Emerging Targeted Therapies HER2-mutant Non-Small Cell Lung Cancer
Cet article décrit les caractéristiques moléculaires et cliniques des cancers du poumon non à petites cellules avec mutation HER2, passe en revue les études cliniques et précliniques concernant les thérapies ciblant HER2 puis examine les perspectives thérapeutiques
HER2-mutant lung cancer represents approximately 2-5% of all NSCLCs and is associated with poor prognosis. Two different HER2-targeted therapeutic approaches with different mechanisms of action -antibody-drug conjugates (ADCs) and HER2-selective tyrosine-kinase inhibitors (TKIs)- have shown convincing efficacy in pretreated patients. 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. Toxicity, while overall manageable, includes an increased risk of interstitial lung disease (ILD), which can be problematic and requires close clinical monitoring. More novel HER2-directed ADCs have confirmed the solid efficacy in this tumor type, showing variable rates of ILD as a class effect of these agents. 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. Toxicities with these agents are mostly related to EGFR wild type inhibition, with significantly lower rates of ILD. Consistent with its selectivity and mechanism of action, zongertinib offers a favorable tolerability profile, with mainly low-grade adverse events including those related to wild type EGFR inhibition. 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
Journal of Thoracic Oncology , résumé, 2026