The efficacy of NAT regimens containing trastuzumab plus pertuzumab (HP) and trastuzumab plus pyrotinib (HPy) was compared. Both HP and HPy combined with chemotherapy can be considered as optional NAT regimens for HER2-positive BC. The nomogram incorporating common clinical indicators provides a basis for clinicians to predict NAT efficacy at an earlier stage.

She received neoadjuvant chemotherapy combined with dual anti-HER2 therapy (trastuzumab and pertuzumab), followed by a right mastectomy with axillary lymph node dissection, locoregional conformal radiotherapy, and stereotactic radiotherapy to the L5 lesion. A complete response, both histological and metabolic, was achieved and has been sustained after two years of follow-up. This case underscores the value of a personalized, multimodal treatment approach.

P2, N=188, Not yet recruiting, Tianjin Medical University Cancer Institute and Hospital

While HER2-targeted therapies such as trastuzumab and pertuzumab have improved clinical outcomes, resistance, particularly to trastuzumab, remains a major therapeutic challenge. Structural modeling suggests that both bpAbs engage HER2 in a trans-binding mode, leading to receptor clustering and interference with ligand-driven HER2 heterodimerization. These findings demonstrate that epitope-guided biparatopic antibody design can enhance HER2 downregulation and restore sensitivity to HER2-targeted therapy in vitro, providing a strategy for the development of next-generation receptor-targeted biologics.

Among the 161 patients receiving neoadjuvant trastuzumab-pertuzumab therapy, 81 achieved pCR (50.31%), while 80 did not (49.69%). However, multivariate logistic regression confirmed Her-2 expression as the sole independent predictor: Her-2 (3+) patients had significantly higher pCR rates than Her-2 (2+)/FISH(+) cases (p=0.005; OR: 0.170 [95% CI: 0.045-0.639]). Her-2 (3+) expression correlates with superior pCR rates, underscoring the need for further research to refine patient selection for optimized targeted therapy benefits.

P3, N=408, Active, not recruiting, BioRay Pharmaceutical Co., Ltd. | Recruiting --> Active, not recruiting | Trial completion date: Nov 2021 --> Dec 2025

P3, N=2000, Not yet recruiting, Cancer Institute and Hospital, Chinese Academy of Medical Sciences

P2, N=402, Active, not recruiting, West German Study Group | Recruiting --> Active, not recruiting | Trial completion date: Jun 2028 --> Jun 2029 | Trial primary completion date: Jun 2026 --> Jun 2025

Although HER2-targeted therapies such as trastuzumab and pertuzumab confer substantial clinical benefits, therapeutic resistance remains a major challenge, necessitating the development of next-generation agents. Structural modeling predicted a trans-binding mode that enables multivalent HER2 clustering, indicative of a distinct mechanism of action. These findings highlight AH as a rationally designed biparatopic binder with potential to overcome trastuzumab resistance and underscore the potential of nanobody-based biparatopic strategies to enhance antitumor efficacy in HER2-positive cancers.

P2, N=18, Active, not recruiting, City of Hope Medical Center | Trial completion date: Oct 2025 --> Sep 2026

Discussion and These findings indicate the potential of achieving prolonged disease control in a subset of patients with HER2-positive MBC, raising questions about therapeutic intensification and potential treatment discontinuation strategies. This study underscores the need for future research to identify predictive factors of durable response and assess the feasibility of adaptive treatment strategies, including planned treatment discontinuation.

Taken together, our findings suggest that dual targeting of HER2 and HER3 with T-DXd and pertuzumab may improve therapeutic outcomes in HER2-positive GC, particularly in tumors enriched with HER2-HER3 heterodimers. These preclinical data provide strong rationale for clinical trials evaluating this combination strategy in HER2-positive GC.