Positioning HER2-Targeted Therapies in the Modern Treatment Paradigm

This segment transitions into a focused discussion on the expanding HER2-targeted therapeutic landscape and how clinicians can begin integrating newer agents into practice. Drs. Patel and Riess first review the strong clinical efficacy of zongertinib, emphasizing its high response rates and median progression-free survival of approximately one year in patients with HER2 exon 20 insertion–mutated metastatic NSCLC. They compare this with established activity from trastuzumab deruxtecan, which is now approved for HER2-mutated disease and continues to demonstrate meaningful benefit.

Key differences between TKIs and ADCs are reviewed, specifically, their mechanisms of action, toxicity patterns, and potential roles across lines of therapy. Dr. Riess notes that although T-DXd provides potent intracellular payload delivery and has activity across heterogeneous mechanisms of resistance, HER2-selective TKIs like zongertinib may offer a well-tolerated oral option with promising intracranial responses.

Sequencing remains an unresolved question. With both mutation-specific and expression-driven indications available, determining the optimal order of TKIs, ADCs, immunotherapy-containing regimens, and chemotherapy will require data from ongoing phase III trials. At present, clinicians must navigate these options by considering disease burden, prior treatments, toxicity profiles, and molecular context.

This segment highlights the importance of thoughtful, individualized decision-making as the number of effective HER2-targeted agents continues to expand.