Clinical Summary

• The phase 2 TALENT trial demonstrated objective response rates of 62% to 72% with neoadjuvant trastuzumab deruxtecan (T-DXd), alone, combined with anastrozole, or followed by docetaxel/cyclophosphamide, in patients with hormone receptor–positive, HER2-low early-stage breast cancer.
• Despite radiographic responses, pathologic complete response (pCR) rates remained below 10% across all 3 treatment arms, and treatment-related safety concerns included three cases of grade 3 interstitial lung disease and one patient death.
• Exploratory biomarker analyses demonstrated significant reductions in Ki-67 and HER2 protein expression following treatment, while high baseline TROP2 expression was associated with pCR, suggesting potential biomarkers for further investigation.

Sara A. Hurvitz, MD, FACP, of Fred Hutchinson Cancer Center and the University of Washington in Seattle, discusses final results from TALENT, a phase 2 investigator-initiated neoadjuvant trial presented at the 2026 European Society for Medical Oncology (ESMO) Congress. The study evaluated trastuzumab deruxtecan (T-DXd), alone, in combination with anastrozole, or followed by docetaxel/cyclophosphamide (TC) chemotherapy in patients with hormone receptor-positive, HER2-low early-stage operable breast cancer. More than half of enrolled patients had tumors with Ki-67 levels of at least 30%, and approximately 44% had grade 3 disease. Although objective response rates ranged from 62% to 72%, pCR rates in the breast and lymph nodes were modest, reaching 7% with T-DXd alone, 3% with T-DXd plus anastrozole, and 9% with T-DXd followed by TC chemotherapy.

Exploratory biomarker analyses revealed significant reductions in Ki-67 across all treatment arms, with the greatest changes observed in patients receiving T-DXd plus anastrozole. HER2 protein expression also declined significantly following treatment, while high baseline TROP2 expression was associated with pCR in a limited patient subset. Safety findings included 3 cases of grade 3 interstitial lung disease and one death associated with significant gastrointestinal toxicity and myocardial infarction. Hurvitz emphasizes that T-DXd is not currently a standard neoadjuvant treatment for hormone receptor–positive, HER2-low early-stage breast cancer. The findings highlight the need for further research to identify patients most likely to benefit from antibody-drug conjugate therapy, validate potential predictive biomarkers, and better define the benefit-risk profile of T-DXd in the early-stage setting.

Transcript

Sara A. Hurvitz, MD, FACP: Hi, I'm Sara Hurvitz from Fred Hutchinson Cancer Center, University of Washington in Seattle, Washington.

I presented the results of TALENT. TALENT was a phase 2 investigator-initiated neoadjuvant clinical trial evaluating T-DXd, either alone or in combination with anastrozole, or followed by docetaxel/cyclophosphamide chemotherapy in patients with hormone receptor–positive, HER2-low early-stage operable breast cancer.

Patients enrolled in this study tended to have higher-risk disease. In fact, more than 50% of patients had a Ki-67 in their tumor of greater than or equal to 30%, and about 44% of patients had grade 3 tumors.

The study was conducted to evaluate pathologic complete response rate, but also to evaluate biomarkers, objective response rate based on imaging, and other endpoints as well. The objective response rate associated with T-DXd alone was 62%. The objective response rate with T-DXd plus anastrozole was 66%. And T-DXd given for 4 cycles followed by 4 cycles of TC chemotherapy had a 72% objective response rate.

However, the pathologic complete response rate in breast and lymph nodes tended to be more modest. In the T-DXd-alone arm, there were 45 patients enrolled, and the pathologic complete response rate was 7%. T-DXd plus anastrozole had only a 3% pathologic complete response rate in the 29 patients treated. And in arm C, T-DXd followed by TC chemotherapy, with 58 patients enrolled, the pathologic complete response rate was 9%.

Tumor biomarkers were taken at baseline, after cycle 1, and at the time of surgery, and a number of analyses were performed. Most notably, central assessment of Ki-67 based on immunohistochemistry demonstrated that Ki-67 significantly dropped from baseline to cycle 2 and from baseline to surgery in all 3 treatment arms. This was most notable in arm B, T-DXd plus anastrozole.

We also evaluated protein quantification using a method called Troplex, which was done centrally at Yale. Based on this, we looked at TROP2 expression levels and showed that they were similar in arms A and B and did not change over time significantly after treatment with T-DXd. In contrast, HER2 protein expression level, while it was similar at baseline in the 2 treatment arms, decreased over time significantly at cycle 2 and at the time of surgery after treatment with T-DXd. Finally, we showed that high baseline TROP2 expression was associated with the achievement of pathologic complete response, although the caveat is that there are only a few patients included in this analysis, and the analysis of RMC is ongoing.

In summary, TALENT showed that T-DXd, either alone, in combination with anastrozole, or followed by chemotherapy, was associated with modest clinical activity, with pathologic complete response rates of less than 10% in each of the treatment arms.

Toxicity was as expected. There were 3 cases of interstitial lung disease, all grade 3, in this study. There was 1 patient death in the T-DXd-alone arm due to significant GI toxicity and myocardial infarction.

At this time, T-DXd is not a standard therapy in the early-stage setting for hormone receptor–positive, HER2-low breast cancer.

Biomarker findings from this study suggest that HER2 expression levels may drop after treatment with T-DXd based on protein quantification. And high baseline HER2 levels may be a biomarker to select patients who are most likely to benefit from T-DXd, although this needs to be validated.

A number of endpoints are continuing to be followed in this study and will be presented at a later date.

Thank you.

Source

Hurvitz SA, McAndrew NP, Chan D, et al. Final results of TALENT: a neoadjuvant trial of T-DXd with or without anastrozole, or in sequence with chemotherapy for HER2-low, HR+ early-stage breast cancer. Presented at: ESMO Congress 2026; October 23-27, 2026; Madrid, Spain. Abstract LBA23.