What question did this study set out to answer?

The study aims to assess the efficacy and safety of STRO-004, a targeted ADC, in solid tumors expressing tissue factor.

April 5, 2026

Abstract 4446: STRO-004, an exatecan-based next-generation tissue factor (TF)-targeted ADC, demonstrates superior efficacy across TF-expressing solid tumors in a comprehensive single-mouse PDX trial

Key Points

The study aims to assess the efficacy and safety of STRO-004, a targeted ADC, in solid tumors expressing tissue factor.
Conducted a single-mouse PDX trial with multiple solid tumor models, including HNSCC, NSCLC, PDAC, and CRC.
Mice received vehicle, STRO-004, or benchmark ADCs at a 5 mg/kg dose.
Evaluated tumor growth inhibition, overall response, and biomarker-response relationships.
Included safety assessments in non-human primates.
STRO-004 showed superior anti-tumor activity across all tested tumor types compared to benchmark ADCs.
Achieved complete responses in multiple models with significant sustained tumor regression in HNSCC.
In NSCLC, activity surpassed or was comparable to benchmark ADCs across histologies.
Biomarker analysis indicated broad anti-tumor activity, while some models exhibited target-independent resistance.
Reduced cytotoxicity was noted towards corneal and skin cells compared to approved ADCs.

Abstract

Abstract Tissue Factor (TF) is aberrantly expressed in multiple solid tumors, including cervical cancer, head and neck squamous cell carcinoma (HNSCC), non–small cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC), and colorectal cancer (CRC), and is associated with poor clinical outcomes. Although TF-targeted antibody–drug conjugates (ADCs) such as tisotumab vedotin have demonstrated clinical activity, their utility is limited by on-target/off-tumor and systemic, platform toxicities associated with premature payload release. This study evaluated the preclinical efficacy and safety of STRO-004, a novel site-specific DAR8 β-glucuronidase–exatecan ADC engineered for enhanced stability, reduced off-target toxicity, and an expanded therapeutic index compared with first-generation TF-directed ADCs.Anti-tumor activity was assessed in a single-mouse PDX (patient-derived xenograft) trial comprising diverse solid tumor indications (HNSCC, NSCLC, PDAC, and CRC; up to n=20 models each). Mice were randomized to receive vehicle, STRO-004, or benchmark approved ADCs administered as a single 5 mg/kg dose, which is considered clinically relevant. Tumor growth inhibition, best overall response (BOR), and biomarker-response relationships were evaluated. In interim analysis, STRO-004 demonstrated superior anti-tumor activity across all tumor types tested, with complete responses (CR) observed in multiple models. In HNSCC, STRO-004 produced sustained tumor regression in 50% more models vs. benchmark at the same 5 mg/kg dose, confirming enhanced potency at therapeutically translatable exposures. In NSCLC, activity was greater than or comparable to benchmark, with responses in both non-squamous and squamous histologies. STRO-004 also induced robust tumor regression in PDAC and CRC. Biomarker analysis in HNSCC revealed anti-tumor activity across a broad TF-expression range, while limited responses in some TF-high models suggest target-independent resistance mechanisms. In vitro, STRO-004 exhibited reduced cytotoxicity toward corneal and skin epithelial cells relative to approved TF ADC. It was well tolerated in NHPs up to 50 mg/kg, with no ocular or hematologic toxicity and approximately 15-fold higher Cmax and 50-fold greater AUC than first-generation TF ADCs.These data demonstrate that STRO-004 achieves broad, durable responses at clinically relevant dosing, with an improved safety profile and therapeutic index compared with approved TF ADC. Because the single-mouse PDX trial design better reflects patient diversity in human trials, these results provide strong support for STRO-004 as a potential best-in-class TF-targeted ADC. The first-in-human Phase 1 study of STRO-004 is ongoing in solid tumor indications that are expected to have high TF expression or prevalence (NCT07227168). Citation Format: Genevive Hernandez, Kshama A. Doshi, Mark Armanini, Helena Kiefel, Sihong Zhou, Brian Vuillemenot, Guifen Xu, Xiaofan Li, Werner Rubas, Gang Yin, Hanspeter Gerber, Alice Yam. STRO-004, an exatecan-based next-generation tissue factor (TF)-targeted ADC, demonstrates superior efficacy across TF-expressing solid tumors in a comprehensive single-mouse PDX trial 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 4446.

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