T-DXd With Pertuzumab Improves PFS in HER2+ Metastatic Breast Cancer

T-DXd demonstrated a PFS benefit across all prespecified subgroups in patients with metastatic HER2-positive breast cancer.

Fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in combination with pertuzumab (Perjeta) elicited an improvement in progression-free survival (PFS) compared with a taxane, trastuzumab (Herceptin), and pertuzumab in the first-line treatment of patients with HER2-positive metastatic breast cancer, according to a release from the developer, AstraZeneca, on findings from the phase 3 DESTINY-Breast09 trial (NCT04784715) .¹

Results came from a planned interim analysis of DESTINY-Breast09, which evaluated the efficacy and safety of T-DXd with or without pertuzumab vs standard of care consisting of a taxane, trastuzumab, and pertuzumab in patients with HER2-positive metastatic breast cancer.²

The trial observed a PFS improvement with T-DXd and pertuzumab in all prespecified patient subgroups. Overall survival (OS) data were not mature at the interim analysis, although they showed a favorable trend with T-DXd and pertuzumab. Additionally, the treatment arm evaluating T-DXd monotherapy is blinded to both patients and investigators; it will continue to the final PFS analysis.

Additional data from the T-DXd plus pertuzumab arm of the trial are planned to be presented at an upcoming medical conference and shared with regulatory authorities.

“This is the first trial in more than a decade to demonstrate superior efficacy across a broad [patient population with] HER2-positive metastatic breast cancer compared to the current first-line standard of care,” stated Susan Galbraith, executive vice president of Oncology Hematology Research and Development at AstraZeneca, in the press release.¹ “This is a significant milestone for patients and sets the foundation for [T-DXd] in combination with pertuzumab as an important treatment option in the first-line HER2-positive setting.”

DESTINY-Breast09 was a global, multicenter, randomized trial that enrolled a total of 1157 patients who were randomly assigned, in a 1:1:1 ratio, to receive 5.4 mg/kg of T-DXd monotherapy; 5.4 mg/kg of T-DXd plus pertuzumab; or a taxane, trastuzumab, and pertuzumab. All agents were administered via intravenous infusion. Trial randomization was stratified based on hormone receptor (HR) status, PIK3CA mutation status, and prior treatment (de novo metastatic disease vs progression from early-stage disease).

Eligible patients were 18 years or older with pathologically documented breast cancer that was advanced or metastatic, locally assessed and confirmed as HER2-positive, and documented by local testing as HR-positive or HR-negative in the metastatic setting. Additionally, patients received no prior chemotherapy or HER2-targeted therapy for advanced or metastatic disease or had 1 prior line of endocrine therapy, had adequate organ and bone marrow function, and had an ECOG performance status of 0 or 1.

Those with substance abuse or other medical conditions that may have interfered with study results, spinal cord compression or clinically active central nervous system metastases, active or prior documented interstitial lung disease, and prior randomization or treatment in a previous T-DXd study regardless of treatment arm assignment were ineligible for participation.

The trial’s primary end point was PFS per blinded independent central review. Secondary end points included PFS by investigator assessment, OS, objective response rate, duration of response, time to second progression, patient-reported treatment tolerability, and safety and tolerability of T-DXd alone and with pertuzumab.

Study investigators reported that the safety profile of T-DXd with pertuzumab was consistent with previously known data of the individual therapies.

Recently, in January 2025, the FDA approved T-DXd in the treatment of patients with unresectable or metastatic HER2-low or HER2-ultralow breast cancer who received at least 1 type of endocrine therapy in the metastatic setting.³ The FDA also approved T-DXd as a treatment for patients with HER2-positive metastatic breast cancer who received prior anti-HER2 treatment followed by disease recurrence during, or within 6 months of, treatment in May 2022.⁴

References

1. ENHERTU® (fam-trastuzumab deruxtecan-nxki) plus pertuzumab demonstrated highly statistically significant and clinically meaningful improvement in progression-free survival vs. THP as 1st-line therapy for patients with HER2-positive metastatic breast cancer. News release. AstraZeneca. April 21, 2025. Accessed April 21, 2025. https://tinyurl.com/ycxdtrvw
2. Trastuzumab deruxtecan (T-DXd) with or without pertuzumab versus taxane, trastuzumab and pertuzumab in HER2-positive metastatic breast cancer (DESTINY-Breast09). ClinicalTrials.gov. Updated December 16, 2024. Accessed April 21, 2025. https://tinyurl.com/2urmbyv7
3. 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, 2025. Accessed April 21, 2025. https://tinyurl.com/5n8ab8sk
4. Enhertu approved in the US for patients with HER2-positive metastatic breast cancer treated with a prior anti-HER2-based regimen. News release. AstraZeneca. May 5, 2022. Accessed April 21, 2025. https://bit.ly/3OZHpSs