P1/2, N=129, Not yet recruiting, Medica Scientia Innovation Research S.L.

Three such agents have gained accelerated US Food and Drug Administration (FDA) approval for use in previously treated HER2-mutant NSCLC: the antibody-drug conjugate, trastuzumab deruxtecan; the HER2-specific tyrosine kinase inhibitor (TKI), zongertinib; and the HER2/EGFR TKI, sevabertinib. Zongertinib has also been granted accelerated FDA approval in a first-line setting. The emergence of multiple treatment options highlights the importance of early HER2 mutation testing to guide treatment sequencing and maximize patient benefit.

In further support, lapatinib, an EGFR/HER2 tyrosine kinase inhibitor, attenuated mitochondrial respiration in NF639 murine mammary tumor epithelial cells. Together, this data highlights that the typical correlation between mitochondrial content and respiratory capacity may not apply to all tumor types and implicates HER2-linked activation of mitochondrial respiration supporting tumorigenesis in this model.

Conjugation of nanoparticles with Herceptin® (trastuzumab) significantly increased cellular uptake and anticancer activity, especially in clathrin-deficient SK-BR-3 cells that overexpress ERBB2. These findings establish that the easily synthesized PL-MNP-pBIRC5/As-BIRC5 and PL-MNP-pBIRC5/dN-BIRC5 nanodrugs have strong potential to overcome BIRC5- and ABCB1-related drug resistance, representing a broadly applicable strategy against various malignancies. While the size of our nanodrug (~400 nm in hydrodynamic diameter) is compatible with reported effective nanoparticle sizes in some models, the extent to which the enhanced permeability and retention (EPR) effect contributes to tumor accumulation in human cancers remains uncertain and will require validation in more clinically relevant models and imaging modalities.

P1, N=150, Recruiting, Shanghai Pharmaceuticals Holding Co., Ltd | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2025 --> Dec 2026

These results indicate a synergistic interaction between tras tuzumab and blood serum in both groups. We also found significant differences in CI values between healthy donors and breast cancer patients: blood serum samples from patients enhance the effect of trastuzumab to a greater extent.

P2, N=54, Not yet recruiting, National Taiwan University Hospital

Trastuzumab deruxtecan (T-DXd) was the first targeted therapy approved for patients with HER2-mutant NSCLC, demonstrating robust and durable responses in about 50% of these patients...On the other hand, novel orally available TKIs with higher specificity and inhibitory potency against HER2 over wild type EGFR such as sevabertinib (a dual HER2/EGFR mutant-selective reversible TKI) or zongertinib (an irreversible HER2-selective TKI that spares EGFR, including mutant EGFR) have further demonstrated deep and durable responses in this disease...In this review, we first describe the molecular landscape and clinical features of HER2-mutant NSCLC. Then, we summarize the clinical and preclinical evidence of HER2-targeted therapies and provide a forward-looking perspective of the treatment landscape of HER2-mutant NSCLC.

P=N/A, N=13, Terminated, University of Washington | Active, not recruiting --> Terminated; Study closed to accrual after meeting grant enrollment goal, prior to reaching protocol accrual goal, due to end of funding.

All patients received anti-HER2 TKI therapy (including pyrotinib and lapatinib) in 28-day cycles. No unexpected toxic effects were reported. After progression following TKI therapy, T-DXd exhibited notable antitumor activity, although no significant efficacy differences were observed among ADC, mAb, and TKI groups.

Failure to correct a vitamin D deficiency was associated with a 1.7-fold higher recurrence risk, although the relationship did not achieve statistical significance. A similar effect size was reported in another retrospective cohort of HER2-positive breast cancer that did achieve statistical significance, and a doubling of pCR rates was seen in two recently completed RCTs in 2025, with benefits particularly seen in the triple-negative and HER2-positive subtypes. Prospective trials evaluating optimized vitamin D repletion in HER2-positive breast cancer are warranted.

This retrospective single-center study included 75 patients with HER2-positive invasive breast cancer treated with neoadjuvant chemotherapy plus dual anti-HER2 blockade (trastuzumab and pertuzumab). Given the modest discriminative performance and lack of external validation, these findings should be interpreted cautiously. Further validation in larger independent cohorts is required before the score can be considered for clinical stratification or implementation.