Enhertu (fam-trastuzumab deruxtecan-nxki)

T-DXd showed remarkable preclinical activity against HER2 FISH-negative, IHC-low EEC both in-vitro and in-vivo. These findings support its use beyond HER2-high expression and may represent a novel and effective treatment option for patients with HER2-low EEC who have progressed on standard chemotherapy and immunotherapy.

P2, N=42, Recruiting, Gruppo Oncologico del Nord-Ovest

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i; palbociclib, ribociclib, abemaciclib, dalpiciclib) combined with endocrine therapy (ET) were a major advance in the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) worldwide...However, clinical development of CDK4/6i in HER2+ MBC slowed, given the advent of highly effective tyrosine-kinase inhibitors (TKIs) (i.e., tucatinib) and antibody-drug conjugates (ADCs) (i.e., trastuzumab deruxtecan), which currently dominate the treatment armamentarium...Subsequently, the phase III PATINA trial (which included patients with 1L HR+HER2+ MBC, treated with palbociclib vs. placebo with maintenance ET+ H[P]) noted a striking PFS improvement of >15 months in the palbociclib arm, renewing interest in CDK4/6i-based treatments for HR+HER2+ MBC. Herein, we review the development of CDK4/6i in HER2+ BC, discussing current challenges and potential future directions.

This classification (refined in ProMisE and TransPORTEC) enables precise treatment: immunotherapy (pembrolizumab, dostarlimab) works excellently in dMMR/MSI-H tumors, PI3K/AKT/mTOR inhibitors and trastuzumab deruxtecan in selected molecular subtypes, and hormone therapy in ER-positive tumors. Integrating the molecular profile with FIGO allows for truly personalized treatment, although MMRp/MSS tumors remain a challenge. The future lies in multi-omics, new biomarkers, and combination therapies.

The present study aimed to investigate the image-derived biodistribution, tolerability, and efficacy of [161Tb]Tb-trastuzumab as a potential therapeutic alternative or supplement to trastuzumab and trastuzumab deruxtecan in HER2-expressing tumors...Biodistribution of [161Tb]Tb-trastuzumab revealed high tumor uptake of more than 10 %ID/g of tissue, peaking at 72 h. [161Tb]Tb-trastuzumab in doses of up to 10 MBq was tolerated and highly effective at inhibiting tumor growth (P = 0.0007). These results support the potential of [161Tb]Tb-trastuzumab as an attractive treatment option for HER2-expressing cancers.

P3, N=0, Withdrawn, Danish Breast Cancer Cooperative Group | N=504 --> 0 | Trial completion date: May 2029 --> Jan 2026 | Not yet recruiting --> Withdrawn | Trial primary completion date: May 2029 --> Jan 2026

This Delphi study found strong consensus on key concepts for sampling, pathological testing, interpretation, and reporting of HER2-low and ultralow breast cancer. While the opinions expressed align with current guidelines, more evidence on the clinicopathological implications is needed.

DS-8201 showed significantly better efficacy and similar overall safety compared to TPC in patients with T-DM1-pretreated HER2-positive advanced breast cancer, supporting its use as a treatment option in this setting.

P3, N=506, Active, not recruiting, AstraZeneca | Trial completion date: Feb 2026 --> May 2026

P3, N=550, Recruiting, Jazz Pharmaceuticals | Trial completion date: Nov 2031 --> Oct 2030 | Trial primary completion date: Sep 2028 --> Apr 2028

P2, N=27, Enrolling by invitation, Yonsei University | Not yet recruiting --> Enrolling by invitation | Trial completion date: Apr 2026 --> Dec 2026 | Trial primary completion date: Jan 2026 --> Dec 2026