First-line treatment with surufatinib, camrelizumab, nab-paclitaxel, and S-1 in locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC): A phase Ib/II randomized study.

4161 Background: PDAC is a highly aggressive cancer with limited treatment options. Previous reports of NCT05218889 showed promising efficacy of nab-Paclitaxel/S-1/Surufatinib/Camrelizumab (anti-PD-1 antibody) combination regimen (NASCA) in mPDAC (2023 ASCO abs# 4142; 2024 ASCO GI abs# 671). Here, we present the updated results. Methods: In phase Ib, a 3+3 dose escalation design was used to determine the RP2D of surufatinib. In phase II, patients were randomized 1:1 to receive the NASCA regimen or nab-paclitaxel plus gemcitabine (AG). The NASCA regimen was administered in 3-week cycles for up to 8 cycles. Patients without disease progression continued treatment with surufatinib, S-1, and camrelizumab, while the control group received AG regimen , q3w. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, or death. The primary endpoints were DLTs and the RP2D of surufatinib in phase Ib, and the ORR in phase II. Results: As of Dec 16, 2024, 96 patients were enrolled in the study (6 in phase Ib, 90 in Phase II). In phase Ib, the RP2D for surufatinib was determined to be 200 mg (1 DLT out of 6 patients). In phase II, 45 patients were assigned to each group. Baseline characteristics were balanced between the groups. Most patients had metastatic disease (82.2% in NASCA vs 77.8% in AG). The NASCA group showed a confirmed ORR of 51.1% (23/45) versus 24.4% (11/45) in the AG group (OR: 3.2, 95% CI 1.3-8.2; p = 0.01). The median PFS were 7.9 and 5.4 months (HR: 0.63, 95% CI 0.40-0.99, p = 0.046), with 12-month OS rates of 55.5% (95% CI 39.4-68.9) in NASCA group and 52.7% (95% CI 36.6-66.5) in AG group. In the subgroup analysis of PFS, the NASCA group showed longer PFS in male patients (HR: 0.56, 95% CI 0.31-1.01), those with metastatic disease (HR: 0.57, 95% CI 0.35-0.94), and patients without liver metastasis (HR: 0.45, 95% CI 0.23-0.90). Furthermore, multiplex immunohistochemistry was performed on baseline tissue samples of 26 NASCA patients. The ratio of M1/M2 macrophage percentages was significantly higher in patients with PR than those with SD and PD (p = 0.04). Using the median as a cutoff, patients with higher levels of M1/M2 cells (p = 0.039), CD8 + cells (p = 0.0024), and CD8 + PD-1 + cells (p = 0.0064) in the stroma had longer PFS than those with lower levels. For Grade 3 and 4 TEAEs, the most frequently observed events in the NASCA group were decreased white blood cell count (31.1%), decreased neutrophil count (33.3%), and decreased lymphocyte count (20.0%). Similarly, these events were common in the AG group (26.7%, 28.9%, 8.9%, respectively). Conclusions: The NASCA regimen demonstrated promising efficacy with a manageable safety profile, showing a significantly higher ORR and longer PFS compared to AG group in patients with locally advanced or metastatic PDAC. Further studies are warranted to confirm these findings. Clinical trial information: NCT05218889 .