Comparing Zongertinib and Sevibertinib: Efficacy and Toxicity Considerations in Patients with HER2-Mutated NSCLC

This segment examines the positioning of sevibertinib in the context of established and emerging HER2-targeted therapies. The discussion begins with Dr. Patel reviewing the SOHO-01 trial, in which sevibertinib demonstrated impressive objective response rates, approximately 50% in treatment-naive patients and up to 65% in those previously treated. These data place sevibertinib’s efficacy in a similar range to zongertinib, prompting important questions about how to differentiate between the two TKIs.

Dr. Riess explains the mechanistic distinction: zongertinib is a HER2-selective inhibitor engineered to spare EGFR, whereas sevibertinib targets both EGFR and HER2. Although this dual activity may be biologically advantageous in some contexts, it also results in a higher incidence of EGFR-related toxicities, particularly diarrhea and GI intolerance. He notes that both agents appear comparably effective based on cross-trial observations, but the toxicity profile may drive clinical decision-making, especially for patients with baseline GI vulnerability or poor performance status.

The experts reinforce the importance of early and frequent toxicity monitoring during the first months of treatment. They describe team-based care models involving advanced practitioners, pharmacists, and close interval visits to ensure prompt dose adjustments and supportive care.

There is an emerging theme in the evolving HER2 landscape: with multiple active TKIs available, individual patient characteristics, tolerability considerations, and multidisciplinary support will increasingly shape therapeutic selection.