The HER2CLIMB trial demonstrated the benefit of tucatinib, trastuzumab and capecitabine (TTC) in human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC). Treatment discontinuation due to toxicity occurred in 7.4% of participants; there were no treatment-related deaths. In this national real-world cohort, TTC demonstrated clinically meaningful activity and was not associated with any new safety signals in HER2-positive ABC, including patients previously exposed to T-Dxd and those with brain metastases.

Data suggest that the Fab-ageritin IT and the individual purified components preserve the toxin and Fab' activity but show enhanced cell toxicity, thus resulting in a structurally well-defined, target-specific new type of immunotoxin. The scheme outlined for its preparation is easily extendable to other therapeutic IgG1 thus providing a significant contribution to the ongoing effort to explore new combinations of payloads and targeting platforms for next-generation immunotoxins.

In vivo, lapatinib suppressed tumor growth and downregulated SLC1A5/GPX4, effects that were reversible by DFO. This study reveals a novel mechanism by which lapatinib inhibits OS via the SLC1A5-GPX4 axis to induce ferroptosis, providing a preclinical rationale for further evaluation of lapatinib repurposing in osteosarcoma.

The temporal relationship between molecular and radiologic findings observed here suggests potential value for earlier detection of disease activity, although whether such lead time translates into improved clinical outcomes requires prospective validation. The findings support prospective evaluation of this approach, including the ongoing TROPHY trial investigating this therapeutic approach.

Therapeutic progress in this population has accelerated over the past several years, first with trastuzumab deruxtecan and more recently with selective HER2 tyrosine kinase inhibitors (TKIs). Zongertinib demonstrates that selective HER2 inhibition can achieve durable responses in HER2 -mutant NSCLC with a favorable safety profile. However, optimal treatment sequencing, resistance mechanisms, and biomarker-guided patient selection remain to be defined.

Neoadjuvant dual HER2 blockade with trastuzumab and pertuzumab plus chemotherapy represents the current standard-of-care for HER2-positive breast cancer. Importantly, Xenium in situ profiling further revealed biological correlates underlying model predictions, including HER2-enriched tumor cell aggregation and neutrophil-helper T-cell interactions, thereby highlighting the mechanistic interpretability of the model. Collectively, HER2-LADDER unites digital pathology and high-resolution spatial profiling into a clinically accessible AI framework, offering a robust, transparent, and biologically grounded tool to tailor individualized HER2-targeted therapy optimization.

P1, N=28, Suspended, H. Lee Moffitt Cancer Center and Research Institute | Recruiting --> Suspended | Trial primary completion date: Apr 2026 --> Aug 2026

In a multivariate regression analysis the cumulative dose of anthracycline (OR = 1.01, 95% CI: 1.00-1.01, p = 0.002) and LVEF at baseline (OR = 0.83, 95% CI: 0.70-0.99, p = 0.0344) were independent predictors of a cardiotoxic effect. Trastuzumab-related cardiotoxicity resulting in early treatment discontinuation negatively influences DFS, but does not seem to influence OS.

Additionally, a 100 ns MD Simulation has resulted in far less deviation, fluctuations, and intermolecular interactions than Tucatinib, suggesting stable protein-ligand interactions, while the binding free energy and total complex energy computed across 0-1000 frames of the MD trajectories indicate that 2-Aoeobenoxmide is a promising in silico candidate. Importantly, because the entire study is computational, the findings should be interpreted as in silico hypotheses, and experimental validation through in vitro and in vivo assays is warranted before any clinical translation is considered.

P1/2, N=71, Not yet recruiting, Chia Tai Tianqing Pharmaceutical Group Nanjing Shunxin Pharmaceutical Co., Ltd.

P1, N=16, Not yet recruiting, Boehringer Ingelheim

P2, N=63, Completed, City of Hope Medical Center | Active, not recruiting --> Completed