Navigating Post-Progression Therapy and Resistance in HER2-Mutated NSCLC

This segment examines therapeutic decision-making after progression on HER2-targeted therapies, with a focus on resistance mechanisms and subsequent treatment strategies. Dr. Patel asks how clinicians should select therapies after agents like T-DXd, raising the question of whether certain molecular or clinical factors might guide next steps.

Dr. Riess explains that although resistance biology is well-characterized in EGFR-mutated NSCLC, the field is still in its early stages for HER2-driven disease. Researchers have yet to identify consistent on-target or bypass-track resistance mechanisms, making it difficult to tailor therapy based on molecular evolution. For this reason, he continues to use T-DXd after TKIs or vice versa, emphasizing that ADCs may retain activity even in the presence of complex resistance because they deliver a potent cytotoxic payload independent of the precise resistance mutation.

The experts underscore the importance of obtaining post-progression biopsies or ctDNA to help build real-world datasets that will ultimately guide future therapy sequencing. They highlight that HER2-mutated NSCLC comprises a small percentage of cases, limiting the availability of resistance-focused data compared with more common oncogenic drivers.

This segment positions resistance profiling as an area of critical unmet need and emphasizes that generating large, multicenter datasets will be essential for advancing next-generation inhibitors, rational combinations, and personalized sequencing strategies.