Previously untargetable, the KRAS G12D mutation—often found in never-smokers—is on the verge of becoming actionable. Emerging specific inhibitors like Zoldanrasib are showing high response rates (over 60%), suggesting a new targeted therapy option for a patient group that previously lacked one.

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.

For never-smokers with HER2 mutations, immunotherapy is largely ineffective and risks severe immune-related adverse events when the patient is later switched to the correct TKI. This paradigm mirrors the approach for EGFR and ALK mutations, where targeted therapy is the standard upfront, even with high PD-L1 expression.

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.

For certain therapies like Enhertu, eligibility is based on immunohistochemistry (IHC), not NGS. Labs must run HER2 IHC in parallel because NGS, as a population-based test, can miss intratumoral heterogeneity (small clusters of positive cells) that IHC can detect, thus identifying more eligible patients for targeted therapy.

In NSCLC, "HER2 positive" can mean one of three largely separate conditions: rare exon 20 mutations (~2%), rare gene amplifications (~2%), or more common protein overexpression (20-30%). Understanding these distinctions is critical for accurate biomarker testing and selecting appropriate therapies.

Clinicians ordering "NGS for lung" often misunderstand that Next-Generation Sequencing alone does not cover all actionable biomarkers, such as PD-L1 or HER2. This requires pathologists to interpret the clinician's intent and order a more comprehensive and appropriate test panel.

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.

For critical driver mutations like ROS1 and ALK fusions, relying solely on DNA-based Next-Generation Sequencing (NGS) is insufficient. A study showed that a significant portion of these fusions are only detectable via RNA sequencing. Clinicians must verify that RNA analysis was included in NGS reports to avoid missing effective targeted therapies for one in five potential patients.