Nationwide real-world data demonstrate favorable survival outcomes following adoption of dual anti-HER2 therapy. While these findings are broadly consistent with the CLEOPATRA trial, the observational design does not allow direct assessment of equivalence between studies.

P2, N=88, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Jun 2026 --> Jun 2027

These findings suggest that disparities in outcomes persist despite financial coverage of high-cost therapies, indicating the influence of structural and geographic factors on cancer care. This study provides real-world evidence to inform policies aimed at reducing inequities in access and outcomes among patients with breast cancer in Chile.

The ADC showed no significant body weight loss or organ damage in mice, indicating good tolerability. These findings validate a modular strategy combining a Fab scaffold, enzymatic site-specific conjugation, and ABD-mediated half-life extension to generate potent, homogeneous ADCs and nominate T-Fab-ABD(H + L)-DM1 as a promising candidate for HER2-positive cancer therapy.

Zenocutuzumab demonstrated clinically meaningful and durable antitumor activity with a favorable safety profile in patients with advanced NRG1+ cholangiocarcinoma.

P4, N=10, Recruiting, City of Hope Medical Center | Trial completion date: May 2026 --> Apr 2027 | Trial primary completion date: May 2026 --> Apr 2027

P1/2, N=400, Recruiting, Bayer | Trial primary completion date: Nov 2026 --> Mar 2026

The past two decades have witnessed transformative advances in HER2-targeted therapeutics, exemplified by tyrosine kinase inhibitors (TKIs), including first-generation reversible pan-HER (e.g., lapatinib), second-generation covalent pan-HER (neratinib, pyrotinib), and novel selective HER2 inhibitors (tucatinib, sevabertinib, zongertinib). This review comprehensively summarizes recent advances in HER2-targeted TKIs and their emergent resistance mechanisms, further analyzing strategies to both mitigate off-target toxicity and overcome resistance through rational design of selective HER2 inhibitors. Collectively, these insights provide a roadmap for developing next-generation precision therapies in HER2-driven cancers.

P1/2, N=83, Suspended, Virginia Commonwealth University | Recruiting --> Suspended

HER2-positive (HER2+) breast cancer often develops resistance to therapies like Lapatinib, potentially involving mitochondrial metabolic and redox reprogramming...This study identifies MTHFD2 and PRDX3 as regulators of mitochondrial oxidative stress in HER2+ breast cancer. Deleterious nsSNPs in these genes may contribute to altered redox balance, potentially influencing metabolic adaptation (MTHFD2) and antioxidant defense (PRDX3).

Trastuzumab + pertuzumab (TP) was the most commonly used regimen in both neoadjuvant and adjuvant settings. The dual HER2 blockade regimens that were widely adopted in China for HR+/HER2+ early breast cancer have demonstrated effectiveness in improving pCR in routine clinical practice; a longer follow‑up is required to validate survival outcomes. None.

Tucatinib-based combinations and trastuzumab deruxtecan have demonstrated substantial intracranial activity in prospective trials, shifting the treatment paradigm by supporting systemic therapy even in the presence of active brain metastases. A major limitation remains the underrepresentation of patients with brain metastases in clinical trials. This review summarizes current evidence on systemic therapies for BCBM across subtypes and highlights the need for CNS-inclusive trials and the development of effective CNS-active treatments.