Neoadjuvant trastuzumab deruxtecan plus trastuzumab, pertuzumab, and docetaxel (T-DXd-THP) significantly improved pathologic complete response (pCR) rates and showed a more favorable safety profile compared to standard anthracycline-based (ddAC-THP) therapy in patients with high-risk, HER2-positive early breast cancer.

These findings from the phase 3 DESTINY-Breast11 trial were presented at the 2025 European Society for Medical Oncology (ESMO) Congress, by Nadia Harbeck, MD, PhD, Ludwig-Maximilians University Hospital, Munich, Germany.

Current neoadjuvant standard of care for HER2-positive early breast cancer combines trastuzumab and pertuzumab concurrently or sequentially with multi-agent chemotherapy. The phase 3 DESTINY-Breast11 trial aimed to evaluate T-DXd–based regimens as potential anthracycline-free alternatives to improve efficacy and reduce toxicity.

Eligible adults with untreated, high-risk HER2-positive early breast cancer (tumor ≥T3, node-positive [N1–3], or inflammatory subtype) were randomized to T-DXd (5.4 mg/kg every 3 weeks for 8 cycles), T-DXd-THP (T-DXd for 4 cycles followed by docetaxel [T] weekly plus H and P every 3 weeks for 4 cycles), or ddAC-THP (doxorubicin/cyclophosphamide every 2 weeks for 4 cycles followed by THP for 4 cycles). 

The primary end point of the trial was pCR (ypT0/Tis ypN0) and secondary end points included event-free survival (EFS) and safety.

As of March 12, 2025, 321 patients received T-DXd-THP and 320 received ddAC-THP. The pCR rate was 67.3% with T-DXd-THP vs 56.3% with ddAC-THP, yielding an absolute difference of 11.2% (95% CI, 4.0 to 18.3; P = .003). Benefits were consistent across subgroups, including hormone receptor (HR)–positive disease (61.4% vs 52.3%) and HR-negative disease (83.1% vs 67.1%). An early favorable trend in EFS was observed (hazard ratio, 0.56; 95% CI, 0.26 to 1.17; 4.5% maturity).

T-DXd-THP demonstrated reduced toxicity compared to ddAC-THP. Grade ≥3 adverse events occurred in 37.5% vs 55.8% of patients, respectively. Serious adverse events were reported in 10.6% vs 20.2%, and treatment discontinuation in 14.1% vs 9.9%. Drug-related interstitial lung disease (ILD)/pneumonitis was infrequent (4.4% vs 5.1%), with few grade ≥3 events (0.6% vs 1.9%). Left ventricular dysfunction occurred less often with T-DXd-THP (1.9% vs 9%). No adverse events prevented surgical resection.

Neoadjuvant T-DXd-THP achieved significantly higher pCR rates, early improvement in EFS, and lower rates of severe toxicity compared with anthracycline-containing ddAC-THP. These findings support T-DXd-THP as a potential new anthracycline-free standard of care for patients with high-risk HER2-positive early breast cancer.

Source:

Harbeck N, Modi S, Pusztai L, et al. DESTINY-Breast11: Neoadjuvant trastuzumab deruxtecan alone (T-DXd) or followed by paclitaxel + trastuzumab + pertuzumab (T-DXd-THP) vs SOC for high-risk HER2+ early breast cancer (eBC). Presented at the 2025 ESMO Congress; October 17-21, 2025. Berlin, Germany. Abstract 281O