FDA Approves Companion Diagnostic for T-DXd in HER2-Ultralow Metastatic Breast Cancer

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The FDA has approved a label expansion for the PATHWAY anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody to identify patients with hormone receptor–positive, HER2-ultralow metastatic breast cancer who may be eligible for treatment with fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu).¹

The expanded approval for the companion diagnostic followed the January 27, 2025, FDA approval of T-DXd for the treatment of adult patients with unresectable or metastatic, hormone receptor–positive, HER2-low (immunohistochemistry [IHC] 1+ or 2+/in situ hybridization [ISH] negative) or HER2-ultralow (IHC 0 with membrane staining) breast cancer, as determined by an FDA-approved test, that has progressed on 1 or more endocrine therapies in the metastatic setting.²

“One in 8 women in the United States will face invasive breast cancer in their lifetime,” Matt Sause, chief executive officer of Roche Diagnostics, stated in a news release.¹ “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 approval of T-DXd was supported by data from the phase 3 DESTINY-Breast06 trial (NCT04494425), which were presented at the 2024 ASCO Annual Meeting and simultaneously published in the New England Journal of Medicine. Findings showed that among the HER2-low population, patients treated with T-DXd (n = 359) experienced a median progression-free survival (PFS) of 13.2 months compared with 8.1 months for physician’s choice of chemotherapy (n = 354; HR, 0.62; 95% CI, 0.51-0.74; P < .0001).³

Among the intention-to-treat (ITT) population, which included patients with HER2-low and HER2-ultralow disease, T-DXd (n = 436) generated a median PFS of 13.2 months vs. 8.1 months for chemotherapy (n = 430; HR, 0.63; 95% CI, 0.53-0.75; P < .0001).

In the HER2-ultralow population, the median PFS was 13.2 months for T-DXd (n = 76) vs 8.3 months for chemotherapy (n = 75; HR, 0.78; 95% CI, 0.50-1.21).

The randomized, multicenter, open-label DESTINY-Breast06 trial enrolled patients with hormone receptor–positive metastatic breast cancer that was HER2-low (IHC 1+ or IHC 2+/ISH negative) or HER2-ultralow (IHC 0 with membrane staining). Patients were required to be naive to chemotherapy in the metastatic setting. However, patients needed to have at received at least 2 prior lines of endocrine therapy with or without targeted therapy in the metastatic setting; or 1 prior line of endocrine therapy in the metastatic setting with disease progression within 6 months of starting first-line endocrine therapy with a CDK4/6 inhibitor or recurrence within 24 months of starting adjuvant endocrine therapy.

Patients were randomly assigned 1:1 to received T-DXd at 5.4 mg/kg once every 3 weeks or physician’s choice of chemotherapy comprising capecitabine, nab-paclitaxel (Abraxane), or paclitaxel. Stratification factors included prior CDK4/6 inhibitor use (yes vs no), HER2 expression (low vs ultralow), and prior taxane use in the nonmetastatic setting (yes vs no).

PFS per blinded independent central review in the HER2-low population served as the trial’s primary end point. Key secondary end points included PFS and overall survival (OS) in the ITT population; and OS in the HER2-low population. Other secondary end points consisted of overall response rate, duration of response, safety, and patient-reported outcomes.

Additional data showed OS data reached maturity of approximately 40%; in the HER2-low population, the 12-month OS rate was 87.6% with T-DXd vs 81.7% for chemotherapy (HR, 0.83; 95% CI, 0.66-1.05; P = .1181). These respective rates were 87.0% and 81.1% in the ITT population (HR, 0.81; 95% CI, 0.65-1.00). In the HER2-ultrallow population, the 12-month OS rate was 84.0% for T-DXd vs 78.7% for chemotherapy (HR, 0.75; 95% CI, 0.43-1.29).

Safety data showed that any-grade treatment-emergent adverse effects (TEAEs) occurred in 98.8% of patients treated with T-DXd (n = 434) vs 95.2% of patients given chemotherapy (n = 417). The rates of any-grade treatment-related AEs were 96.1% and 89.4%, respectively. Serious TEAEs were reported in 20.3% and 16.1% of patients, respectively.

In the T-DXd arm, TEAEs led to treatment discontinuation, dose interruptions, and dose reductions in 14.3%, 48.4%, and 24.7% of patients, respectively. These respective rates were 9.4%, 38.4%, and 38.6%. TEAEs led to death in 2.5% of patients in the experimental arm vs 1.4% of patients in the control arm. TEAEs leading to death were deemed related to treatment in 1.2% of patients in the T-DXd arm vs no patients in the chemotherapy arm.

References

1. Roche receives FDA approval for the first companion diagnostic to identify patients with HER2-ultralow metastatic breast cancer eligible for Enhertu. News release. Roche. January 30, 2025. Accessed February 3, 2025. https://www.roche.com/media/releases/med-cor-2025-01-31
2. Enhertu approved in the US as first HER2-directed therapy for patients with HER2-low or HER2-ultralow metastatic breast cancer following disease progression after one or more endocrine therapies. News Release. AstraZeneca. January 27, 2025. Accessed February 3, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/enhertu-approved-in-us-for-breast-cancer-post-et.html
3. Curigliano G, Hu X, Dent RA, et al. Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): Primary results from DESTINY-Breast06 (DB-06). J Clin Oncol. 2024;42(suppl 17):LBA1000. doi:10.1200/JCO.2024.42.17_suppl.LBA1000