Clinical Trials Underway for T-DXd in Breast Cancer

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The current standard of care for the neoadjuvant treatment of HER2-positive early-stage breast cancer consists of trastuzumab plus pertuzumab and polychemotherapy. But some patients, particularly those with locally advanced or inflammatory disease, still relapse and die. Furthermore, multiagent regimens also expose patients to short- and long-term toxicities.

In an effort to improve upon these efficacy outcomes and tolerability issues, fam-trastuzumab deruxtecan-nxki (T-DXd) is being evaluated in the neoadjuvant setting and as an approach to residual disease following neoadjuvant treatment. These key studies were described at the 2021 San Antonio Breast Cancer Symposium.


The randomized multicenter phase III DESTINY-Breast05 trial ( identifier NCT04622319) will evaluate T-DXd vs ado-trastuzumab emtansine (T-DM1) as postneoadjuvant treatment for high-risk patients with HER2-positive residual invasive breast cancer after neoadjuvant therapy.1 High risk is defined for this study as inoperable tumors at presentation or positive pathologic nodal status after neoadjuvant therapy. The primary endpoint will be invasive disease–free survival.

Charles Geyer, MD

Charles Geyer, MD

The study aims to improve upon outcomes of treatment of this population with adjuvant T-DM1, which showed benefit in adjuvant treatment of patients with residual disease relative to trastuzumab in the KATHERINE trial,2 according to Charles Geyer, MD, of the National Surgical Adjuvant Breast and Bowel Project (NSABP) and Houston Methodist Cancer Center. Further support for the rationale for the current study comes from the findings of DESTINY-Breast03, a randomized phase III trial in previously treated metastatic breast cancer in which T-DXd was superior to T-DM1 in improvingprogression free survival (hazard ratio [HR] = 0.28; P = 7.8 × 10-22).

Patients will be randomly assigned to T-DXd at 5.4 mg/kg or T-DM1 at 3.6 mg/kg every 3 weeks for 14 cycles.

“DESTINY-Breast05 is currently recruiting patients and will include approximately 400 sites globally,” Dr. Geyer said.


The randomized, multicenter open-label two-stage phase II TRIO-US B-12 TALENT trial is evaluating T-DXd with or without anastrozole in HER2-low, hormone receptor–positive early breast cancer (NCT04553770). Sara A. Hurvitz, MD, of the University of California Los Angeles Jonsson Comprehensive Cancer Center, described the rationale for the study.3

“We know HER2 may be expressed at low levels (1+, 2+ by immunohistochemistry) in up to two-thirds of patients with hormone receptor–positive, HER2-negative, HER2-nonamplified breast cancer. T-DXd has demonstrated promising clinical efficacy in HER2-low breast cancer, with an objective response rate of about 37%,4” Dr. Hurvitz said.

Sara A. Hurvitz, MD

Sara A. Hurvitz, MD

TALENT will identify the treatment arm with the strongest efficacy, based on pathologic complete response rate (breast and lymph nodes) at definitive surgery. It will also evaluate molecular changes in tumor biomarkers and investigate potential serum and tumor biomarkers of response.

The study will enroll 58 participants (men or women, pre- or postmenopausal) with previously untreated, operable invasive breast cancer > 2.0 cm (excluding recurrent, metastatic, and inflammatory breast cancer). Patients are randomly assigned to receive six cycles of T-DXd (5.4 mg/kg every 21 days) either alone or in combination with anastrozole (1 mg daily). If more than two participants in an arm achieve a pathologic complete response, that arm will enroll an additional 15 participants, for a total of 44 per arm. A pathologic complete response rate of > 10% (5/44) would be considered favorable, warranting further evaluation of the treatment in a larger trial.

“To our knowledge, this is the only ongoing study evaluating T-DXd with or without endocrine therapy in the neoadjuvant setting for hormone receptor–positive, HER2-low early-stage breast cancer,” Dr. Hurvitz said. The trial is currently open at 10 sites in California, Florida, Indiana, Kansas, and Massachusetts.


The global, open-label DESTINY-Breast11 trial (NCT05113251) is evaluating several T-DXd regimens in the neoadjuvant setting.5 Patients with high-risk disease will receive T-DXd monotherapy or T-DXd followed by paclitaxel/trastuzumab/pertuzumab (THP) vs dose-dense doxorubicin plus cyclophosphamide followed by THP (ddAC-THP).

