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

Circulating tumor DNA mutation status may serve as a prognostic biomarker in patients receiving HER2-targeted therapies. PIK3CA mutations were associated with worse outcomes, whereas ERBB2 mutations showed no significant effect. The prognostic significance of ctDNA was most pronounced in patients treated with TKIs, particularly pyrotinib, and remained evident in monotherapy and capecitabine-based regimens. These findings support the potential utility of ctDNA monitoring for risk stratification and personalized management in advanced HER2-positive breast cancer.

This case illustrates successful management of HER2-positive brain metastases from cervical cancer using a multimodal approach combining surgery, radiotherapy, and systemic therapy with pyrotinib and capecitabine. The durable complete response with manageable toxicity underscores the therapeutic potential of HER2-targeted therapy as part of a multimodal regimen; however, further studies are required to validate these findings and optimize personalized treatment strategies.

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.

P2, N=8, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Recruiting --> Active, not recruiting | N=36 --> 8

P2, N=182, Recruiting, Hebei Medical University Fourth Hospital

Patient characteristics reflect current Chinese practice. Increasing adoption of diarrhoea prophylaxis in real-world practice reflects growing clinical experience with neratinib and its recognised benefit in preventing diarrhoea.

Treatment of HER2+ mBC with and without BMs in Saudi Arabia largely aligned with international recommendations identified in our literature analysis, although access to lapatinib, tucatinib and neratinib can be limited and may lead to use of alternative regimens. The tucatinib-combination may be considered the standard of care for adult patients with HER2+ locally advanced or mBC who have received at least two prior anti-HER2+ treatment regimens, including patients with BMs. Ensuring access to innovative HER2+ mBC therapies across Saudi Arabia is crucial to supporting best practice.

Existing studies are generally limited by small sample sizes and a lack of long-term survival data, and high-level evidence directly comparing pyrotinib-based strategies with trastuzumab plus pertuzumab is scarce. Future research should prioritize biomarker-driven patient selection, response-adaptive trial designs, and standardized toxicity management to optimize clinical decision-making.

Kaplan-Meier survival curve and Cox regression model was used to analyze the effect of different levels of NLR and LDH before T-DM1 treatment on the survival of patients. Elevated NLR and LDH were associated with poor PFS and OS. Future data are needed to validate and update our results.

In a real-world setting the addition of pyrotinib to trastuzumab and chemotherapy significantly improved pathological and radiographic responses and prolonged PFS, albeit with an increased but manageable toxicity profile.