P2, N=56, Not yet recruiting, BioRay Pharmaceutical Co., Ltd.

P1, N=164, Recruiting, BioRay Pharmaceutical Co., Ltd. | Not yet recruiting --> Recruiting

Ladiratuzumab vedotin (SGN-LIV1A), a LIV-1 targeting ADC with payload of monomethyl auristatin E, has been discontinued from clinical development...Here, we demonstrated a novel LIV-1 directed ADC, SDP-LIV1, consisting of an in-house developed anti-LIV-1 antibody conjugated to a proprietary topoisomerase I inhibitor via a cleavable GGFG (glycine-glycine-phenylalanine-glycine) linker, with an optimized average drug-to-antibody ratio of 6. Preclinical studies revealed that SDP-LIV1 showed promising in vitro and in vivo efficacy in breast and gastric cancers with favorable preclinical pharmacokinetics and safety profiles, suggesting that SDP-LIV1 has great potential for the clinical treatment of patients with solid tumor expressing LIV-1.

Antibody-drug conjugates (ADCs) have emerged as a leading therapeutic strategy: sacituzumab govitecan extended mPFS to 5.6 months (ASCENT trial), SKB264 to 6.7 months, and datopotamab deruxtecan achieved an ORR of 79%. In Human epidermal growth factor receptor 2 (HER2)-low TNBC, trastuzumab deruxtecan prolonged OS to 18.2 months, while disitamab vedotin and SHR-A1811 achieved ORRs of 26% and 60%, respectively...Bispecific ADCs, linker optimization, and combination regimens (ICI, PARPi) are under investigation. Future efforts will focus on targeting epidermal growth factor receptor (EGFR) and FRα and on developing multimodal immunovascular strategies to sustain clinical benefit.

This study has identified SLC39A6 as a potential therapeutic target in CRC. BRY812 is expected to become a highly promising therapeutic drug, bringing new hope to patients with CRC.

The mechanism of action of the IMC involves tumor recognition via surface antigens and Fcγ-mediated phagocytosis, followed by activation of myeloid cells to efficiently present tumor antigens to T-cells, thereby eliciting antitumor immunity. The designed IMCs demonstrate the ability to activate myeloid cells in the presence of tumor cells, display robust antitumor activity, and are well tolerated in toxicology studies.

P1/2, N=186, Completed, Seagen Inc. | Active, not recruiting --> Completed | Trial completion date: Jan 2026 --> Sep 2024 | Trial primary completion date: Jan 2026 --> Sep 2024

This narrative review explores key predictive factors influencing the efficacy of ADCs, focusing on HER2-targeted therapies, such as trastuzumab emtansine and trastuzumab deruxtecan, as well as sacituzumab govitecan for triple-negative breast cancer. Finally, future perspectives on the sequential use of ADCs and potential combination therapies are highlighted, along with emerging agents targeting alternative antigens like HER3 and LIV-1. Overall, identifying predictive biomarkers and overcoming resistance mechanisms are essential for optimizing the use of ADCs in metastatic breast cancer, thereby improving patient outcomes.

P1/2, N=186, Active, not recruiting, Seagen Inc. | Trial completion date: Dec 2024 --> Jan 2026 | Trial primary completion date: Mar 2024 --> Jan 2026

P=N/A, N=0, Available, Seagen Inc.

Recently, in the United States of America, FDA approved the use of a new drug targeting LIV1, antibody drug conjugate SGN-LIV1A for treatment of TNBC patients...Finally, TNBC patients with 3+ staining intensity showed poor survival (4.44 year) as compared to patients with 2+ LIV1 expression (5.47 year), emphasizing that LIV1 expression is a poor prognostic factor in TNBC. In conclusion, the study reports elevated expression of LIV1 in a large Indian TNBC cohort; high expression is a poor prognostic factor and correlated with aggressive disease and indicating the need for LIV1 targeted therapies.

This article reviews recent advances in the application of ADCs in the treatment of HER2-low breast cancer. Additionally, this review explores the underlying factors contributing to the impact of target selection on ADC efficacy to provide new insights for optimizing the clinical application of ADCs in individuals with low HER2 expression in advanced breast cancer.