The Dutch Healthcare Institute (ZIN) has recommended trastuzumab deruxtecan (Enhertu) for inclusion in the Netherlands’ basic insurance package for HER2-low metastatic breast cancer. This recommendation is contingent on a price reduction exceeding 68%. The DESTINY-Breast04 trial demonstrated a median overall survival (OS) benefit of 6.6 months compared to chemotherapy. Despite this efficacy, the incremental cost-effectiveness ratio (ICER) of €219,803 per quality-adjusted life year (QALY) far exceeds the Dutch threshold of €80,000, necessitating significant price concessions. The ZIN emphasizes concerns over missing quality-of-life (QoL) data and variability in HER2-low diagnostic standardization, which could impact real-world effectiveness and cost calculations.

Clinical and Economic Insights

Efficacy and Diagnostic Challenges

Trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate, has redefined treatment paradigms for HER2-low breast cancer, a subtype historically classified as HER2-negative. The DESTINY-Breast04 trial showed a 38% reduction in progression-free survival (PFS) risk (median PFS: 13.2 vs. 8.1 months) and a 36% OS improvement, establishing it as a first-line option post-endocrine therapy. However, HER2-low identification relies on immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), with variability in testing methods leading to potential misclassification. The ZIN highlights the need for standardized diagnostics, aligning with the Ventana UltraView assay used in clinical trials, to ensure equitable patient access.

Cost-Effectiveness and Budget Impact

The ZIN’s cost-effectiveness analysis estimates a budget impact of €40.6 million annually by year three, treating approximately 475 patients. At current pricing, Enhertu’s lifetime treatment cost (€136,751) dwarfs chemotherapy (€41,902), driven by its €9,574 per-cycle list price. This aligns with broader European trends, where England’s NICE rejected Enhertu due to exceeding acceptable cost-effectiveness ranges. In Germany, similar debates have arisen, with the G-BA noting insufficient comparative data for HER2-mutated NSCLC.

Global Context and Policy Implications

Epidemiological and Health System Considerations

HER2-low breast cancer represents approximately 60% of HER2-negative cases, with higher prevalence in hormone receptor (HR)-positive tumors. The WHO’s Global Breast Cancer Initiative aims to reduce mortality by 2.5% annually, yet disparities persist. The five-year survival rate in high-income countries exceeds 90%, compared to only 40% in South Africa. Enhertu’s approval in the EU for HER2-low and HER2-ultralow tumors (April 2025) reflects shifting diagnostic thresholds, but affordability remains a barrier in lower-resource settings.

Enhertu Reimbursement Analysis and Pricing Dynamics

The ZIN’s demand for a more than 68% price reduction resonates with stringent European cost-containment strategies. In Germany, the G-BA evaluates therapies under §35a SGB V, often requiring comparative effectiveness data absent in single-arm trials. The Netherlands’ threshold of €80,000/QALY, adjusted for disease severity, contrasts with Germany’s implied threshold of approximately €90,000/QALY. These disparities highlight tensions between innovation incentives and fiscal sustainability, especially as developers explore label expansions into gastric and NSCLC indications.

Recommendations for Health Economics and Outcomes Research (HEOR)

1. Real-World Evidence Generation: Post-marketing studies should address QoL gaps and long-term survival data absent from pivotal trials. Registries tracking HER2-low diagnostic consistency (e.g., IHC 1+ vs. 2+/ISH-) could optimize patient selection.
2. Value-Based Pricing Models: Outcomes-based agreements, such as the Netherlands’ proposed two-year financial arrangement, could link reimbursement to real-world effectiveness while mitigating budget shocks.
3. Diagnostic Harmonization: Collaboration between pathologists and payers, as seen in the Dutch HER2-low standardization initiative, is critical to ensuring equitable access and reducing geographic treatment disparities.

The Enhertu reimbursement analysis encapsulates the growing imperative for alignment between clinical innovation, health technology assessment (HTA) methodologies, and affordability safeguards in an era of precision oncology. As HER2-targeted therapies expand into earlier lines and novel subtypes, stakeholders must balance therapeutic promise with sustainable financing—a challenge epitomized by the Dutch ZIN’s cautious endorsement.