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.

Concordance between local and central HER2 testing for ovarian cancer is poor. However, early data suggests the T-DXd antibody-drug conjugate is effective regardless of this variability, meaning any positive signal could be clinically actionable for this difficult-to-treat cancer.

Unlike in breast cancer, where HER2 IHC 2+ requires FISH confirmation, in gynecologic cancers an IHC 2+ result is often considered directly actionable for prescribing HER2-targeted ADCs like T-DXD. This reflects a different, less stringent clinical standard for biomarker-guided therapy in this setting.

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.

For HER2+ metastatic colorectal cancer, experts choose HER2-targeted therapies like TDXD or tucatinib/trastuzumab over standard second-line chemotherapy (FOLFIRI/BEV), despite label constraints. The rationale is the significantly higher response rate from targeting the oncogenic driver directly.

When a highly effective therapy like EV Pembro was approved for 'cisplatin ineligible' patients, the definition of 'ineligible' became very elastic in practice. This demonstrates that when a new treatment is seen as transformative, clinicians find ways to qualify patients, putting pressure on established guidelines.

Clinicians face a strategic dilemma where using an ADC off-label for a patient with a low-expressing biomarker (e.g., TDXD for HER2 1+) could provide benefit but also render that patient ineligible for a future clinical trial of a potentially more effective ADC. This highlights a tension between immediate access and optimizing long-term treatment sequencing.

Although HER2 expression is rare in cervical cancer, it is a crucial biomarker to test for. In these uncommon cases, patients who have progressed on standard immunotherapy can achieve "wonderful responses" with trastuzumab deruxtecan (T-DXd), highlighting a powerful, targeted option for a population with high unmet need.

The standard HER2 tests were developed to identify HER2-positive tumors, not to precisely quantify low levels of expression. This creates a diagnostic challenge for identifying patients eligible for HER2-low targeted ADCs, requiring closer collaboration with pathology to interpret results that may be near the threshold, such as HER2-zero but with some minimal staining.