A novel bispecific antibody targeting both PD-L1 and VEGF-A pathways has demonstrated encouraging clinical activity in patients with unresectable mesothelioma, according to initial data from a phase 2 trial presented at the 2025 American Society of Clinical Oncology Annual Meeting. The combination of BNT327/PM8002 with standard chemotherapy achieved durable responses across both pleural and peritoneal mesothelioma subtypes.
Strong Response Rates Across Mesothelioma Subtypes
At a median follow-up of 22.3 months, the 31 patients enrolled in the single-arm trial achieved a confirmed overall response rate (cORR) of 51.6% (95% CI, 33.1%-69.9%), including one complete response and 15 partial responses. The disease control rate reached 90.3% (95% CI, 74.3%-98.0%), with 12 patients achieving stable disease and only two experiencing progressive disease.
"In the context of phase 3 trials with the current standard of care in this indication, our efficacy results in patients with pleural mesothelioma looked particularly encouraging," said presenter Liang Zhang, MD, of the Department of Thoracic Oncology at Jilin Cancer Hospital in Changchun, China. "This is also one of the first trials to report the results of immuno-oncology therapy in combination with chemotherapy in peritoneal mesothelioma."
The results varied notably between mesothelioma subtypes. Among 23 patients with pleural mesothelioma, the cORR was 43.5% (95% CI, 23.2%-65.5%) with a disease control rate of 87.0%. However, patients with peritoneal mesothelioma demonstrated particularly robust responses, with 6 of 8 patients (75%) achieving partial responses and all patients maintaining disease control (100% DCR).
Dual Mechanism of Action Shows Promise
BNT327/PM8002 represents a novel approach to cancer immunotherapy through its bispecific design targeting both PD-L1 and VEGF-A pathways. The antibody is designed to restore effector T-cell function by binding to PD-L1 while simultaneously localizing VEGF-A neutralization within the tumor microenvironment. This dual mechanism aims to reverse the dampening effects of VEGF signaling on immune cell infiltration and activation while normalizing tumor vasculature.
"Dual targeting of PD-L1 and VEGF-A is hypothesized to efficiently improve efficacy and safety," Zhang explained. The current trial represents the first combination of BNT327/PM8002 with platinum-based chemotherapy in the first-line setting for malignant mesothelioma patients.
Durable Clinical Benefit Observed
The median duration of response across all patients was 15.2 months (95% CI, 5.8-17.8), with patients achieving median progression-free survival of 16.6 months (95% CI, 8.6-19.3). The 15-month progression-free survival rate was 57.7% (95% CI, 37.6%-73.4%).
Peritoneal mesothelioma patients showed particularly durable benefit, with median progression-free survival not yet reached and a 15-month PFS rate of 83.3%. In contrast, pleural mesothelioma patients achieved a median PFS of 15.8 months with a 15-month rate of 50.3%.
Overall survival data remained immature at the time of analysis, though 15-month survival rates were encouraging at 77.4% overall, 82.6% for pleural mesothelioma, and 62.5% for peritoneal mesothelioma patients.
Treatment Protocol and Patient Population
The trial enrolled patients with histologically confirmed, unresectable malignant mesothelioma who had not received prior antitumor therapy. Patients received BNT327/PM8002 at 30 mg/kg plus pemetrexed at 500 mg/m² and platinum chemotherapy intravenously every 3 weeks for 4 to 6 cycles, followed by maintenance BNT327/PM8002 every 3 weeks until disease progression or unacceptable toxicity.
The patient population had a median age of 58 years, with 51.6% male patients and 80.6% having an ECOG performance status of 1. Most patients (93.6%) had advanced disease, with 48.4% having stage III and 45.2% having stage IV disease at enrollment.
Safety Profile Shows Manageable Toxicity
All patients experienced treatment-related adverse events, with 93.5% experiencing grade 3/4 toxicities. However, no treatment-related deaths occurred during the study period. The most common treatment-related adverse events included decreased neutrophil counts (87.1% any grade, 32.3% grade 3), decreased white blood cell counts (83.9%), proteinuria (77.4%), and anemia (74.2%).
Treatment-related adverse events led to dose interruption in 48.4% of patients, discontinuation in 19.4%, and dose reduction in 19.4%. The median treatment exposure was 15.9 months, with five patients remaining on treatment at the data cutoff.
Clinical Context and Future Directions
The results build upon established efficacy of immunotherapy combinations in mesothelioma. Previous phase 3 trials including CheckMate 743 with ipilimumab plus chemotherapy and KEYNOTE-483 with pembrolizumab plus chemotherapy have demonstrated improved outcomes compared to chemotherapy alone in pleural mesothelioma.
BNT327/PM8002 has previously shown activity in other thoracic malignancies, with a phase 2 study in extensive-stage small cell lung cancer achieving an 85.4% response rate when combined with etoposide and platinum chemotherapy.
Zhang acknowledged the study's limitations, including its small sample size, single-arm design, and conduct in a Chinese-only population. "Nevertheless, the results presented are scientifically meaningful despite the small sample size," Zhang explained. "BNT327/PM8002 plus chemotherapy should be tested in a larger and broader group of patients with malignant mesothelioma."
