High Responses With BNT327/PM8002 Plus Chemo in Mesothelioma

Frontline BNT327/PM8002 plus chemotherapy led to a confirmed ORR of 51.6% and a DCR of 90.3% in patients with unresectable pleural and peritoneal mesothelioma.

Initial data from a phase 2 trial (NCT05918107/CTR20221048) indicated activity and durable responses with frontline BNT327/PM8002 plus chemotherapy in patients with unresectable pleural and peritoneal mesothelioma, according to a presentation from the 2025 American Society of Clinical Oncology Annual Meeting.1

At a data cutoff of March 28, 2025, and a median follow-up of 22.3 months for patients in the total population (n = 31), the confirmed overall response rate (cORR) was 51.6% (95% CI, 33.1%-69.9%), including 1 complete response (CR), 15 partial responses (PRs), 12 instances of stable disease (SD), and 2 instances of progressive disease (PD). The disease control rate (DCR) was 90.3% (95% CI, 74.3%-98.0%). Among patients in the total population with epithelioid histology (n = 19), the cORR was 47.4% (95% CI, 24.5%-71.1%), and the DCR was 89.5% (95% CI, 66.9%-98.7%).

Among patients with pleural mesothelioma (n = 23), at a median follow-up of 24.0 months, the cORR was 43.5% (95% CI, 23.2%-65.5%), including 1 CR, 9 PRs, 10 instances of SD, and 2 instances of PD. The DCR was 87.0% (95% CI, 66.4%-97.2%). Among patients in the pleural mesothelioma population with epithelioid histology (n = 13), the cORR was 30.8% (95% CI, 9.1%-61.4%), and the DCR was 84.6% (95% CI, 54.6%-98.1%).

Among patients with peritoneal mesothelioma (n = 8), at a median follow-up of 20.3 months, the cORR was 75.0% (95% CI, 34.9%-96.8%), including 6 PRs and 12 instances of SD; no CRs or PD were reported, and the DCR was 100% (95% CI, 63.0%-100%). Among patients in this population with epithelioid histology (n = 6), the cORR was 83.3% (95% CI, 35.9%-99.6%), and the DCR was 100% (95% CI, 54.1%-100%).

“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,” presenter Liang Zhang, MD, of the Department of Thoracic Oncology at Jilin Cancer Hospital in Changchun, China, said. “This is also one of the first trials to report the results of immuno-oncology therapy in combination with chemotherapy in peritoneal mesothelioma.”

Setting the Scene for Further Development of BNT327/PM8002 in Thoracic Malignancies

Phase 3 trials have demonstrated the efficacy of immunotherapy combinations for the frontline management of malignant pleural mesothelioma. CheckMate 743 (NCT02899299) showed that ipilimumab (Yervoy) plus chemotherapy improved overall survival (OS) and progression-free survival (PFS) outcomes vs chemotherapy. KEYNOTE-483 (NCT02784171) demonstrated similar outcomes with pembrolizumab (Keytruda) plus chemotherapy vs chemotherapy alone. Additionally, the BEAT-meso trial (NCT03762018) showed a PFS improvement with atezolizumab (Tecentriq) plus bevacizumab (Avastin) and chemotherapy compared with bevacizumab plus chemotherapy alone, although no statistically significant OS difference was noted.

BNT327/PM8002 is a PD-L1/VEGF-A–directed bispecific antibody that has demonstrated early signals of clinical activity and a tolerable safety profile in patients with thoracic malignancies. For instance, a phase 2 study (NCT05844150) conducted in China showed that at a median follow-up of 14.5 months (95% CI, 13.4-15.3), among patients with previously untreated extensive-stage small cell lung cancer (n = 48), the cORR with BNT327/PM8002 plus etoposide and platinum was 85.4% (95% CI, 72.2%-93.9%).2

BNT327/PM8002 is designed to restore effector T-cell function by binding to PD-L1, as well as localize VEGF-A neutralization within the tumor microenvironment, therefore reversing the dampening of VEGF signaling on immune cell infiltration and activation, normalizing tumor vasculature, and inhibiting tumor growth.1

“Dual targeting of PD-L1 and VEGF-A is hypothesized to efficiently improve efficacy and safety,” Zhang explained.

Notably, the present phase 2 trial is the first to combine BNT327/PM8002 with platinum-based chemotherapy in the first-line setting for patients with malignant mesothelioma.

Diving into the Trial Design

The present single-arm, open-label phase 2 trial was conducted in China and enrolled patients at least 18 years of age with histologically confirmed, unresectable malignant mesothelioma. Patients needed to have a life expectancy of at least 12 weeks, adequate organ function, an ECOG performance status of 0 or 1, no prior antitumor therapy, and at least 1 measurable lesion (per mRECIST 1.1 criteria for pleural mesothelioma and RECIST 1.1 criteria for peritoneal mesothelioma).

A total of 31 patients were enrolled and received BNT327/PM8002 at 30 mg/kg plus pemetrexed at 500 mg/m2 and platinum chemotherapy intravenously (IV) every 3 weeks for 4 to 6 cycles, followed by maintenance BNT327/PM8002 at 30 mg/kg IV every 3 weeks until disease progression or unacceptable toxicity.

The coprimary end points were ORR (per mRECIST 1.1 criteria for pleural mesothelioma and RECIST 1.1 criteria for peritoneal mesothelioma) and treatment-related adverse effects (TRAEs). Secondary end points included PFS, DCR, and duration of response (DOR; all per mRECIST 1.1 criteria for pleural mesothelioma and RECIST 1.1 criteria for peritoneal mesothelioma); and OS.

