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.

The SAVANNAH study showed that targeting MET amplification after TKI failure is only effective with stringent diagnostic criteria (e.g., IHC 3+ in >90% of cells). Lower cutoffs lead to poor outcomes, highlighting the need for precise biomarker testing to select patients for this therapy.

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.

Standard Next-Generation Sequencing (NGS) reports often just state "MET amplification" without a specific copy number. To make informed treatment decisions with MET inhibitors, clinicians must proactively contact the testing company's molecular pathology department to obtain this crucial, unlisted data point.

Unlike rare biomarkers that necessitate a 'test-and-wait' approach, IB6 is expressed in over 80-90% of NSCLC tumors. This ubiquity could make pre-screening unnecessary for drugs like Sigvotatug Vedotin, allowing clinicians to initiate targeted therapy much faster and for a broader patient population.

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.

Contrary to the standard 'TKI-first' approach for driver mutations, a study in MET exon 14 skipping NSCLC suggests a different strategy. Patients with high PD-L1 expression appeared to have better outcomes with first-line chemoimmunotherapy, reserving the targeted therapy for later. This challenges the conventional wisdom of prioritizing the driver mutation over immunotherapy biomarkers in this specific subgroup.

Despite major advances in immunotherapy, patient selection remains crude compared to targeted therapies. PD-L1 is still the primary, yet imperfect, biomarker used. Dr. Carbone highlights an urgent need to develop better predictive biomarkers to customize immunotherapy regimens, as is standard for targeted agents.

The success of perioperative osimertinib means oncologists cannot choose the optimal strategy (targeted therapy vs. chemoimmunotherapy) for resectable lung cancer without first knowing the patient's EGFR, ALK, and PD-L1 status. This elevates biomarker profiling from a metastatic-setting tool to a critical first step in early-stage disease.