FDA Accepts sBLA for T-DXd Followed by THP in High-Risk, HER2+ Early-Stage Breast Cancer

The FDA has accepted a supplemental biologics license application (sBLA) seeking the approval of neoadjuvant fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) followed by paclitaxel, trastuzumab (Herceptin), and pertuzumab (Perjeta; THP) for the treatment of adult patients with high-risk, HER2-positive (immunohistochemistry 3+ or in situ hybridization–positive), stage II/III breast cancer.1

This submission was supported by data from the phase 3 DESTINY-Breast11 trial (NCT05113251), in which patients with high-risk, locally advanced, HER2-positive early-stage breast cancer who received neoadjuvant T-DXd followed by THP achieved a statistically significant and clinically meaningful improvement in pathologic complete response (pCR) rate compared with those who received neoadjuvant dose-dense doxorubicin and cyclophosphamide followed by THP. The trial also showed an early positive trend in event-free survival (EFS) favoring the T-DXd arm, as well as an improved safety profile with T-DXd vs dose-dense doxorubicin and cyclophosphamide followed by THP.

The safety profiles of T-DXd and THP were consistent with the known safety profiles of each individual treatment, and no new safety signals were identified. Notably, an independent adjudication committee determined that rates of interstitial lung disease were similar between the T-DXd/THP and dose-dense doxorubicin/cyclophosphamide/THP arms.

The FDA has set a Prescription Drug User Fee Act target action date of May 18, 2026, for their regulatory decision. Data from DESTINY-Breast11 are planned to be presented at an upcoming medical meeting.2

“Achieving a pCR prior to surgery in HER2-positive early-stage breast cancer is critical to reducing the risk of disease recurrence and improving the potential for cure,” Ken Takeshita, MD, global head of research and development at Daiichi Sankyo, stated in a news release.1 “If approved, [T-DXd] could change how patients with high-risk, HER2-positive early-stage breast cancer are treated, and we look forward to working closely with the FDA to bring this innovative treatment regimen to patients in this setting.”

What Was the Design of DESTINY-Breast11?

The global, multicenter, randomized, open-label trial investigated the efficacy and safety of neoadjuvant T-DXd at 5.4 mg/kg as monotherapy or followed by THP vs dose-dense doxorubicin and cyclophosphamide followed by THP in 927 patients with high-risk, locally advanced or inflammatory HER2-positive early breast cancer.1,3 To enroll in the trial, patients needed to be 18 years or older, have an ECOG performance status of 0 or 1, have adequate bone marrow and organ function, have a left ventricular ejection fraction of at least 50% within 28 days before random assignment, and have 2 cores of FFPE tissue block or 20 freshly cute serial tumor slides for HER2 assessment by a central lab.

Patients were randomly assigned 1:1:1 to receive 8 cycles of T-DXd monotherapy, 4 cycles of T-DXd followed by 4 cycles of THP, or 4 cycles of dose-dense doxorubicin and cyclophosphamide followed by 4 cycles of THP.1

pCR rate was the primary end point. Secondary end points included EFS, invasive disease–free survival, overall survival, and safety.1,2

Notably, as recommended by an independent data monitoring committee, enrollment to the T-DXd monotherapy arm of DESTINY-Breast11 was closed based on findings from a prior efficacy evaluation.1

“The clinically meaningful improvement in pCR and favorable safety profile seen with DESTINY-Breast11 highlight the opportunity for [T-DXd] followed by THP to become an important new approach for patients with HER2-positive early breast cancer,” Susan Galbraith, MBBChir, PhD, executive vice president of oncology R&D at AstraZeneca, added in the news release. “[T-DXd] is already established in the metastatic setting, and now we have the potential to expand its use into earlier stages of disease where cure is possible.”

References

1. Enhertu followed by THP supplemental biologics license application accepted in the U.S. for patients with high-risk HER2 positive early-stage breast cancer prior to surgery. News release. Daiichi Sankyo. October 1, 2025. Accessed October 1, 2025. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202510/20251001_E.pdf
2. Enhertu followed by THP before surgery showed statistically significant and clinically meaningful improvement in pathologic complete response in patients with high-risk HER2-positive early-stage breast cancer in DESTINY-Breast11 phase III trial. News release. AstraZeneca. May 7, 2025. Accessed October 1, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/enhertu-improved-pcr-in-early-stage-breast-cancer.html
3. Trastuzumab deruxtecan (T-DXd) alone or in sequence with THP, versus standard treatment (ddAC-THP), in HER2-positive early breast cancer. ClinicalTrials.gov. Updated August 3, 2025. Accessed October 1, 2025. https://clinicaltrials.gov/study/NCT05113251