Zooming in on Patient Baseline Characteristics

In the total population, patients had a median age of 58.0 years (range, 43-71), most patients were male (51.6%), and most patients had an ECOG performance status of 1 (80.6%). Clinical stage II, III, and IV disease was reported in 6.5%, 48.4%, and 45.2% of patients, respectively. Epithelioid histology status was unknown for 22.6% of patients. In total, 16.1%, 58.1%, and 25.8% of patients had 0, 1 to 2, and 3 or more metastatic sites, respectively. Metastases were present in the liver (6.5%) and lung (22.6%); no baseline brain metastases were reported. Additionally, 25.8% of patients were smokers.

Zhang noted that the baseline characteristics were consistent between the pleural and peritoneal mesothelioma subgroups.

Highlighting Additional Efficacy Findings

In the total population, the median DOR was 15.2 months (95% CI, 5.8-17.8). In patients with pleural and peritoneal mesothelioma, the respective median DORs were 11.8 months (95% CI, 5.6-17.8) and 16.3 months (95% CI, 4.8-not calculated [NC]).

In the total population, the median PFS was 16.6 months (95% CI, 8.6-19.3), the 15-month PFS rate was 57.7% (95% CI, 37.6%-73.4%), and the median PFS among patients with epithelioid histology was 16.6 months (95% CI, 7.7-19.5). In the pleural mesothelioma population, the median PFS was 15.8 months (95% CI, 8.3-17.3), the 15-month PFS rate was 50.3% (95% CI, 28.5%-68.7%), and the median PFS among patients with epithelioid histology was 15.8 months (95% CI, 5.5-19.3). In peritoneal mesothelioma population, the median PFS was not yet mature, the 15-month PFS rate was 83.3% (95% CI, 27.3%-97.5%), and the median PFS among patients with epithelioid histology was 19.5 months (95% CI, 7.7-NC).

Median OS data were not yet mature for any population. In the overall, pleural mesothelioma, and peritoneal mesothelioma populations, the respective 15-month OS rates were 77.4% (95% CI, 58.4%-88.5%), 82.6% (95% CI, 60.1%-93.1%), and 62.5% (95% CI, 22.9%-86.1%).

Noting Safety Data in the Total Population

All patients experienced treatment-emergent AEs (TEAEs) and TRAEs. The rates of grade 3/4 TEAEs and TRAEs were both 93.5%. Notably, no grade 5 TEAEs or TRAEs were reported.

Any-cause serious AEs occurred in 45.2% of patients at any grade and 29.0% of patients at grade 3/4. Serious TRAEs occurred in 32.3% of patients at any grade and 16.1% of patients at grade 3/4.

Any-cause TEAEs led to dose interruption, discontinuation, or reduction in 71.0%, 19.4%, and 22.6% of patients, respectively. Treatment-related TEAEs led to these respective outcomes in 48.4%, 19.4%, and 19.4% of patients.

In the total population, the median treatment exposure was 15.9 months (95% CI, 8.1-18.4), and 5 patients remained on treatment at the data cutoff. In the pleural and peritoneal mesothelioma populations, the respective median treatment exposures were 13.6 months (95% CI, 8.1-17.2) and 19.6 months (95% CI, 0.8-NC).

The most common TRAEs were decreased neutrophil counts (any-grade, 87.1%; grade 3, 32.3%), decreased white blood cell counts (83.9%; 16.1%; 3.2%), proteinuria (77.4%; 12.9%; 0%), anemia (74.2%; 9.7%; 0%), decreased platelet count (61.3%; 12.9%; 3.2%), nausea (51.6%; 0%; 0%), increased alanine aminotransferase levels (45.2%; 6.5%; 0%), increased aspartate aminotransferase levels (45.2%; 6.5%; 0%), decreased appetite (38.7%; 3.2%; 0%), hypoalbuminemia (35.5%; 0%; 0%), increased gamma-glutamyltransferase levels (32.3%; 6.5%; 0%), decreased lymphocyte counts (32.3%; 6.5%; 0%), rash (29.0%; 0%; 0%), increased blood creatinine levels (25.8%; 0%; 0%), hypertension (25.8%; 19.4%; 0%), asthenia (22.6%; 0%; 0%), and decreased weight (22.6%; 0%; 0%).

TRAEs of special interest other than proteinuria and hypertension were all grade 1/2 and included epistaxis, hematochezia, lower gastrointestinal hemorrhage, hemoptysis, and hematuria (3.2% each). Notably, 1 patient experienced dermatitis as a grade 3 immune-related AE.

Looking Toward the Future

Zhang noted that these findings should be interpreted within the context of the study’s limitations, including its small sample size, small subgroup sizes, single-arm design, and the fact that it was conducted 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.”

Disclosures: Zhang had no relationships to disclose.

References

1. Cheng Y, Lu L, Zhuang W, et al. First report of efficacy and safety results from a phase 2 trial evaluating BNT327/PM8002 plus chemotherapy (chemo) as first-line treatment (1L) in unresectable malignant mesothelioma. J Clin Oncol. 2025;43(suppl_16):8511. doi:10.1200/JCO.2025.43.16_suppl.8511
2. Cheng Y, Shi J, Meng X, et al. Phase II study of the efficacy and safety of BNT327/PM8002 plus systemic chemotherapy as first-line therapy for extensive-stage small-cell lung cancer (ES-SCLC). J Thorac Oncol. 2025;20(suppl 3):S185. doi:10.1016/S1556-0864(25)00494-0