HER2-directed TKIs (like zongertinib) and ADCs (trastuzumab-deruxtecan/TDXD) have different mechanisms, and clinical data shows they are effective when used sequentially. Zongertinib works post-TDXD, and vice-versa. However, there is no evidence to support using one HER2 TKI after another has failed.

Historically, HER2-mutated lung cancer was treated with cytotoxic chemotherapy, unlike other oncogene-driven cancers that used targeted therapies upfront. Zongertinib's approval as a first-line oral TKI marks a significant philosophical shift, aligning its treatment strategy with the biomarker-driven care standard in lung oncology.

Despite both Zongertinib and Sevabirtinib showing high efficacy in HER2-mutant NSCLC, Zongertinib's selective nature results in a much better safety profile. Sevabirtinib's dual EGFR/HER2 inhibition leads to significant GI and skin toxicities, making tolerability, not just efficacy, the key factor for clinical preference.

NGS testing is revealing that acquired HER2 kinase domain mutations, not amplifications, are an emerging resistance mechanism in ER+ lobular breast cancer. This creates a targetable population for HER2 TKIs like neratinib or tucatinib, offering a new line of targeted therapy.

For HER2-mutant NSCLC, Zongertinib (a TKI) is now the first-line choice. While TKIs show activity after ADCs like TDXD, the effectiveness of using an ADC after TKI failure remains an unproven but critical clinical question for oncologists.

The new treatment paradigm for HER2-positive lung cancer will likely involve sequencing a TKI like zongertinib first, followed by an antibody-drug conjugate (ADC). Early data suggests that the efficacy of TKIs is significantly reduced when used after an ADC, making the TKI-first approach critical for maximizing patient outcomes.

The success of both MOUNTAINEER (tucatinib/trastuzumab) and DESTINY-CRC02 (T-DXd) has introduced two effective, mechanistically different HER2-targeted therapies. This creates a new clinical challenge for oncologists: how to optimally sequence these agents, as there is no head-to-head data to guide the choice.

Contrary to concerns about cross-resistance between HER2 antibody-drug conjugates (ADCs), retrospective data shows TDM-1 remains effective after progression on TDXD. This suggests the different cytotoxic payloads are key, allowing for effective sequencing and challenging the assumption that progression on one ADC class member precludes using another.

While most HER2 mutations in NSCLC occur in the tyrosine kinase domain (TKD), about 20% arise elsewhere. Current HER2 TKIs show high activity against TKD mutations but have significantly lower response rates (~30%) for non-TKD mutations, highlighting an area of unmet need for this patient subset.