Future Directions and Key Takeaways in HER2-Mutated NSCLC

The final segment provides a forward-looking perspective on HER2-mutated NSCLC and summarizes the key takeaways for clinical practice. Drs. Patel and Riess highlight that understanding sequencing, including T-DXd versus zongertinib versus emerging TKIs, will require phase III trial results. Current approvals position chemotherapy as the standard first-line therapy, but accumulating data suggest that HER2-targeted agents may eventually move into earlier lines.

The discussion transitions to novel therapies in development, such as sevibertinib, next-generation TKIs designed for broader resistance coverage, and agents engineered for enhanced CNS penetration, including investigational compounds like NVL-330. The experts also highlight ongoing innovation in ADC payloads and linker technologies, which may further expand the therapeutic window.

Beyond metastatic disease, they emphasize the future potential of HER2-targeted agents in stage III (post–chemoradiation), neoadjuvant, and adjuvant settings, paralleling treatment evolution seen in EGFR-mutated lung cancer.

To close, Dr. Riess underscores the central message: clinicians must test comprehensively using NGS and HER2 IHC to identify both HER2 mutations and HER2 3+ expression. These alterations are actionable and increasingly associated with highly effective targeted therapies. As more HER2 agents emerge, meticulous biomarker assessment, timely toxicity management, and engagement with multidisciplinary resources will be key to optimizing patient outcomes.