“Replacing the standard of care with T-DXd or displacing anthracyclines with T-DXd followed by THP is expected to improve patient outcomes and could reduce treatment burden and overall toxicity for patients with HER2-positive early breast cancer,” said lead investigator Nadia Harbeck, MD, of the LMU University Hospital Munich in Germany.

Nadia Harbeck, MD

Nadia Harbeck, MD

The target population is 624 participants with HER2-positive locally advanced, hormone receptor–positive or –negative breast cancer; patients will have lymph node–positive disease with any tumor stage up to 5 cm (inclusive of inflammatory breast cancer) or ≥ T3 tumors and any nodal status. The primary endpoint is pathologic complete response in the breast and lymph nodes.

Patients are being randomly assigned to one of three arms: T-DXd monotherapy at 5.4 mg/kg every 3 weeks for eight cycles; T-DXd at 5.4 mg/kg every 3 weeks for four cycles followed by THP every 3 weeks for four cycles; or ddAC every 2 weeks for four cycles followed by THP every 3 weeks for four cycles.

The study is currently enrolling more than 600 patients from 19 international sites, including the United States. 

Other Trials in Progress

  • HER3CLIMB-04: Phase II trial of tucatinib plus T-DXd in patients with HER2-positive locally advanced or metastatic breast cancer with and without brain metastases (NCT05539938)
  • DESTINY-Breast09: Phase III study of T-DXd with or without pertuzumab vs a taxane, trastuzumab and pertuzumab in first-line HER2-positive metastatic breast cancer (NCT04784715)
  • DESTINY-Breast12: Phase IIIb/IV study of T-DXd in patients with and without baseline brain metastasis with previously treated advanced/metastatic HER2-positive breast cancer (NCT04739761)

DISCLOSURE: Dr. Geyer has served as a consultant or advisor for Athenex, Exact Sciences, Genentech, Roche, Daiichi Sankyo, and Seattle Genetics; has received honoraria from Athenex and Exact Sciences; has received travel accomodations/expenses from Genentech/Roche, AstraZeneca, and Daiichi Sankyo; and has written medical manuscripts for Roche and AbbVie. Dr. Hurvitz has an immediate family member who holds stock or other ownership interests in Ideal Implant and ROMTech; has received institutional research funding from Ambrx, Amgen, AstraZeneca, Arvinas, Bayer, CytomX, Daiichi Sankyo, Dignitana, Genentech/Roche, Gilead, GSK, Immunomedics, Lilly, MacroGenics, Novartis, Pfizer, OBI Pharma, Pieris, Puma Biotechnology, Radius, Sanofi, Seattle Genetics/Seagen, Zymeworks, Phoenix Molecular Designs, and Samumed; and has been reimbursed for travel or accommodations by Lilly. Dr. Harbeck has received fees for consulting and other services from Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, Exact Sciences, Gilead, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Sandoz, and Seagen.


1. Geyer CE, Untch M, Prat A, et al: Trastuzumab deruxtecan vs trastuzumab emtansine in high-risk patients with HER2-positive, residual, invasive, early breast cancer after neoadjuvant therapy: A randomized phase 3 trial (DESTINY-Breast05). 2021 San Antonio Breast Cancer Symposium. Abstract OT1-02-03. Presented December 8, 2021.

2. Von Minckwitz G, Huang CS, Mano MS, et al: Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med 380:617-628, 2019.

3. Hurvitz S, Bardia A, Tetef ML, et al: TRIO-US B-12 TALENT: Phase II neoadjuvant trial evaluating trastuzumab deruxtecan with or without anastrozole for HER2-low, HR+ early stage breast cancer. 2021 San Antonio Breast Cancer Symposium. Abstract OT1-12-05. Presented December 8, 2021.

4. Modi S, Park H, Murthy RK, et al: Antitumor activity and safety of trastuzumab deruxtecan in patients with HER2-low-expressing advanced breast cancer: Results from a phase Ib study. J Clin Oncol 38:1887-1896, 2020.

5. Harbeck N, Boileau JF, Modi S, et al: A phase 3, open-label trial of neoadjuvant trastuzumab deruxtecan monotherapy or T-DXd followed by THP compared with ddAC-THP in patients with high-risk HER2-positive early breast cancer (DESTINY-Breast11). 2021 San Antonio Breast Cancer Symposium. Abstract OT1-12-04. Presented December 8, 2021.