T-DXd Followed by THP Improves pCR Rate in HER2+ Early Breast Cancer

HER2+ Breast Cancer |
Image Credit: © Sebastian Kaulitzki
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Treatment with neoadjuvant fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) followed by trastuzumab (Herceptin), pertuzumab (Perjeta), and paclitaxel (THP) demonstrated a statistically significant and clinically meaningful improvement in pathologic complete response (pCR) rate compared with standard-of-care dose-dense doxorubicin and cyclophosphamide followed by THP (ddAC-THP) in patients with high-risk, locally advanced, HER2-positive early-stage breast cancer, according to results from the phase 3 DESTINY-Breast11 trial (NCT05113251).¹

Although data for the key secondary end point of event-free survival (EFS) was not mature at the time of this analysis, early EFS findings favored the T-DXd–based regimen compared with ddAC-THP.

"The clinically meaningful improvement in pCR [rate] and the safety data seen in DESTINY-Breast11 highlight the potential of T-DXd to challenge the current standard of care in early-stage HER2-positive breast cancer. T-DXd is already an important treatment option in the metastatic setting, and these data have the potential to allow this medicine to move into early stages of the disease where cure is possible," Susan Galbraith, executive vice president of Oncology Hematology R&D at AstraZeneca, stated in a news release.

Following a recommendation from the study’s independent data monitoring committee at a prior interim efficacy assessment, enrollment in the third arm of the DESTINY-Breast11 trial evaluating T-DXd monotherapy was closed. Full data from the trial will be presented at an upcoming medical meeting and submitted to regulatory authorities for review.

"There are still many patients with early-stage breast cancer who do not achieve a pCR with treatment in the neoadjuvant setting, increasing the risk of disease recurrence. These topline results from DESTINY-Breast11 demonstrate that T-DXd followed by THP could offer patients with HER2-positive breast cancer a promising new treatment approach prior to surgery, setting more patients on a path towards a potential cure," Ken Takeshita, global head of R&D at Daiichi Sankyo, added in a news release.

DESTINY-Breast11 Trial Design and Enrollment Criteria

Eligible patients for the open-label study were at least 18 years of age with histologically confirmed HER2-positive early breast cancer, classified as T0-4 N1-3, M0; or T3, N0, M0.² Additional eligibility requirements included an ECOG performance status of 0 or 1, adequate organ and bone marrow function, a left ventrical ejection fraction greater than 50% within 28 days prior to randomization, and availability of tumor tissue for central HER2 testing.

Ineligible patients include those with a prior history of invasive breast cancer or stage IV disease; any primary malignancy within the past 3 years except resected non-melanoma skin cancer or curatively treated in situ disease; a history of ductal carcinoma in situ unless treated with mastectomy more than 5 years prior to the current diagnosis; a history of or current interstitial lung disease or pneumonitis; prior systemic therapy for breast cancer; or prior treatment with anthracyclines, cyclophosphamide, or taxanes for any malignancy.

The study enrolled a total of 927 patients who were randomly assigned in a 1:1:1 ratio to receive one of three neoadjuvant regimens: T-DXd monotherapy (arm A); T-DXd followed by THP (arm B), or ddAC-THP (arm C).

The primary end point was pCR rate, defined as the absence of invasive cancer in the breast and lymph nodes following surgery. Secondary end points included EFS, invasive disease–free survival, overall survival, safety, and tolerability.

In the advanced-stage setting, T-DXd is currently approved by the FDA for adult patients with unresectable or metastatic HER2-positive breast cancer who have previously received an anti–HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting, and have developed disease recurrence during or within 6 months of therapy completion.³

T-DXd is also indicated for adult patients with unresectable or metastatic, hormone receptor–positive, HER2-low (immunohistochemistry [IHC] 1+ or 2+/in situ hybridization negative) or HER2-ultralow (IHC 0 with membrane staining) breast cancer, as determined by an FDA-approved test, that has progressed on 1 or more endocrine therapies in the metastatic setting.⁴

References

1. Enhertu (fam-trastuzumab deruxtecan-nxki) 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. Astra Zeneca. News Release. May 7, 2025. Accessed May 7, 2025. https://www.astrazeneca-us.com/media/press-releases/2025/ENHERTU-fam-trastuzumab-deruxtecan-nxki-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.html
2. Trastuzumab deruxtecan (T-DXd) alone or in sequence with THP, versus standard treatment (ddAC-THP), in HER2-positive early breast cancer. ClinicalTrials.gov Updated May 6, 2025. Accessed May 7, 2025. https://clinicaltrials.gov/study/NCT05113251
3. FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer. FDA. May 4, 2022. Accessed May 7, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-fam-trastuzumab-deruxtecan-nxki-breast-cancer
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. AstraZeneca. January 27, 2025. Accessed May 7, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/enhertu-approved-in-us-for-breast-cancer-post-et.html