HER2-Altered Non-Small Cell Lung Cancer: A Journey from Current Approaches to Emerging Strategies

Simple Summary The introduction of trastuzumab deruxtecan is significantly changing the therapeutic landscape of advanced HER2-mutated non-small cell lung cancer (NSCLC). The results of the DESTINY-Lung04 trial are highly anticipated for their potential to redefine the first-line therapeutic standard for HER2-mutant disease. Furthermore, several studies evaluating combination therapy regimes are currently ongoing. This review outlines the current state of the art in the clinical management of HER2-altered NSCLC and explores potential future perspectives in the field of HER2 targeted strategies.Abstract For patients diagnosed with advanced HER2-altered non-small cell lung cancer (NSCLC), the current standard of care is represented by a platinum-pemetrexed-based chemotherapy, eventually in combination with immunotherapy. Different pan-HER tyrosine kinase inhibitors have been evaluated in limited phase II trials, yielding generally unsatisfactory outcomes, although certain genotypes demonstrated some clinical benefit. Conversely, antibody-drug conjugates (ADCs) targeting HER2, particularly trastuzumab-deruxtecan, have shown promising results against HER2-mutant disease, including a great intracranial activity in patients with brain metastasis. Based on the results obtained from DESTINY-Lung01 and DESTINY-Lung02 trials, trastuzumab deruxtecan received regulatory approval as the first targeted therapy for pre-treated, HER2-mutant, advanced NSCLC patients. More recently, the Food and Drug Administration (FDA) granted the accelerated approval of trastuzumab deruxtecan for advanced, pre-treated HER2-positive solid tumours with no other treatment options. In this scenario, emerging evidence is increasingly pointing towards the exploration of combination regimens with synergistic effects in the advanced disease. In this review, we provide a detailed summary of current approaches and emerging strategies in the management of HER2-altered NSCLC, also focusing on unmet needs, including the treatment of patients with brain metastases.