CHMP Recommends T-DXd EU Approval in HER2-Low/Ultralow Breast Cancer

The FDA approved T-DXd for patients with HER2-low or HER2-ultralow breast cancer based on findings from the DESTINY-Breast06 trial in January 2025.

The European Medicine Agency’s Committee for Medical Products for Human Use (CHMP) has recommended the approval of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in the EU as a treatment for adults with metastatic or unresectable hormone receptor (HR)–positive, HER2-low or HER2-ultralow breast cancer previously treated with at least 1 endocrine therapy (ET) in the metastatic setting, and are not eligible for ET in the next line setting, according to a press release from the developer, AstraZeneca.¹

The CHMP based its recommendation on findings from the phase 3 DESTINY-Breast06 trial (NCT04494425), which evaluated treatment with T-DXd vs investigator’s choice of chemotherapy in patients with HR-positive, HER2-low or HER2-ultralow advanced or metastatic breast cancer. Investigators previously published findings from the DESTINY-Breast06 trial in The New England Journal of Medicine.²

With a data cutoff date of March 18, 2024, the median progression-free survival (PFS) among patients with HER2-low disease was 13.2 months (95% CI, 11.4-15.2) with T-DXd vs 8.1 months (95% CI, 7.0-9.0) with chemotherapy (HR, 0.62; 95% CI, 0.52-0.75; P <.001). Additionally, the median PFS was 13.2 months (95% CI, 12.0-15.2) and 8.1 months (95% CI, 7.0-9.0) in each respective arm across the intent-to-treat population (HR, 0.64; 95% CI, 0.54-0.76; P <.001). In the HER2-ultralow population, data showed a median PFS of 13.2 months (95% CI, 9.8-17.3) vs 8.3 months (95% CI, 5.8-15.2) across each arm (HR, 0.78; 95% CI, 0.50-1.21).

The safety profile of T-DXd in the DESTINY-Breast06 trial was comparable with prior reports of the agent; investigators observed no new safety signals.

“Endocrine therapy is typically used in the initial treatment of HR-positive metastatic breast cancer but as the disease progresses the benefit of continued endocrine therapy is limited, and subsequent standard-of-care chemotherapy is associated with poor outcomes,” Susan Galbraith, executive vice president of Oncology Hematology Research & Development at AstraZeneca, stated in the press release.¹ “[T-DXd] has the potential to be the first HER2-directed treatment for patients in the EU with HR-positive, HER2-low or HER2-ultralow metastatic breast cancer directly following endocrine therapy, which would mark an important shift in how patients in this setting are treated.”

In the international, open-label phase 3 DESTINY-Breast06 trial, 866 patients were randomly assigned 1:1 to receive T-DXd at 5.4 mg/kg once every 3 weeks (n = 436) or investigator’s choice of chemotherapy (n = 430). Treatment options in the comparator arm included capecitabine, paclitaxel, or nab-paclitaxel.

The trial’s primary end point was PFS among patients with HR-positive, HER2-low disease per blinded independent central review. Secondary end points included PFS per BICR in the overall population, overall survival (OS) in the HER2-low population, and OS in the overall population.

Patients 18 years and older with progressive disease following 2 or more prior lines of endocrine-based therapy for metastatic disease and no prior chemotherapy were eligible for enrollment on the trial. Other requirements for study entry included having adequate tumor samples for assessing HER2 status and adequate organ and bone marrow function.³

Those with lung-specific intercurrent clinically significant illness, uncontrolled or significant cardiovascular disease or infection, or clinically active central nervous system metastases were ineligible for study entry.

The FDA approved T-DXd for patients with HER2-low or HER2-ultralow breast cancer based on findings from the DESTINY-Breast06 trial in January 2025.⁴

“In DESTINY-Breast06, T-DXd was superior to standard chemotherapy with both capecitabine as well as taxanes for patients with metastatic HR–positive breast cancer…A significant improvement in PFS is seen with T-DXd in this setting,” Aditya Bardia, MD, MPH, FASCO, professor in the Department of Medicine, Division of Hematology/Oncology, and director of Translational Research Integration at the University of California Los Angels Health Jonsson Comprehensive Cancer Center, stated in an interview with CancerNetwork^® about the FDA approval.

References

1. Enhertu recommended for approval in the EU by CHMP for patients with HER2-low or HER2-ultralow metastatic breast cancer following at least one endocrine therapy. News release. AstraZeneca. February 28, 2025. Accessed March 3, 2025. https://tinyurl.com/2vxekwfe
2. Bardia A, Hu X, Dent R, et al. Trastuzumab deruxtecan after endocrine therapy in metastatic breast cancer. N Engl J Med. 2024;391(22):2110-2122. doi: 10.1056/NEJMoa2407086
3. Study of trastuzumab deruxtecan (T-DXd) vs investigator's choice chemotherapy in HER2-low, hormone receptor positive, metastatic breast cancer (DB-06). ClinicalTrials.gov. Updated January 15, 2025. Accessed March 3, 2025. https://tinyurl.com/w8s42yy7
4. 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. FDA. January 27, 2024. Accessed March 3, 2025. https://tinyurl.com/5n8ab8sk