FDA Grants Priority Review to T-DXd in HR+, HER2-Low/-Ultralow Breast Cancer

The FDA has accepted and granted priority review to the supplemental biologics license application for fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) for the treatment of patients with unresectable or metastatic hormone receptor–positive, HER2-low and HER2-ultralow breast cancer who previously received 1 or more endocrine therapies in the metastatic setting.¹

The regulatory decision was supported by findings from the phase 3 DESTINY-Breast06 trial (NCT04494425), in which the agent generated a statistically significant and clinically meaningful progression-free survival (PFS) benefit over physician’s choice of chemotherapy.

Primary results from the trial were presented at the 2024 ASCO Annual Meeting.² At the data cutoff of March 18, 2024, the risk of disease progression or death was reduced by 37% (HR, 0.63; 95% CI, 0.53-0.75; P <.0001) and the median progression-free survival (PFS) by blinded independent central review (BICR) increased by 5.1 months with T-DXd in the overall study population (n = 866).

Results were comparable between the HER2-low and -ultralow populations. In the HER2-low population, the median PFS was 13.2 months with T-DXd (n = 359) vs 8.1 months with chemotherapy (n = 354; HR, 0.62; 95% CI, 0.51-0.74; P < .0001). In a prespecified exploratory analysis of patients with HER2-ultralow disease (n = 152), the median PFS was 13.2 months vs 8.3 months with these respective regimens (HR, 0.78; 95% CI, 0.50-1.21). No new safety signals were observed with the regimen.²

“While endocrine therapies are widely used in the initial treatment of hormone receptor–positive metastatic breast cancer, most patients see limited benefit with additional lines of treatment, and subsequent chemotherapy is often associated with poor response rates and outcomes,” Susan Galbraith, executive vice president of Oncology Research and Development at AstraZeneca stated in a news release. “The results from DESTINY-Breast06 show that [T-DXd] has the potential to evolve the current hormone receptor–positive treatment landscape and become the first targeted treatment for patients with HER2-low or HER2-ultralow expression following endocrine therapy.”

In August 2024, T-DXd received FDA breakthrough therapy designation for use in this patient population.³ The agent is currently FDA approved for patients with HER2-low metastatic breast cancer who have received prior systemic therapy in the metastatic setting or experienced recurrence during or within 6 months of completing adjuvant chemotherapy, among other indications.¹

“This priority review highlights the potential to expand the existing indication of [T-DXd] in HER2-low metastatic breast cancer to include use in an earlier disease setting as well as in a broader patient population that includes HER2-ultralow. We look forward to working closely with the FDA with the goal of bringing [T-DXd] to more patients as quickly as possible,” Ken Takeshita, MD, global head of Research and Development at Daiichi Sankyo, concluded.

DESTINY-Breast06 Overview and Additional Data

The multicenter, open-label trial enrolled patients with hormone receptor–positive metastatic breast cancer who had not been previously exposed to chemotherapy in the metastatic setting. Patients were required to have HER2-low disease, defined as immunohistochemistry (IHC) 1+ or IHC 2+/in situ hybridization–negative, or HER2-ultralow disease, defined as IHC 0 with membrane staining.² Other key inclusion criteria included two or more prior lines of endocrine therapy plus targeted therapy in the metastatic setting; or 1 prior line of therapy in the metastatic setting followed by progression no more than 6 months after starting frontline treatment with endocrine therapy and a CDK4/6 inhibitor or recurrence no more than 24 months after starting adjuvant endocrine therapy.

Upon enrollment, 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). In the control arm, treatment options comprised capecitabine (Xeloda), nab-paclitaxel (Abraxane), and paclitaxel. Patients were stratified according to prior treatment with CDK4/6 inhibitors, HER2 expression, and prior taxane use in the non-metastatic setting.

The study’s primary end point was PFS per BICR in the HER2-low population. PFS in the intention-to-treat (ITT) population, overall survival (OS) in the HER2-low group, and OS in the ITT population served as key secondary end points. Additional secondary end points included overall response rate (ORR), duration of response, safety and tolerability, and patient-reported outcomes.

Additional findings from DESTINY-Breast06 showed that patients in the HER2-low population achieved an ORR of 56.5% with T-DXd vs 32.2% with chemotherapy. Among those with HER2-ultralow disease, ORRs were 61.8% vs 26.3%, respectively.

OS data were at 40% maturity at the data cutoff but demonstrated a trend in favor of T-DXd in both the HER2-low (HR, 0.83; 95% CI, 0.66-1.05; P = .1181) and ITT (HR, 0.81; 95% CI, 0.65-1.00) patient populations at 12 months. Second interim and final OS analyses are planned in the HER2-low population once the data reach approximately 56% and 74% maturity, respectively.²

Regarding safety, 98.8% and 95.2% of patients in the T-DXd and chemotherapy arms, respectively, experienced any-grade treatment-emergent adverse effects (TEAEs) Serious TEAEs occurred in 20.3% and 16.1% of patients in these respective arms. The most commonly reported treatment-related TEAEs in the T-DXd and chemotherapy arms, respectively, were nausea (65.9%; 23.5%), fatigue (46.8%; 34.3%), and alopecia (45.4%; 19.4%).

References

1. Enhertu (fam-trastuzumab deruxtecan-nxki) granted priority review in the US for patients with HER2-low or HER2-ultralow metastatic breast cancer who have received at least one line of endocrine therapy.News release. AztraZeneca. October 1, 2024. Accessed October 1, 2024. https://www.astrazeneca-us.com/media/press-releases/2024/enhertu-granted-priority-review-us-for-patients-her2-low-or-her2-ultralow-metastatic-breast-cancer-who-have-received-at-least-1-line-endocrine-therapy.html#:~:text=AstraZeneca%20and%20Daiichi%20Sankyo's%20supplemental,HER2%20ultralow%20(IHC%200%20with
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 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 October 1, 2024. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202408/20240819_E1.pdf