Neoadjuvant T-DXd Demonstrates Activity in Phase II Study of Patients With HER2-Low Breast Cancer

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A pilot study provides a signal that the novel HER2 antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (T-DXd), is active in the neoadjuvant setting in patients with HER2-low breast cancer. Overall response rates were 75% with T-DXd alone and 63% when T-DXd was combined with endocrine therapy (anastrozole), suggesting that endocrine therapy does not appear to enhance the benefit of T-DXd in this setting. These results of the investigator-initiated, phase II TRIO-US B-12 TALENT trial were reported at the 2022 San Antonio Breast Cancer Symposium.1

“This is the first report of neoadjuvant T-DXd for patients with hormone receptor–positive, HER2-low localized breast cancer,” said lead author Aditya Bardia, MD, MPH, attending physician at Mass General Cancer Center and Director of Breast Cancer Research and Associate Professor at Harvard Medical School. “Neoadjuvant T-DXd demonstrated preliminary evidence of clinical activity in HER2-low, hormone receptor–positive localized breast cancer, with a toxicity profile consistent with previous reports. These translational results lay the groundwork for future studies with antibody-drug conjugates, including T-DXd, for patients with early-stage breast cancer.”

“These translational results lay 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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T-DXd has demonstrated efficacy in metastatic HER2-low breast cancer, but it has not been well studied in localized HER2-low breast cancer. Patients with high-risk hormone receptor–positive breast cancer are treated with neoadjuvant anthracycline/taxane-based combination chemotherapy, but it has been associated with low pathologic complete response rates of about 5%, including in HER2-low breast cancer. Radiologic response is around 50% with this chemotherapy, and there are significant toxicities such as myelosuppression, neuropathy, cardiomyopathy, and risk of leukemia.

The phase II TRIO-US B-12 TALENT trial was designed to evaluate the efficacy of neoadjuvant T-DXd in patients with hormone receptor–positive, HER2-low breast cancer with stage II and III disease. Another objective of the study was to evaluate whether endocrine therapy would improve the efficacy of T-DXd in this setting. “We were interested in this because of the potential crosstalk between estrogen receptor and HER2,” Dr. Bardia explained.

In addition to being able to deliver a “payload” of chemotherapy to cancer cells by binding to an antibody, T-DXd also has a “bystander effect,” Dr. Bardia explained. “This drug can attack cells that don’t express the target.”

Study Details

Between September 2020 and October 2022, 29 patients were enrolled in each arm and received six cycles of either T-DXd or T-DXd plus anastrozole. The trial was emended to include eight cycles after half the patients were enrolled.

“Only a minority of patients discontinued treatment due to adverse events, and only one patient experienced disease progression during the trial,” Dr. Bardia told listeners.

Baseline characteristics were well balanced between the two arms. Most patients (about 80%) were HER2 IHC1+ (immunohistochemistry 1+). About half had lymph node–positive disease. About one-third of cancers were grade 3. Four patients were HER1 IHC 1+ by local lab assessment and IHC 0 by central review.

Key Results

According to a waterfall plot, the objective response rate was 68% with T-DXd alone and 58% with the combination of T-DXd plus anastrozole. There were two complete responses in each arm.

“The addition of endocrine therapy did not appear to enhance efficacy, but we need to be cautious in interpreting these results given the small number of patients,” he noted.

“Dynamic changes in HER2 tissue expression were noted after treatment with T-DXd,” Dr. Bardia told listeners. Almost half the patients (48.6%) had changes in HER2 IHC expression after treatment with T-DXd. Among those who experienced such a change, the majority (88.2%) had decreases in HER2 expression.”


For more on the use of neoadjuvant trastuzumab deruxtecan in patients with HER2-low, early-stage breast cancer in the TRIO-US B-12 TALENT trial, see an interview with Sara A. Hurvitz, MD, on The ASCO Post Newsreels at

He pointed out that “HER2-low” is an operational definition defined by IHC testing. “HER2 0 is not necessarily zero with the current methods of testing. There is a need for better analytic tools for HER2 detection, particularly low levels, as it is potentially actionable,” Dr. Bardia said.


A total of 5% of all patients had dose reductions due to adverse events. There were no cases of grade 3 or 4 pneumonitis and no cases of cardiomyopathy or neuropathy. Adverse events were comparable in each arm, with nausea, fatigue, and alopecia being the most common. Gastrointestinal adverse events appeared to decrease over time, which Dr. Bardia attributed to better supportive care.

Additional Comments

“The phase II TRIO-US B-12 TALENT trial is a translational study. It provides a rich platform for the development of biomarkers and understanding the mechanisms of resistance in patients with residual disease to guide future therapeutic strategies,” he stated.

During the discussion following Dr. Bardia’s presentation at a press conference, he commented: “Crosstalk between the estrogen receptor and HER2 may not be relevant in the case of antibody-drug conjugates, which deliver potent payloads to cancer cells. While we need additional data, so far, there is no evidence to suggest that the addition of endocrine therapy is beneficial in this setting.” 

DISCLOSURE: Dr. Bardia has served as a consultant or advisor to Pfizer, Novartis, Genentech, Merck, Radius Health/Menarini, Immunomedics/Gilead Sciences, Sanofi, Daiichi Pharma/AstraZeneca, Phillips, Eli Lilly, Mersana, and Foundation Medicine; and has received institutional research funding from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health/Menarini, Immunomedics/Gilead, Sciences, Daiichi Pharma/AstraZeneca, and Eli Lilly.


1. Hurvitz SA, Bardia A, Press MF, et al: TRIO-US B-12 TALENT: Neoadjuvant trastuzumab deruxtecan with or without anastrozole for HER2-low, HR+ early stage breast cancer. 2022 San Antonio Breast Cancer Symposium. Abstract GS2-03. Presented December 7, 2022.

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Expert Point of View: Jason Aboudi Mouabbi, MD

“These results [from the TRIO-US B-12 TALENT trial] are exciting and impressive in HER2-low, hormone receptor–positive patients. The authors were testing the waters and got a positive signal,” said Jason Aboudi Mouabbi, MD, a medical oncologist at MD Anderson Cancer Center, Houston.

Jason Aboudi Mouabbi, MD