Emerging Targeted Therapies for HER2-Mutant NSCLC

HER2-mutant lung cancer represents approximately 2% to 5% of all NSCLCs and is associated with poor prognosis. Two different HER2-targeted therapeutic approaches with different mechanisms of action-antibody-drug conjugates and HER2-selective tyrosine kinase inhibitors (TKIs)-have demonstrated convincing efficacy in pretreated patients. Trastuzumab deruxtecan was the first targeted therapy approved for patients with HER2-mutant NSCLC, demonstrating robust and durable responses in approximately 50% of these patients. Toxicity, although overall manageable, includes an increased risk of interstitial lung disease (ILD), which can be problematic and requires close clinical monitoring. More novel HER2-directed antibody-drug conjugates have confirmed the solid efficacy in this tumor type, revealing variable rates of ILD as a class effect of these agents. However, novel orally available TKIs with higher specificity and inhibitory potency against HER2 than 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.