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.

Synthakyne's drug demonstrated a 75% response rate in lung cancer patients with STK11 and KEAP1 mutations, a subgroup where the published response rate for standard care is only 7%. This suggests the drug is highly effective in the most immunologically resistant patient populations, a significant differentiator.

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.

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.

Oncologists distinguish between HER2 amplification (the target for ADCs like TDXD) and activating mutations. A patient whose tumor loses amplification but retains a mutation is considered "HER2 mutated," not "HER2 positive," and is generally not a candidate for ADC therapy.

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 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.

In HER2-positive colorectal cancer, the choice of targeted therapy depends on RAS mutation status. The tucatinib/trastuzumab combination is effective only in RAS wild-type patients. In contrast, the antibody-drug conjugate trastuzumab deruxtecan (TDXD) shows efficacy regardless of whether a RAS mutation is present.

Data from the WUCONG-1B trial shows the TKI sunvosertinib's response rate is nearly halved in patients with prior exposure to the antibody amivantamab. This suggests a potential lack of efficacy after amivantamab and has major implications for treatment sequencing in this disease.