ASCO: Enhertu by AstraZeneca and Daiichi aims for historic impact in HER2-ultralow breast cancer

AstraZeneca and Daiichi Sankyo are optimistic about their antibody-drug conjugate, Enhertu, potentially benefiting a broader range of breast cancer patients. Enhertu, which initially made strides in the HER2-low category, is now showing promise for even lower HER2 expressions, known as HER2-ultralow, according to recent trial data presented at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago.

Promising Trial Results

The DESTINY-Breast06 trial assessed patients with previously treated, hormone receptor (HR)-positive metastatic breast cancer with low HER2 expression levels. Enhertu demonstrated a 37% reduction in the risk of disease progression or death compared to standard chemotherapy options. This significant result contrasts with the earlier DESTINY-Breast04 trial, which led to Enhertu's FDA approval for HER2-low breast cancer in 2022. Notably, DESTINY-Breast06 did not include HR-negative patients and aimed at an earlier treatment phase before chemotherapy.

HER2 Expression and Diagnostic Challenges

HER2 expression is measured using immunohistochemistry (IHC), a method that stains tissues to reveal biomarker presence. HER2-low is defined by an IHC score of 1+, indicating faint membrane staining in at least 10% of tumor cells. The HER2-ultralow category includes cases with even lower HER2 levels, extending into IHC 0, but with faint membrane staining.

In the trial, 60% to 65% of traditional HR-positive, HER2-negative metastatic breast cancer cases were categorized as HER2-low, while 20% to 25% fit the HER2-ultralow definition. A subgroup analysis of 152 HER2-ultralow patients in DESTINY-Breast06 showed Enhertu reduced disease progression or death risk by 22% compared to chemotherapy, although this result lacked statistical significance. Median progression-free survival (PFS) for Enhertu was 13.2 months versus 8.3 months for chemotherapy in the ultralow group. The primary endpoint revealed Enhertu's statistically significant 38% risk reduction in the HER2-low group, extending PFS by 5.1 months compared to the control group.

Excitement and Caution

Despite immature overall survival data, early results showed a favorable trend toward improved survival in HER2-low and HER2-ultralow patients. Dr. Susan Galbraith of AstraZeneca and Dr. Mark Rutstein of Daiichi Sankyo expressed enthusiasm about Enhertu's potential to redefine breast cancer treatment.

However, experts acknowledge the challenges ahead. Dr. Erica Mayer from the Dana-Farber Cancer Institute noted that while the results are promising, Enhertu's associated toxicities, such as interstitial lung disease (ILD), must be carefully managed. In the Enhertu group, 49 patients (11.3%) experienced ILD, with three fatalities. This underscores the need for a balanced approach when integrating Enhertu into earlier treatment stages.

Future Directions and Patient Identification

One critical aspect for Enhertu's future success is accurately identifying patients with HER2-ultralow expression. Differentiating between IHC 1+ and IHC 0 can be challenging for pathologists, complicating patient categorization. Dr. Julie Gralow of ASCO emphasized the importance of collaboration with pathology experts to ensure reliable identification.

Enhertu's potential to address unmet needs in breast cancer treatment is clear, but researchers must navigate diagnostic and safety challenges carefully. AstraZeneca and Daiichi Sankyo are committed to refining their approach, with hopes that precise patient selection and improved diagnostic techniques will facilitate the broader use of Enhertu in treating breast cancer.

In conclusion, Enhertu has shown significant promise in extending its benefits to patients with varying levels of HER2 expression. While challenges remain, the ongoing efforts by AstraZeneca and Daiichi Sankyo aim to enhance breast cancer treatment outcomes and offer new hope to patients.

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