastases. In pts with liver metastases, responders displayed a higher stromal PD-1+ cells than nonresponders (p=0.036). Conclusions: Updated results proved that NASCA regimen presented higher clinical activity than the standard AG treatment, especially in pts with liver metastases, with a manageable safety profile. This trial is ongoing and NASCA regimen deserves further exploration in mPDAC. Clinical trial information: NCT05218889.