Abstract 1388: Ex vivo micro-tumor testing platform to guide patient stratification for clinical development of ADCs.

Abstract Background Antibody-Drug Conjugates (ADCs) are revolutionizing cancer therapy. Yet, more than 90% fail to reach approval and ADC efficacy often poorly correlates with target expression, emphasizing the high need for improved prediction of patient responses to ADCs. Ex vivo micro-tumor testing enables near-clinical evaluation across drug classes, including ADCs, and has been shown to predict clinical responses to platinum therapy (Koedoot et al., npj Precision Oncology, 2025). This study evaluates ex vivo sensitivity to clinically relevant ADCs in ovarian (OC), non-small cell lung (NSCLC), and colorectal (CRC) cancer, aiming to identify predictive biomarkers and guide patient stratification to optimize clinical benefit. Materials and Methods Ex vivo evaluation of patient specific responses to ADCs was performed by testing mirvetuximab-soravtansine (MIRV) in OC patient samples (N=25), ifinatamab deruxtecan (IFI) in CRC patient samples (N=5) and telisotuzumab vedotin (TEL) in NSCLC patient samples (N=10). Tumor tissue was processed within 48 hours. Enriched patient micro-tumors with preserved tumor microenvironment (TME) were embedded in hydrogel and exposed to standard of care therapy, ADCs and their respective payloads. Screening plates were fixed, stained and imaged, followed by high-dimensional image analysis and phenotypical feature extraction. Drug sensitivity profiles were established based on anti-tumor activity. Target protein expression profiling was performed by immunofluorescence staining of ex vivo micro-tumors. Results Ex vivo testing of OC, NSCLC and CRC patient samples revealed patient-specific sensitivity to the respective ADCs. For MIRV, 32% (8/25) of the OC patients demonstrated strong sensitivity (Emax < 50%), 48% (12/25) of the patients demonstrated intermediate sensitivity (Emax 50-90%) and 20% of the patients (5/25) demonstrated complete MIRV resistance (Emax > 90%). Reproducible responses were observed for different drainages from the same patient (N=3). A strong correlation was observed between MIRV and paclitaxel sensitivity (R = 0.86), both of which target tubulin. A reduced correlation was observed for MIRV and carboplatin (R = 0.59), that acts by crosslinking DNA. Target protein expression profiling revealed inter- and intra-tumor heterogeneity. Some patients exhibited low target protein expression in all micro-tumors, while others exhibited high expression in a fraction of micro-tumors. Conclusions This study reports an ex vivo micro-tumor testing platform that enables near clinical assessment of patient responses to ADCs. The platform is future-ready, offering multimodal capabilities including tumor microenvironment (TME) characterization, target protein profiling capturing patient heterogeneity, and assessment of bystander and synergistic responses. The next step is to correlate the ex vivo sensitivity to actual clinical outcome. Citation Format: Esmee Koedoot, Felix M. Behr, Timothy JP Sijsenaar, Dieudonné J. van der Meer, Léa Le Large, Farbod Khoraminia, Nelleke Ottevanger, Judith R. Kroep, Cor D. de Kroon, Willemijn Vader. Ex vivo micro-tumor testing platform to guide patient stratification for clinical development of ADCs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1388.