A phase 1b/2 study of surufatinib plus camrelizumab, nab-paclitaxel, and S-1 (NASCA) as first-line therapy for metastatic pancreatic adenocarcinoma (mPDAC).

4142 Background: PD-1 blockade combined with anti-angiogenesis such as surufatinib (targeting VEGFR 1-3, FGFR1 and CSF1-R) might change tumor environment thus improve the efficacy in several solid tumors. A phase 1b/2 clinical study was conducted to explore the efficacy and safety of surufatinib combined with camrelizumab (PD-1 antibody), nab-paclitaxel and S-1 (NASCA) as first-line treatment compared with nab-paclitaxel and gemcitabine (AG) in mPDAC. Methods: In phase 1b, patients (pts) with mPDAC received surufatinib (200mg to 300mg, orally daily), camrelizumab (200mg, I.V., D1, Q3W), nab-paclitaxel (125mg/m 2 , 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 recommended phase 2 dose (RP2D) and overall response rate (ORR) per RECIST v1.1. Tumor tissue samples were collected at diagnosis for mIHC to evaluate tumor microenvironment. Results: Six pts were enrolled in phase 1b and RP2D was determined as surufatinib 200mg. By Jan 10, 2023, 28 pts were enrolled in phase 2 and 27 pts were evaluable for efficacy (14 in NASCA and 13 in AG). The ORR was 55.0% (11/20) (95% CI: 34.2-74.2) in NASCA and 23.1% (3/13) (95% CI: 8.2-50.3) in AG group. Pts receiving NASCA with liver metastases exhibited significant higher ORR than those without liver metastases (90.0% vs 20.0%, p=0.0017). Median progression-free survival was 8.8 months (95% CI: 5.5-12.0) in NASCA and 5.8 months (95% CI: 1.5-10.1) in AG group at the median follow-up of 8.9 months. The most frequent adverse events (AEs) of all grades in pts treated with NASCA were neutropenia (55.0%), hepatotoxicity (45.0%), neuropathy (35.0%) and diarrhea (15.0%). Immune-related AEs were observed in 4 pts (20.0%) with grade 3 hepatotoxicity. Safety was comparable in two groups except for hepatotoxicity and diarrhea. The tissue of 13 pts receiving NASCA were stained for multiple markers of immune cells. CD3 + T cells infiltrated most in the tumor core, followed by CD68 + CD163 - (M1) macrophages, and FOXP3 + T cells. Majority of immune cells and therapeutic biomarkers were expressed at higher levels in the stroma than tumor core. Pts with liver metastases displayed elevated infiltration of tumoral FOXP3 + T cells (p=0.031), PD-L1 + CD68 + macrophages (p=0.014), and decreased density of stromal CD8 + T cells (p=0.064) than pts without liver metastases. In pts with liver metastases, responders displayed a higher proportion of stromal PD-1 + cells than non-responders (p=0.036). Conclusions: Preliminary results showed 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 .