SEA-CD40 Combo Shows Antitumor Activity in Pancreatic Cancer
核心洞察
The combination of SEA-CD40 with gemcitabine, nab-paclitaxel, and pembrolizumab demonstrated a 44% objective response rate in metastatic pancreatic ductal adenocarcinoma (搜索) (PDAC).
The study showed comparable response rates at SEA-CD40 doses of 10 µg/kg (48% ORR) and 30 µg/kg (38% ORR), indicating potential efficacy across different dose levels.
The median duration of response was 5.7 months in both the 10 µg/kg and 30 µg/kg cohorts, with a median overall survival of 13.8 months for the combined cohorts.
The combination of SEA-CD40, gemcitabine, nab-paclitaxel, and pembrolizumab has shown promising early efficacy in patients with metastatic pancreatic ductal adenocarcinoma (搜索) (PDAC). Updated results from the phase 1 SGNS40-001 study, presented at the 2023 Gastrointestinal Cancers Symposium, indicate a total confirmed objective response rate (ORR) of 44% in patients treated with the combination.
The SGNS40-001 trial is an ongoing, single-arm study evaluating SEA-CD40 alone and in combination with gemcitabine, nab-paclitaxel, and pembrolizumab in patients with PDAC. The study enrolled 61 patients, with 40 receiving SEA-CD40 at 10 µg/kg and 21 receiving it at 30 µg/kg, the recommended phase 2 dose.
Efficacy Data
The confirmed ORR was 48% (95% CI, 31.5%-63.9%) in patients who received SEA-CD40 at 10 µg/kg and 38% (95% CI, 18.1%-61.6%) in those who received it at 30 µg/kg. One patient from the 10 µg/kg cohort achieved a complete response. The median duration of response (DOR) was 5.7 months (95% CI, 3.9-7.4) and 5.7 months (95% CI, 2.3-9.2) in the 10 µg/kg and 30 µg/kg cohorts, respectively.
At a median follow-up of 6.9 months, the median progression-free survival (PFS) for both cohorts combined was 7.4 months (95% CI, 5.6-9.0). The median overall survival (OS) for both cohorts combined was 13.8 months (95% CI, 7.8-16.2), with a median follow-up of 11.9 months.
Mechanism of Action
SEA-CD40 is a nonfucosylated, receptor-agnostic, humanized IgG1 CD40 (搜索)-directed monoclonal antibody. It binds with increased affinity to FcγRIIIa, enhancing effector function and CD40 agonism. This mechanism potentially allows for PD-1 pathway blockade and immune stimulation amplification. Preclinical models suggest that a CD40 agonist combined with chemotherapy may produce durable antitumor activity.
Safety Profile
Infusion-related reactions were the most common SEA-CD40–related adverse events (AEs), with grade 1-2 reactions occurring in 56% of patients and grade ≥3 reactions in 8%. Other treatment-related AEs included fatigue, nausea, neutropenia, chills, pyrexia, and diarrhea. The 10 µg/kg cohort trended toward greater tolerability.
Adverse events leading to treatment discontinuation included immune-mediated lung disease (8%) and septic shock (3%) with SEA-CD40 at 10 µg/kg, and colitis (5%) and portal vein thrombosis (5%) with SEA-CD40 at 30 µg/kg.
Investigator Comments
According to Andrew L. Coveler, MD, of Fred Hutchinson Cancer Center and the University of Washington School of Medicine, "Patients with pancreas cancer need more and better treatments. The combination of SEA-CD40, pembrolizumab, gemcitabine, and nab-paclitaxel compared favorably with historical controls, demonstrating that immunotherapy may one day be a treatment for patients with pancreas cancer."
The study authors concluded that SEA-CD40 in combination with gemcitabine, nab-paclitaxel, and pembrolizumab has an acceptable safety profile, with evidence of immune activation consistent with the proposed SEA-CD40 mechanism of action.