Neoadjuvant Trastuzumab Deruxtecan Dosed in First Patient With Early-Stage HER2+ Breast Cancer

Pipeline Report | <b>Pipeline Report: December 2021</b>

The first patient with high-risk, early-stage HER2-positive breast cancer has received a dose of neoadjuvant fam-trastuzumab deruxtecan-nxki as part of the global, phase 3 DESTINY-Breast11 trial.

The first patient with high-risk, early-stage HER2-positive breast cancer has received a dose of neoadjuvant fam-trastuzumab deruxtecan-nxki (Enhertu) as part of the global, phase 3 DESTINY-Breast11 trial (NCT05113251), according to a news release from Daiichi Sankyo.1

The DESTINY-Breast11 trial is evaluating the safety and efficacy of neoadjuvant trastuzumab deruxtecan alone or followed by paclitaxel, trastuzumab (Herceptin), and pertuzumab (Perjeta; THP) compared with standard-of-care doxorubicin and cyclophosphamide followed by THP (ddAC-THP) in patients with lymph node–positive N1 to N3 or primary tumor stage T3 to T4, locally advanced or inflammatory, early-stage HER2-positive breast cancer.1,2

“DESTINY-Breast11 is the first trial to evaluate [trastuzumab deruxtecan] in the neoadjuvant setting in patients with high-risk, HER2-positive, early-stage breast cancer,” said Gilles Gallant, BPharm, PhD, FOPQ, senior vice president and global head of Oncology Development at Daiichi Sankyo in the news release.1 “The goal of this study is to determine if [trastuzumab deruxtecan] alone or followed by chemotherapy can potentially replace the current standard of care or displace the use of anthracyclines in the neoadjuvant setting.”

Trastuzumab deruxtecan is a HER2-directed antibody-drug conjugate indicated for use in HER2-positive breast, gastric, and gastroesophageal junction cancers.

The current neoadjuvant standard of care for patients with early-stage HER2-positive breast cancer consists of THP, a dual HER2-targeted therapy. The regimen can induce pathologic complete responses (pCRs), but it is associated with significant toxicity and patients often relapse following neoadjuvant THP.

As such, replacing neoadjuvant THP or displacing anthracyclines with trastuzumab deruxtecan followed by THP could improve outcomes and reduce the risk of toxicity for patients.

The trial is planned to enroll 624 men and women who will be randomized 1:1:1 to receive 5.4 mg/kg of single-agent trastuzumab deruxtecan (arm A), trastuzumab deruxtecan followed by THP (arm B), or ddAC-THP (arm C).1,2 All regimens are to be administered by intravenous infusion. Patients in arm A will receive 8 cycles of trastuzumab deruxtecan, whereas patients in arms B and C will receive 4 cycles of trastuzumab deruxtecan followed by 4 cycles of THP, or 4 cycles of ddAC followed by 4 cycles of THP, respectively.

The primary end point of the trial is pCR rate defined by the proportion of participants who have no evidence of residual invasive disease by H&E staining for up to 32 months following study initiation.2 Secondary end points, which are followed for up to 62 months after study start, include event-free survival, invasive disease-free survival, overall survival, pharmacokinetics, immunogenicity, and safety.1,2

Inclusion criteria for the trial state that patients must be at least 18 years of age with histologically documented HER2-positive early-stage breast cancer, including a clinical stage at presentation of T0 to T4, N1 to N3, M0 or at least T3, N0, M0 per the 8th edition of the American Joint Committee on Cancer (AJCC) staging system criteria. Additionally, patients must have an ECOG performance status of 0 or 1 at the time of randomization.2

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

Patients are being enrolled from 129 centers across Asia, Europe, North America, and South America.

The estimated primary completion date is January 30, 2024, and the estimated study completion date is June 26, 2026.


  1. DESTINY-Breast11 neoadjuvant phase 3 trial of ENHERTU initiated in patients with high-risk HER2 positive early-stage breast cancer. News release. Daiichi Sankyo. November 30, 2021. Accessed December 1, 2021.
  2. Trastuzumab deruxtecan (T-DXd) alone or in sequence with THP, versus standard treatment (ddAC-THP), in HER2-positive early breast cancer. Updated November 9, 2021. Accessed December 1, 2021.