Treatment Sequencing Beyond Second Line: Evidence for Cross-Class Sequencing and Future Considerations

This episode addresses how second-line HER2-directed therapy selection influences subsequent treatment options in advanced HER2-mutant non-small cell lung cancer. Dr. Doroshow frames the current therapeutic landscape in terms of two main drug classes: the antibody-drug conjugate trastuzumab deruxtecan and the HER2-selective tyrosine kinase inhibitors zongertinib and sevabertinib.

Dr. Doroshow explains that current evidence supports sequencing across drug classes rather than within classes. After progression on a tyrosine kinase inhibitor, moving to the antibody-drug conjugate represents a reasonable approach; similarly, after progression on the antibody-drug conjugate, transitioning to a tyrosine kinase inhibitor is supported by available data. However, she is explicit that using one tyrosine kinase inhibitor after progression on another is not currently warranted, as no evidence supports effectiveness of within-class sequencing for HER2-selective inhibitors.

Beyond the class-based sequencing framework, Dr. Doroshow emphasizes real-world treatment decisions must incorporate additional patient-specific factors. These include how patients are feeling and tolerating their current treatment, which toxicities they have already experienced and wish to avoid, what treatment options might reasonably be "held in the back pocket" for later lines of therapy, and ongoing patient preferences around oral versus intravenous administration and clinic visit frequency. Dr. Doroshow also notes sequencing strategies will likely evolve as more data mature from ongoing clinical trials and as post-marketing experience expands. The relatively recent approvals of zongertinib and sevabertinib mean real-world experience with sequencing these agents is still accumulating, and optimal approaches may become clearer with time and additional evidence.

In the next episode, "Evolving Treatment Landscape and Future Directions: Front-Line HER2-Targeted Therapy and Individualized Selection," Dr. Doroshow looks ahead at how the HER2-mutant NSCLC treatment paradigm is likely to change over the next several years.