patritumab deruxtecan (U3-1402)

Basal-like PAM50 intrinsic subtype, limited prior exposure to chemotherapy and intrinsic sensitivity to the TOP1i irinotecan were associated with long-term response. Long-term responders exhibited persistent DNA damage and lacked early transcriptional activation of the G2/M cell cycle checkpoint that allow for DNA repair and RNA-DNA hybrid (R-loop) resolution, in parallel resulting in immune pathways transcriptional activation. Notably, characteristics linked to long-term response were primarily associated with the TOP1i payload activity.

P1/2, N=180, Recruiting, Merck Sharp & Dohme LLC | Trial completion date: Jul 2028 --> Dec 2028 | Trial primary completion date: Jul 2028 --> Dec 2028

HER3-DXd showed promising clinical activity in patients with metastatic breast cancer and active brain metastases, and could offer a novel therapeutic option in this setting.

HER3-DXd showed promising clinical activity in patients with advanced NSCLC and active brain metastases, and could represent a novel treatment option in this setting.

P1/2, N=81, Recruiting, Merck Sharp & Dohme LLC | Trial completion date: Sep 2029 --> Apr 2030 | Trial primary completion date: Sep 2029 --> Apr 2030

HER3-DXd has also shown preclinical antitumor efficacy in HER3-expressing cancers including cutaneous melanoma, gastric cancer, and prostate cancer, among others. The aim of this global phase II HERTHENA-PanTumor01 multicohort study is to assess the efficacy and safety of HER3-DXd in patients with relapsed or refractory locally advanced or metastatic solid tumors including melanoma, head and neck squamous cell, gastric/gastroesophageal junction, ovarian, cervical, endometrial, bladder, esophageal squamous cell, pancreatic, and prostate cancers.Clinical trial registration: NCT06172478 (ClinicalTrials.gov); 2023-507641-29-00 (EudraCT); jRCT2031230575 (Japan Registry of Clinical Trials).

P1/2, N=180, Recruiting, Merck Sharp & Dohme LLC | N=130 --> 180

P2, N=740, Recruiting, Daiichi Sankyo | N=400 --> 740 | Trial completion date: Apr 2026 --> Oct 2028 | Trial primary completion date: Jun 2025 --> Sep 2027

Overall, HER3-DXd showed promising activity and manageable tolerability in patients with HR+HER2- metastatic breast cancer who progressed on CDK4/6 inhibitors. These findings highlight the need for larger trials to define HER3-DXd efficacy relative to other drugs, including antibody-drug conjugates (ClinicalTrials.gov Identifier: NCT04965766 ).

Antibody-drug conjugate (ADC) therapies designed to target HER2 (trastuzumab-deruxtecan) or HER3 (patritumab-deruxtecan) significantly diminished prostate cancer cell growth in vitro and tumor size in vivo, despite Aspn in the TME. Collectively, these findings indicate ASPN functions as a HER3 ligand to induce cellular migration, and inhibition with anti-HER2 or anti-HER3 ADC therapies highlights potential clinical utility for patients with metastatic castration-resistant prostate cancer that expresses HER2 or HER3.

P3, N=1000, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting

It examines HER3's impact on tumor progression - like invasion and metastasis - and resistance to therapies such as trastuzumab, endocrine treatments, and chemotherapy across HER2- positive, hormone receptor-positive, and triple-negative subtypes, based on extensive literature. Clinically, it assesses HER3's prognostic role, with overexpression in 30-50% of cases, and therapeutic advances, notably antibody-drug conjugates (ADCs) like patritumab deruxtecan, promising in trials...These demand innovative solutions, such as refined diagnostics and multi-target therapies. Given its demonstrated efficacy, HER3-targeted therapies, supported by novel therapeutic combinations and bioengineering innovations, are expected to become integral to routine clinical practice in the coming years, advancing precision oncology.