Abstract 648: Activity of BNT327/PM8002 (PD-L1 x VEGF-A bispecific antibody) in combination with BNT325/DB-1305 (TROP2 ADC) in solid tumors: Early preclinical and clinical evidence to support BNT327 + ADC combinations

Abstract Emerging data suggest that IO-ADC combinations may lead to better patient outcomes. BNT327 (also known as PM8002) is an investigational anti-PD-L1 x VEGF-A bispecific antibody that has shown encouraging efficacy and tolerability across tumor types, including “cold” tumors not generally responsive to IO therapies (eg, low PD-L1 levels) (Wu J, SABCS 2024 PS3-08; Wu YL, ESMO 2024 1255MO). BNT325 (also known as DB-1305) is an investigational topoisomerase-I-inhibitor-based anti-TROP2 ADC that has so far shown manageable safety and encouraging early clinical activity (Rubinstein M, SGO 2025). The combination of BNT327 with BNT325 may allow for improved efficacy without compounding overlapping toxicities. The monotherapy safety profiles are characterized by low-grade proteinuria, hypertension, and elevated transaminases (BNT327; Guo Y, ASCO 2023 #414802) and stomatitis (BNT325; Marathe O, ESMO 2023 689P). Herein we provide evidence of early preclinical and clinical data to support the novel combination of an anti-PD-L1 x VEGF-A bispecific antibody with an ADC. Preclinical in vivo models testing the combination of BNT327 with BNT325 showed superior tumor growth inhibition (TGI) compared with each treatment alone. In a xenograft A375 + PBMC co-injection model (hTROP2+A375 in B.NDG B2M KO plus mice), the combination of BNT325 (1 mg/kg Q2D*5) and BNT327 (20 mg/kg Q2D*2) had TGI of 111.3% vs. 33.6% for BNT325 or 78.2% for BNT327 alone. In a syngeneic hTROP2+MC38 model, BNT325 (20 mg/kg QW*4) combined with a surrogate BNT327 (surBNT327, anti-mPD-L1 x mVEGF) showed TGI of 106.1% and 106.9% for surBNT327 (5 mg/kg Q2D*4 and 20 mg/kg Q2D*4, respectively) vs. 51.4% for BNT325 alone or 47.6% for surBNT327 (5 mg/kg) and 71.4% for surBNT327 (20 mg/kg) alone. In the clinic, as of Nov 21, 2024, 8 patients (breast cancer n=2, ovarian cancer n=2, other n=4) have received the combination of BNT327 and BNT325 in an ongoing first-in-human phase 1/2a study of patients with advanced solid tumors (NCT05438329). No DLTs were reported in the DLT-evaluable patients (first 6 patients). Stomatitis was reported in 6/8 patients (Grade 3 in 2 patients), which led to a dose reduction of BNT325 in 3 patients. There were no adverse events leading to dose discontinuation. Tumor response analyses and biomarker testing are ongoing. Overall BNT327 plus BNT325 demonstrated superior anti-tumor effects preclinically compared to each drug alone. Early clinical data showed successful dose escalation allowing enrollment to NSCLC, TNBC, ovarian, and cervical cancer expansion cohorts, with updated clinical data planned to be presented. Further evaluation is ongoing of BNT327 with ADCs against HER2 (BNT323/DB-1303), B7H3 (BNT324/DB-1311) and HER3 (BNT326/YL202), with a focus on tumors where early monotherapy efficacy has been observed with these ADCs. Citation Format: Erika P. Hamilton, Jianqing Zhu, Wu Zhuang, Ying Cheng, Jianhua Shi, Harshad Amin, Kathleen Moore, Hua Yang, Yuping Sun, Keith A. Lerro, Kuan Sheng, Yang Qiu, Xi Li, Chenggang Li, Yi Lou, Andy Tsun, Weifeng Huang, Shaogang Peng, Ping Wang, Friederike Gieseke, Sascha Tillmanns, Darlington Akahara, Secil Koseoglu, Aurora M. Obrate, Claudia-Nanette Gann, Michael Wenger, Ilhan Celik, Özlem Türeci, Ugur Sahin. Activity of BNT327/PM8002 (PD-L1 x VEGF-A bispecific antibody) in combination with BNT325/DB-1305 (TROP2 ADC) in solid tumors: Early preclinical and clinical evidence to support BNT327 + ADC combinations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 648.