Abstract A134: TROP-2-Targeted ADC DB-1305/BNT325 Demonstrates Preclinical Efficacy and Early Clinical Activity in Patients with Diffuse Pleural Mesothelioma

Abstract Background: Diffuse pleural mesothelioma (DPM) remains challenging to treat, with a median survival of ∼18 months and no standard-of-care for second-line treatment or targeted therapies exists. High fidelity patient-derived xenografts (PDXs) (Offin et al. 2022), have shown that TROP-2 is expressed in ∼80% of tumors, especially in the epithelioid subtype, indicating aggressive tumor biology. However, TROP2-targeted therapies are still investigational in patients with DPM. DB-1305/BNT325, an investigational anti-TROP-2 antibody-drug conjugate (ADC) with a topoisomerase-I inhibitor, has shown manageable safety and promising early clinical activity (Rubinstein M, SGO 2025; Hamilton E, AACR 2025). Here, we present its preclinical and clinical potential for DPM. Methods: Preclinical: Using established DPM PDX models (MSK_LX13, MSK_LX_333, and MSK_LX606), all of which had at least one systemic therapy prior to PDX creation, we performed in vivo activity assessments of DB-1305 in comparison with gemcitabine (standard of care) or irinotecan (payload analog) at varying doses/schedules. Clinical: In the ongoing Phase 1/2a trial (NCT05438329), patients with advanced/metastatic DPM were treated with DB-1305 and anti-tumor activity (RECIST v1.1) as well as safety was assessed. Results: Preclinical: Treatment with DB-1305 led to tumor growth suppression in all three DPM PDXs. Under optimized dose regimens, DB-1305 induced complete tumor growth inhibition [TGI] for all three PDX models. DB-1305 treatment had improved TGI than gemcitabine or irinotecan treatment. Clinical: As of May 16, 2025, 7 patients with DPM had been treated with DB-1305 in Phase 2a, with a median of 8 treatment cycles. Median age was 74 years, and 72% had ECOG 1. Histologic subtypes included epithelioid (n=1), biphasic (n=2), and not otherwise specified (n=5). All had received prior immunotherapy, with a median of 2 prior treatment lines (range: 1, 4) prior to trial enrollment. Among the 6 efficacy-evaluable patients, one complete response (biphasic histologic subtype; ongoing for 7.1 months, still on treatment) and five stable disease cases (two with duration > 6 months; median duration of 5.5 months) were observed, achieving a disease control rate of 100% (95% CI: 54%, 100%). The median progression-free survival was 6.9 months (95% CI: 4.47, NE). The most common treatment-related adverse event (TRAE) was stomatitis (57.1%, predominantly Grade 1-2), while other TRAEs were each reported in only one patient. Conclusion: DB-1305 demonstrated robust and reproducible antitumor activity in PDX models and clinically meaningful efficacy in heavily treated advanced/metastatic DPM, including a complete response in a patient with biphasic DPM. The safety profile was consistent with prior reports of DB-1305 in other tumor types, supporting further development in mesothelioma. Citation Format: Michael Offin, Esther Redin Resano, Alvaro Q Villalonga, Charles M Rudin, Elisa Destanchina, Dennis Kinyua, Erika Hamilton, Aaron Lisberg, Nashat Gabrail, Alexander Spira, Melissa Johnson, Yang Qiu, Rick Chu, Zhongyuan Zhu, Xiaodong Sun, Zhongwei Jia, Bin Zhang, Hua Mu. TROP-2-Targeted ADC DB-1305/BNT325 Demonstrates Preclinical Efficacy and Early Clinical Activity in Patients with Diffuse Pleural Mesothelioma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A134.