First-line treatment with chemotherapy, surufatinib (an angio-immuno kinase inhibitor), and camrelizumab (an anti-PD-1 antibody) for locally advanced or metastatic pancreatic ductal adenocarcinoma: a phase Ib/II randomized study.

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis and limited first-line treatments. This phase Ib/II randomized trial (NCT05218889) investigated the efficacy and safety of surufatinib plus camrelizumab and nab-paclitaxel/S-1 (NASCA) versus nab-paclitaxel and gemcitabine in patients with locally advanced or metastatic PDAC. The primary endpoints were dose-limiting toxicities and the recommended phase II dose (RP2D) of surufatinib in phase Ib, and the objective response rate (ORR) in phase II. Phase Ib used a 3 + 3 dose-escalation design to determine the RP2D of surufatinib in six patients, which was established at 200 mg. In phase II, patients were randomized 1:1 to receive the NASCA (45 patients) or nab-paclitaxel and gemcitabine (45 patients). NASCA group showed an ORR of 51.1% (23/45) versus 24.4% (11/45) in the nab-paclitaxel and gemcitabine group (odds ratio 3.2, 95% CI 1.3-8.2, p = 0.01). The median progression-free survival (PFS) was 7.9 vs. 5.3 months (HR 0.63, 95% CI 0.40-0.99, p = 0.045). The median overall survival was 13.0 vs. 11.0 months (HR 0.77, 95% CI 0.47-1.28, p = 0.318). The most common Grade ≥3 treatment-related adverse event was decreased neutrophil count (33.3% vs. 35.6%). In the NASCA group, enrichment of CD8 and CD8PD-1 cells, a high baseline M1/M2 macrophage ratio, and a reduction in CA19-9 levels at weeks 6 and 12 were associated with improved PFS compared to patients without these features. The NASCA regimen showed promising efficacy with tolerable safety relative to nab-paclitaxel and gemcitabine for locally advanced or metastatic PDAC.