Background: PDAC has a 5-year survival rate of <5% in patients with metastatic disease. Despite established frontline therapy with gemcitabine + nab-paclitaxel (GnP), outcomes remain poor and additional therapies are urgently needed. SEA-CD40 is a receptor-agonistic, nonfucosylated IgG1 antibody directed to CD40. SEA-CD40 binding to FcγRIIIa results in enhanced effector function and CD40 agonism, allowing amplification of immune stimulation and antitumor activity. In preliminary results of a phase 1 study, SEA-CD40 + GnP + pembrolizumab (pembro) showed a tolerable safety profile and evidence of immune activation in patients (pts) with PDAC. Here, we present updated clinical results for this cohort. Methods: Pts were ≥18 years old with untreated metastatic PDAC and ECOG Performance Status of 0 or 1. Gemcitabine (1000 mg/m²) and nab-paclitaxel (125 mg/m²)were given on days 1, 8, and 15 and SEA-CD40 (10 or 30 µg/kg) was given on day 3 of each 28-day cycle. Pembro (400 mg) was given every 6 weeks starting on day 8 for up to 2 years. Results: As of August 16, 2022, 61 pts were treated with 10 µg/kg (N=40) or 30 µg/kg (N=21) SEA-CD40. Median duration of exposure was 25.1 weeks. Confirmed objective responses were observed in 19 pts (48% [95% CI 31.5, 63.9]) at 10 µg/kg and 8 pts (38% [95% CI 18.1, 61.6]) at 30 µg/kg. Median duration of response (months) was 5.7 (95% CI 3.9, 7.4) and 5.7 (95% CI 2.3, 9.2) for the 10 and 30 µg/kg dose groups, respectively. Additional efficacy results are summarized. The most common treatment-emergent adverse events (TEAEs) across dose groups were fatigue (84%), nausea (74%), and neutropenia (67%). The most common grade ≥3 TEAEs across the groups were neutropenia (61%), anemia (33%), and thrombocytopenia (20%). TEAEs leading to treatment discontinuation were reported in 10% of pts, including immune-mediated lung disease (n=3) and septic shock (n=1) in the 10 µg/kg dose group, and colitis (n=1) and portal vein thrombosis (n=1) in the 30 µg/kg dose group. Conclusions: The combination of SEA-CD40 + GnP + pembro has an acceptable safety profile and shows evidence of antitumor activity in pts with PDAC. This regimen may warrant further evaluation. Clinical trial information: NCT02376699.

CI: confidence interval; CR: complete response; NE: not evaluable; OS: overall survival; PD: progressive disease; PFS: progression-free survival; PR: partial response; SD: stable disease.