Second-Line Sequencing After Progression on Zongertinib: ADC, TKI Switch, or Chemotherapy

Because zongertinib and sevabertinib were both approved recently, prospective data on optimal sequencing within the HER2-selective tyrosine kinase inhibitor (TKI) class do not yet exist. Dr. Wu is direct: Switching from zongertinib to sevabertinib (or vice versa) for true radiographic progression is not supported by evidence of efficacy. He considers a TKI-to-TKI switch reasonable only for toxicity management—for example, when hepatotoxicity makes continuing the first TKI untenable and the patient is willing to try the alternate agent.

For true progression on first-line zongertinib, Dr. Wu's second-line options align with the National Cancer Comprehensive Network (NCCN) guidelines: the antibody-drug conjugates (ADCs) fam-trastuzumab deruxtecan (T-DXd) and ado-trastuzumab emtansine (T-DM1), or standard systemic chemotherapy. While patients in the pivotal T-DXd trials had not received a prior HER2-directed oral TKI, sequencing from a TKI to an ADC is biologically reasonable because an ADC carries a chemotherapy payload rather than relying solely on HER2-pathway inhibition.

Practical toxicity considerations shape the conversation. T-DXd carries dose-dependent interstitial lung disease (ILD) and pneumonitis risk; higher doses (6.4 mg/kg vs 5.4 mg/kg) correlate with higher ILD rates. T-DXd also produces typical chemotherapy-class toxicities such as anemia, thrombocytopenia, and neutropenia because of its cytotoxic payload.

Dr. Wu notes a mechanistic nuance: Zongertinib is an irreversible HER2-selective TKI, while sevabertinib is reversible. In theory, this could influence cross-resistance patterns, but in the absence of clinical data, he does not use this distinction to justify a within-class switch for efficacy. On safety overlap, the two HER2-selective TKIs share hepatotoxicity and left ventricular dysfunction signals; if a patient experienced either on zongertinib, those toxicities would inform any decision to try sevabertinib.

In the next episode, “Clinical Trial Representation and Extrapolating Data to the Patient in Front of You,” Dr. Wu addresses William's direct question about whether the HER2-directed data apply to a Black male patient in his age range.