Neoadjuvant treatment with the HER2-directed antibody drug conjugate trastuzumab deruxtecan-nxki (T-DXd), whether alone or with endocrine therapy or chemotherapy, results in low pathologic complete response (pCR) rates in patients with HER2-low, hormone receptor (HR)-positive early-stage breast cancer, as shown in the TALENT trial.
“Neoadjuvant T-DXd demonstrated modest clinical activity in HER2-low HR-positive localized breast cancer,” said Dr Sara Hurvitz, senior vice president and director of the Clinical Research Division at Fred Hutchinson Cancer Center and head and professor of the Division of Hematology and Oncology at the University of Washington School of Medicine, US, who presented the study at ESMO Congress 2026.
“The addition of endocrine therapy to T-DXd did not improve [pCR], and sequencing T-DXd with multiagent chemotherapy only marginally improved it,” she added. [https://ascopost.com/news/october-2026/talent-neoadjuvant-t-dxd-in-her2-low-early-breast-cancer/]
TALENT enrolled men and pre- or postmenopausal women with HR-positive, HER2-low, stage II‒III operable breast cancer. Hurvitz and her team randomized the first 58 patients to group A (T-DXd 5.4 mg/kg alone) or group B (T-DXd with anastrozole 1 mg), with a GnRH analogue for men and premenopausal women. [ESMO 2026, abstract LBA23]
Due to concerns that a single antibody drug conjugate might be insufficient for patients with high-risk disease, a third arm was added (group C: four cycles of T-DXd, followed by four cycles of docetaxel 75 mg/m2 plus cyclophosphamide 600 mg/m2).
Initially, patients received six cycles. After enrolling 29 participants, treatment increased to eight cycles following near-complete responses at six. At least two pCRs were needed to expand enrolment into any arm. Group A met the criteria and included 16 more patients, but group B did not. Group C likewise met the requirement and enrolled 58 patients.
PCR in the breast and lymph nodes, defined as residual cancer burden (RCB) 0, was the primary endpoint. Hurvitz and colleagues also collected tumour tissue, blood for circulating tumour DNA, and imaging at several timepoints.
Overall, 132 patients were enrolled: 45 in group A, 29 in group B, and 58 in group C. Baseline characteristics were comparable across groups, but group C included fewer postmenopausal patients and more participants with node-positive disease. Patients also had high-risk disease, with most having a baseline Ki-67 ≥30 percent and 44 percent having grade 3 tumours.
Low pCR rates
Objective response rates were high across groups: 62 percent in group A, 66 percent in group B, and 72 percent in group C. However, pCR rates were low: 7 percent in group A, 3 percent in group B, and 9 percent in group C. For patients with RCB 0/1, the corresponding pCR rates were 16 percent, 17 percent, and 17 percent.
In terms of safety, the most common treatment-related adverse events (TRAEs) across groups were nausea, fatigue, and alopecia. Patients in group C experienced more grade ≥3 TRAEs. Furthermore, only three patients had interstitial lung disease (all grade 2), one in group B and two in group C. One patient died in group A due to severe gastrointestinal toxicity and a myocardial infarction.
Notably, HER2 levels were higher in patients with RCB0 (2,691 and 1,221 amol/mm2) than those with RCB 1/2/3 (715‒947 and 440‒608 amol/mm2) at baseline and cycle 2, respectively. This finding suggests the HER2 level may be associated with treatment outcomes.
“Interestingly, baseline HER2 protein level does appear to be associated with the achievement of pCR (p=0.0329),” Hurvitz said, noting caution in this interpretation as the study’s sample size was small.
Invited discussant Dr Barbara Pistilli, head of the Breast Cancer Unit at Gustave Roussy in Villejuif, France, stressed that only groups A and C achieved the prespecified criteria for stage two expansion and that overall pCR rates were low and similar to those previously achieved with standard chemotherapy.
“However, [the TALENT trial] offers some very interesting clinical and translational findings,” she said. [https://ascopost.com/news/october-2026/talent-neoadjuvant-t-dxd-in-her2-low-early-breast-cancer/]
Pistilli’s takeaways included the following: pCR rates were higher eight vs six cycles of T-DXd; four cycles of T-DXd followed by four of chemotherapy appeared similar to eight cycles of T-DXd alone, but grade ≥3 toxicities and discontinuations were common; and the addition of aromatase inhibitor did not seem to boost T-DXd activity.