Effective treatment of HER2-driven NSCLC requires more than just identifying mutations. HER2 is a multiplexed biomarker where both genetic mutations (TKD and non-TKD) and protein overexpression (via IHC) are independently actionable. Comprehensive testing is crucial to ensure patients are eligible for the full range of available targeted therapies, including TKIs and ADCs.

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.

Real-world data suggests that using one antibody-drug conjugate (ADC) immediately after another is often ineffective. A potential strategy to overcome this resistance is to administer a different class of chemotherapy before starting the second ADC.

The specific type of HER2 mutation significantly impacts TKI efficacy. YVMA exon 20 insertions show the highest response rates. Other TKD (tyrosine kinase domain) mutations perform moderately well, while non-TKD mutations respond poorly. This molecular nuance is critical for predicting treatment success and managing patient expectations.

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.

Emerging data shows that a second ADC, particularly one with the same payload, often has limited efficacy. This suggests clinicians must be highly strategic in selecting the first ADC, as it may be their most impactful opportunity for this class of drugs.

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.

The list of oncogenic drivers where single-agent immunotherapy is ineffective should be expanded beyond EGFR and ALK to include HER2 mutations. Citing a study where the response rate to immunotherapy was zero percent for these patients, experts advise against using it in this specific molecular subtype.

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.