FDA Approves First HER2-Ultralow Companion Diagnostic, Expanding Treatment Eligibility

Today, the FDA granted a label expansion approval for Roche’s PATHWAY anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody, a companion diagnostic, to identify patients with HR-positive, HER2-ultralow metastatic breast cancer who may be eligible for treatment with trastuzumab deruxtecan (Enhertu).¹

Roche’s PATHWAY HER2 (4B5) test helps identify patients with HER2-ultralow breast cancer, who may be eligible for targeted therapy. | Image credit: angellodeco - stock.adobe.com

This approval is a significant milestone in advancing breast cancer diagnostics and treatment, as trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate (ADC) developed by Daiichi Sankyo and jointly commercialized by Daiichi Sankyo and AstraZeneca, shows promise in improving patient outcomes.

“One in eight women in the United States will face invasive breast cancer in their lifetime,” said Matt Sause, chief executive officer of Roche Diagnostics, in a statement. “The rising incidence of metastatic breast cancer, particularly among younger populations, underscores the urgent need for new diagnostic options. The approval of our test for determining HER2-ultralow status offers new hope to patients by providing a possible path to HER2-targeted treatment where none existed before, helping clinicians transform outcomes for many facing this challenging disease.”

The introduction of HER2-low status in 2022 marked a significant shift in the classification of HER2 expression levels in breast cancer. Prior to this, HER2 status was limited to “positive” or “negative” categories, based on the amount of HER2 receptor protein present on cancer cells. However, with the new "HER2-ultralow" category, patients with very low levels of HER2 expression—lower than the previously defined HER2-low category—can now be identified. This classification opens the door to personalized treatment options for a previously underserved group of patients with metastatic breast cancer.

HER2, a receptor protein, plays a critical role in promoting the growth of cancer cells. Traditionally, pathologists determine HER2 status by evaluating the level of HER2 expression in breast cancer tissue samples. In the case of patients with HER2-ultralow breast cancer, the PATHWAY HER2 (4B5) test can identify those who have very low HER2 levels, enabling clinicians to assess eligibility for treatment with trastuzumab deruxtecan, which has demonstrated efficacy in clinical trials.

In the DESTINY-Breast06 trial, trastuzumab deruxtecan demonstrated a 36% reduction in the risk of disease progression or death compared with chemotherapy (HR, 0.64; 95% CI, 0.54-0.76; P < .0001) in patients with chemotherapy-naïve HER2-low or HER2-ultralow metastatic breast cancer.² Patients treated with trastuzumab deruxtecan achieved a median progression-free survival of 13.2 months vs 8.1 months for those receiving chemotherapy.

Importantly, an exploratory analysis of the trial found that the outcomes for HER2-low and HER2-ultralow patients were consistent, further validating the test’s expanded use.¹

The approval of the PATHWAY HER2 (4B5) test to include HER2-ultralow status enhances Roche’s breast cancer diagnostic portfolio, empowering clinicians to make more informed decisions and providing patients with targeted therapies that can significantly improve their outcomes, while also ensuring patients who would not respond to therapy are not receiving these expensive therapies.

With this approval, Roche hopes to solidify its leadership in HER2 diagnostics and aims to continue expanding personalized treatment for metastatic breast cancer.

Additionally, Roche’s PATHWAY (4B5), when used with the BenchMark IHC/ISH slide staining system, standardizes immunohistochemistry (IHC) processes to reduce variability and minimize human error. Furthermore, the test has demonstrated high proficiency and strong concordance with HER2 FISH assays, ensuring reliable results that support clinical decision-making.

References

1. Roche receives FDA approval for the first companion diagnostic to identify patients with HER2-ultralow metastatic breast cancer eligible for Enhertu. Roche. News release. January 31, 2025. https://www.globenewswire.com/news-release/2025/01/31/3018924/0/en/Roche-receives-FDA-approval-for-the-first-companion-diagnostic-to-identify-patients-with-HER2-ultralow-metastatic-breast-cancer-eligible-for-ENHERTU.html.

2. Steinzor P. FDA approves trastuzumab deruxtecan for HER2-low/ultralow breast cancer. AJMC. January 28, 2025. Accessed January 31, 2025. https://www.ajmc.com/view/fda-approves-trastuzumab-deruxtecan-for-her2-low-ultralow-breast-cancer.