Integrated penpulimab (a PD-1 inhibitor), anlotinib (an antiangiogenic targeted drug), nab-paclitaxel and gemcitabine as first-line regimen for metastatic pancreatic cancer: A multi-centered, randomized controlled trial (RCT-PAAG).

655 Background: Metastatic pancreatic cancer (mPC) remains one of the deadliest advanced malignant tumors, which features high level of chemotherapy resistance and poor prognosis. A modest number of recent studies have demonstrated the potentially improved efficacy of integrated regimen on pancreatic cancer that involves chemotherapy, immunotherapy and antiangiogenic targeted therapy, yet these findings remain to be evidenced by prospective randomized controlled trials. Methods: This is an open-labelled, multi-centered, randomized controlled trial. Patients with treatment-naïve mPC who signed informed consent were enrolled in this study and were randomly assigned into experimental group (PAAG, Receiving Nab-Paclitaxel 125mg/m 2 d1,8 + Gemcitabine 1.6g/m 2 d1,8 + Penpulimab 200mg d1 + Anlotinib 12mg d1-14, q21d per cycle) or controlled group (AG, Receiving Nab-Paclitaxel 125mg/m 2 d1,8 + Gemcitabine 1.6g/m 2 d1,8, q21d per cycle) at a ratio of 2:1. Exact doses were adjustable on this basis according to individual tolerance. Imaging follow-ups were performed every two cycles for efficacy evaluation. Patients who finished 8 cycles without progression would then enter maintenance therapy. The primary endpoint of this study was progression-free survival (PFS), while other endpoints included overall survival (OS), objective response rate (ORR), disease-controlled rate (DCR), safety and exploratory efficacy-monitoring biomarkers. Results: From August 2023 to June 2025, a total number of 155 patients (103 in PAAG, 52 in AG) were included in Intention-To-Treatment (ITT) set, of whom 94 in PAAG and 49 in AG had at least once imaging-based efficacy evaluation. The mPFS of PAAG and AG was 7.7 months [95%CI: 6.7 ~ 8.7] and 4.5 months [95%CI: 3.3 ~ 5.8], respectively, which demonstrated a significant statistical difference ( P < 0.001). Neither group has reached the endpoint of mOS. Patients from PAAG had a statistically improved ORR (47.87% vs 28.57%, P = 0.026) and DCR (92.55% vs 67.35%, P < 0.001) than those from AG. Nearly all patients (93.20% in PAAG, 94.23% in AG, P = 1) underwent once or more treatment-related adverse events (AEs). Rates of Grade 3 or higher AEs in PAAG (41.75%) and AG (38.46%) were comparable ( P = 0.694), with leukocytopenia being the most common in both groups. No Grade 5 AE was observed. Conclusions: The integrated regimen involving Penpulimab, Anlotinib, Nab-Paclitaxel and Gemcitabine appears to be a more preferable choice than Gemcitabine-based chemotherapy alone for the first-line treatment of mPC on account of its improved efficacy and acceptable safety. Future follow-up is warranted in confirmation of its impact on OS. Clinical trial information: NCT06051851 .