T-DXd Earns FDA Breakthrough Therapy Status in HER2-Low Breast Cancer

Supporting data for this breakthrough therapy designation came from the phase 3 DESTINY-Breast06 trial (NCT04494425) assessing the safety and efficacy of T-DXd vs investigator’s choice of chemotherapy in HR–positive, HER2-low or HER2-ultralow advanced or metastatic breast cancer.

The FDA has granted breakthrough therapy designation to fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) as a treatment for those with unresectable or metastatic hormone receptor (HR)–positive, HER2-low or HER2-ultralow breast cancer, according to a press release from the developer, Daiichi Sankyo.¹

Specifically, the breakthrough therapy status supports the use of T-DXd for patients with 2 prior lines of endocrine therapy in the metastatic setting or those with 1 line of endocrine therapy following disease progression within 6 months of initiating frontline endocrine therapy plus a CDK4/6 inhibitor or within 2 years of beginning adjuvant endocrine therapy.

“If approved, [T-DXd] could once again change the treatment paradigm for certain patients with breast cancer, pushing past old boundaries and broadening the number of people who may be eligible for a HER2-directed therapy,” Ken Takeshita, MD, global head of Research and Development at Daiichi Sankyo, said in the press release.¹

Supporting data for this breakthrough therapy designation came from the phase 3 DESTINY-Breast06 trial (NCT04494425) assessing the safety and efficacy of T-DXd vs investigator’s choice of chemotherapy in HR–positive, HER2-low or HER2-ultralow advanced or metastatic breast cancer. Investigators previously presented findings from the DESTINY-Breast06 trial at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.²

Across the HR–positive HER2-low population, T-DXd produced a median progression-free survival (PFS) of 13.2 months per blinded independent central review (BICR) compared with 8.1 months in the chemotherapy arm (HR, 0.62; 95% CI, 0.51-0.74; P <.0001). Across the intent-to-treat (ITT) population, the median PFS was 13.2 months vs 8.1 months in each respective arm (HR, 0.63; 95% CI, 0.53-0.75; P <.0001).

Among patients with HER2-low disease, T-DXd yielded an objective response rate (ORR) of 56.5% compared with 32.2% in the chemotherapy arm. For those with HER2-ultralow disease, the respective ORRs were 61.8% vs 26.3%.

Any-grade treatment-emergent adverse effects (TEAEs) occurred in 98.8% and 95.2% of the T-DXd and chemotherapy arms, respectively. Serious TEAEs affected 20.3% and 16.1% of patients in each arm. Common drug-related TEAEs in each respective arm included nausea (65.9% vs 23.5%), fatigue (46.8% vs 34.3%), and alopecia (45.4% vs 19.4%).

“Endocrine therapies are widely used early in the treatment of HR-positive metastatic breast cancer, but following 1 or more lines of treatment, patients often derive limited efficacy from further endocrine-based therapy,” lead investigator Giuseppe Curigliano, MD, PhD, a professor of Medical Oncology at the University of Milan and the Head of the Division of Early Drug Development at the European Institute of Oncology, IRCCS, Italy, said in a press release on these findings.³ “With a median [PFS] of more than a year, the results from DESTINY-Breast06 show that [T-DXd] could become a new standard of care for patients with HER2-low and HER2-ultralow expressing tumors following endocrine therapy in the metastatic setting.”

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

The trial’s primary end point was PFS per BICR in the HER2-low population. Key secondary end points included PFS in the ITT population, overall survival (OS) in the HER2-low group, and OS across the ITT population. Other secondary end points included ORR, duration of response, safety and tolerability, and patient-reported outcomes.

Those with HR-positive metastatic breast and no prior chemotherapy in the metastatic setting were eligible for enrollment on the trial. Investigators stratified patients based on prior treatment with CDK4/6 inhibitors, HER2 expression, and prior taxane in the non-metastatic setting.

References

1. ENHERTU® granted breakthrough therapy designation in U.S. for certain patients with HER2 low or HER2 ultralow metastatic breast cancer. News release. Daiichi Sankyo. August 19, 2024. Accessed August 19, 2024. https://tinyurl.com/2k9bfnp2
2. 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
3. ENHERTU® demonstrated a median progression-free survival of 13.2 Months in HR positive, HER2 low and HER2 ultralow metastatic breast cancer following one or more lines of endocrine therapy. News release. Daiichi Sankyo. June 2, 2024. Accessed August 19, 2024. https://tinyurl.com/yb3u7y3z