Kadcyla (ado-trastuzumab emtansine)

Combining palbociclib, trastuzumab, and ET was safe and improved significantly PFS, compared to TPC in previously treated HER2-positive, PAM50 luminal A/B ABC patients.

P2, N=56, Recruiting, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

P1/2, N=210, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Oct 2026 --> Jul 2026 | Trial primary completion date: Oct 2025 --> Jul 2026

P=N/A, N=50, Active, not recruiting, Nagoya City University | Enrolling by invitation --> Active, not recruiting

Neoadjuvant regimens included doxorubicin plus cyclophosphamide followed by trastuzumab-paclitaxel, doxorubicin plus cyclophosphamide with pertuzumab-trastuzumab-docetaxel, or docetaxel-carboplatin-trastuzumab-pertuzumab. Baseline characteristics varied across regimens, reflecting real-world treatment preferences, but survival outcomes remained comparable. Adjuvant T-DM1 was associated with high survival rates and manageable toxicity across different neoadjuvant regimens, underscoring its consistent benefit in routine clinical practice.

However, recent research has led to the development of antibody-drug conjugates (ADCs), such as trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), with the latter showing promising results in treating these patients. In this context, the interplay between miRNAs and HER2-targeted therapies, particularly their modulation of common essential genes and signaling pathways, could reshape HER2-low therapy strategies to transform current practices aimed at improving the overall patient outcomes. Therefore, this review aims to elucidate the mechanisms underlying current HER2-targeted therapy and explore a potential crosstalk with miRNAs, ultimately serving as a guide for the development of personalized therapeutic strategies.

In HER2-positive breast cancer, T-DXd significantly outperformed trastuzumab emtansine (T-DM1), with substantial improvements in progression-free and overall survival, while also showing benefit in HER2-low disease. The recent tumor-agnostic FDA approval highlights its broad clinical potential across solid tumors. This review summarizes the mechanism of action, pivotal clinical evidence, and emerging applications of T-DXd, underscoring its transformative role in modern oncology and outlining future prospects for combination strategies, biomarker-driven patient selection, and expanded global access.

P2, N=393, Active, not recruiting, MedSIR | Trial primary completion date: Sep 2025 --> Mar 2027

P=N/A, N=36, Active, not recruiting, Mayo Clinic | Trial completion date: Jun 2026 --> Aug 2027 | Trial primary completion date: Jun 2026 --> Aug 2027

The addition of tucatinib to T-DM1 improved PFS in patients with previously treated HER2+ LA/MBC, including patients with BMs, and exhibited a manageable safety profile.

P3, N=608, Active, not recruiting, Daiichi Sankyo | Trial completion date: Jul 2025 --> Jan 2026

Efficacy varied substantially among agents: trastuzumab deruxtecan (T-DXd) and DP303c demonstrated the highest ORRs (42.5% and 42.9%, respectively), whereas others, such as Trastuzumab emtansine (T-DM1), showed lower efficacy (20.6%). Managing toxicities such as anemia and neutropenia is essential for optimizing treatment. https://www.crd.york.ac.uk/PROSPERO/view/CRD420250653886, identifier PROSPERO CRD420250653886.