Neoadjuvant T-DXd Shows Clinical Activity in Patients With HER2-Low Breast Cancer

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Patients with localized, hormone receptor (HR)-positive, HER2-low breast cancer treated with fam-trastuzumab deruxtecan-nxki (T-DXd) in the neoadjuvant setting had an overall response rate of 75% without combining the agent with anastrozole and 63% in combination with anastrozole, according to results from the phase II TRIO-US B-12 TALENT trial presented by Aditya Bardia, MD, MPH, and colleagues at the 2022 San Antonio Breast Cancer Symposium (Abstract GS2-03).

This is the first report of neoadjuvant T-DXd for patients with HR-positive, HER2-low, localized breast cancer.... It could provide the groundwork for future studies with antibody-drug conjugates—including T-DXd—for patients with early-stage breast cancer.
— Aditya Bardia, MD, MPH

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“This is the first report of neoadjuvant T-DXd for patients with HR-positive, HER2-low, localized breast cancer,” said Dr. Bardia, an attending physician at Mass General Cancer Center and Director of Breast Cancer Research and an Associate Professor at Harvard Medical School. “It could provide the groundwork for future studies with antibody-drug conjugates—including T-DXd—for patients with early-stage breast cancer.”

Patients with localized, high-risk breast cancer are often given chemotherapy before undergoing surgery. However, when such tumors express the estrogen receptor and/or the progesterone receptor, the pathological complete response rate to neoadjuvant chemotherapy is less than 5%, necessitating new treatment options, Dr. Bardia said.

T-DXd is an antibody-drug conjugate that is internalized into cancer cells upon binding to HER2. Once inside, it releases a cytotoxic payload that causes DNA damage and kills the cancer cell. It is currently approved by the U.S. Food and Drug Administration (FDA) to treat several types of tumors that overexpress HER2, and it was recently approved to treat metastatic breast cancer with low HER2 expression.

“While T-DXd demonstrated impressive efficacy in metastatic HER2-low breast cancer, to date, no trial has evaluated T-DXd in localized, early-stage, potentially curable HER2-low breast cancer, which led us to design this neoadjuvant clinical trial,” said study coauthor Sara Hurvitz, MD, Medical Director of the Clinical Research Unit at Jonsson Comprehensive Cancer Center and Professor of Medicine in the Division of Hematology/Oncology at the University of California, Los Angeles. 

TRIO-US B-12 TALENT Details and Results

Drs. Bardia and Hurvitz and their colleagues conducted the phase II TRIO-US B-12 TALENT clinical trial to assess the safety and efficacy of T-DXd when used as a neoadjuvant treatment, either alone or in combination with the aromatase inhibitor anastrozole. At the time of first data cutoff (October 2022), 17 patients had completed the planned eight cycles of T-DXd, and 16 patients had completed the planned six cycles of T-DXd plus anastrozole.

According to Dr. Bardia, the primary endpoint for the study was a 5% pathologic complete response (pCR) rate, defined as complete tumor regression and no lymph node involvement at the time of surgery. At the time of first data cutoff, no patients had experienced a pCR in the combination treatment arm, and 1 of 19 patients (5.3%) had experienced a pCR in the solo treatment arm.

As of the data cutoff, 33 patients had completed neoadjuvant treatment and undergone surgery, 7 patients were awaiting surgery, and 13 patients were still undergoing T-DXd treatment. Among the response-evaluable population, in the solo treatment arm, the overall response rate was 75%, including 11 partial responses and 1 complete response. In the combination treatment arm, the overall response rate was 63%, including 10 partial responses and 2 complete responses.

The most common treatment-related adverse events of grade 3 or higher were hypokalemia, diarrhea, neutropenia, fatigue, headache, vomiting, dehydration, and nausea, each of which occurred in fewer than 6% of patients. One patient developed grade 2 interstitial lung disease, which resolved after treatment discontinuation.

Total patient numbers and efficacy data are immature and will be updated.

Dr. Hurvitz stressed that the clinical outcome results, including pCR and overall response rate, are not mature, as not all patients had scans or underwent surgery by the time of data cutoff. Overall, the tolerability and overall response data were encouraging and may warrant future studies on T-DXd in this patient population, she noted.

“The study demonstrated that T-DXd was relatively safe in HER2-low, HR-positive, localized breast cancer. It provides translational framework for future studies, including combination regimens in the neoadjuvant setting to further improve clinical outcomes,” Dr. Bardia said.

Future Directions and Current Limitations

Drs. Bardia and Hurvitz and their colleagues aim to follow up on this work by analyzing potential biomarkers from tumor tissue and blood samples taken before, during, and after treatment. Dr. Bardia hopes these biomarkers will help researchers more accurately assess HER2 status, predict which tumors will have the best responses to T-DXd treatment, and illuminate potential mechanisms of T-DXd resistance.

Limitations of this study include a small sample size characteristic of phase II studies, which did not allow for a formal comparison of the two treatment arms. Additionally, the primary and secondary endpoints of this study assessed response but did not evaluate long-term survival.


Disclosure: The study was conducted as an investigator-initiated study by the Translational Research In Oncology (TRIO)-US network. Funding for this study was provided by Daiichi Sankyo. Dr. Bardia serves as a consultant or advisory board member for Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics/Gilead Sciences, Sanofi, Daiichi Sankyo, AstraZeneca, and Eli Lilly and Company, and has received research funding from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead Sciences, Daiichi Sankyo, AstraZeneca, and Eli Lilly and Company. Dr. Hurvitz has received a speaker honorarium from Daiichi Sankyo and research funding from Ambrx, Amgen, Arvinas, AstraZeneca, Bayer, Biomarin Pharmaceutical, Cascadian Therapeutics, CytomX Therapeutics, Daiichi Sankyo, Dantari, Dignitana, Genentech/Roche, G1 Therapeutics, Gilead Sciences, GlaxoSmithKline, Immunomedics, Eli Lilly, MacroGenics, Merrimack Pharmaceuticals, Novartis, OBI Pharma, Orinove, Pfizer, Phoenix Molecular Designs, Pieris Pharmaceuticals, Puma Biotechnology, Radius Health, Sanofi, Seattle Genetics, and Zymeworks.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.