BERLIN — The antibody drug conjugate (ADC) trastuzumab deruxtecan (T-DXd, Enhertu) took an important step into the early breast cancer setting, based on new findings from two trials presented at the European Society for Medical Oncology (ESMO) Annual Meeting 2025.

While T-DXd has demonstrated improved survival in the metastatic breast cancer setting and has several FDA-approved indications in that setting, the ADC’s role in early breast cancer has been less clear. Now, data from the phase 3 DESTINY-Breast 11 and 05 trials reveal that the drug can improve cancer outcomes for patients with HER2-positive early-stage breast cancer in both the neoadjuvant and adjuvant settings.

In DESTINY-Breast 11, more than two thirds of patients who received a T-DXd-based regimen before surgery had a pathologic complete response compared with 56% of those on standard of care, and the ADC regimen came with fewer serious toxicities.

In DESTINY-Breast 05, T-DXd was associated with a 53% reduced risk for invasive disease recurrence or death compared to standard trastuzumab emtansine (T-DM1) after surgery in patients with high-risk HER2-positive early breast cancer who have residual invasive disease following neoadjuvant therapy.

“These two studies establish T-DXd as a foundational treatment in HER2-positive early breast cancer,” said Nadia Harbeck, MD, PhD, lead author of DESTINY-Breast 11 and director of the Breast Center and the Center for Hereditary Breast and Ovarian Cancer at Ludwig-Maximilian University Hospital, Munich, Germany. The findings also “highlight the need to use this drug at the earliest opportunity to increase the chances of cure for our patients.”

Inside DESTINY-Breast 11

In HER2-positive early-stage breast cancer, there’s a need for more effective and less toxic neoadjuvant regimens, Harbeck explained. With the current standard regimens, many patients do not achieve a pathologic complete response and the regimens come with significant acute hematological and gastrointestinal adverse events as well as long-term complications, including cardiotoxicity and neuropathy.

In DESTINY-Breast 11, Harbeck and colleagues assessed whether T-DXd could improve efficacy and safety in previously untreated high-risk patients with HER2-positive early breast cancer.

Overall, 927 patients were randomized into three groups before surgery: 321 received T-DXd followed by paclitaxel, trastuzumab, and pertuzumab (THP), 320 received standard-of-care dose-dense anthracycline plus cyclophosphamide (ddAC) alongside THP, and 286 got T-DXd alone. The T-DXd alone arm closed early after an assessment from an independent data monitoring committee found a low probability that the monotherapy would be superior to standard of care.

High-risk disease was defined as clinical stage T3 or higher with nodal status N0-3 or cT0-4 with N1-3, or inflammatory breast cancer.

The primary endpoint was pathologic complete response, which is prognostic for event-free survival and overall survival in this setting, Harbeck explained. Secondary endpoints included event-free survival, brain metastasis-free survival, and safety.

The researchers found that significantly more patients in the T-DXd combination arm had a pathologic complete response — 67.3% vs 56.3% in the ddAC plus THP arm (P = .003).

The benefit of T-DXd plus THP was independent of hormone receptor status. In hormone receptor-positive patients, the pathologic complete response rate was 61.4% in the T-DXd combination arm vs 52.3% in the ddAC plus THP arm. In hormone receptor-negative patients, the rates were 83.1% vs 67.1%.

As for residual cancer burden, 81.3% of patients receiving T-DXd plus THP had no or minimal residual invasive cancer detected in the resected breast or lymph node tissue vs 69.1% of those receiving ddAC plus THP. This benefit also held regardless of hormone receptor status.

At data cutoff, Harbeck and colleagues observed a trend towards improved event-free survival in the T-DXd plus THP arm at 2 years — 96.9% vs 93.1% (hazard ratio [HR], 0.56; 95% CI, 0.26-1.17).

As for safety, grade 3 or higher treatment-emergent adverse events occurred less often in the T-DXd plus THP arm — 37.5% vs 55.8% — as did any serious adverse event — 10.6% vs 20.2%. The most common side effects of any grade in each group were nausea (65% vs 52%), diarrhea (59% vs 54%), hair loss (48% vs 49%), and fatigue (41% vs 55%).

Focusing on events of particular interest, rates of left ventricular dysfunction — 1.3% vs 6.1% overall — and interstitial lung disease were lower in the TxD combination arm — 4.4% vs 5.1% overall and 0.6% vs 1.9% for grade 3 or higher.

Overall, the T-DXd plus THP arm demonstrated “the highest reported” pathologic complete response rate in the neoadjuvant setting in this high-risk patient population, Harbeck said.

Inside DESTINY-Breast 05

After surgery, patients with HER2-positive early breast cancer who have residual invasive disease remain at high risk for recurrence.

In DESTINY-Breast 05, researchers presented interim data comparing T-DXd with standard T-DM1 in the adjuvant setting in this population.

The open label, phase 3 trial randomized 1635 patients 1:1 to T-DXd (5.4 mg/kg) or T-DM1 (3.6 mg/kg) once every 3 weeks for 14 cycles. The primary endpoint was invasive disease-free survival (DFS). Secondary endpoint included DFS and safety.

At 3 years, the investigators reported a 53% lower risk for invasive DFS among patients who received T-DXd than among those who received T-DM1 — 92.4% vs 83.7% (HR, 0.47; P < .0001). This benefit was observed in all subgroups, evaluated, and noted by lead investigator Charles E. Geyer, Jr, MD, of the University of Pittsburgh Medical Centre Hillman Cancer Center, Pittsburgh.

The 3-year DFS with T-DXd was also significantly better (HR, 0.47; P < .0001). And although not significant, Geyer and colleagues observed a brain metastasis-free interval benefit with T-DXd (HR, 0.64; 95% CI, 0.35-1.17).

Grade 3 or higher treatment-emergent adverse events were similar in both arms — 50.6% of patients who received T-DXd and 51.9% who received T-DM1. However, drug-related interstitial lung disease occurred in significantly more patients who received T-DXd — 9.6% vs 1.6%. Most cases of interstitial lung disease were grade 1 or 2, but two patients in the T-DXd arm died.

Although interstitial lung disease was a bigger issue in DESTINY-Breast 05, safety monitoring with regular low-dose CT scans paid off because “fortunately, the majority were reversible,” Geyer said.

Overall, the findings are “remarkable,” said study discussant Sara Tolaney, MD, of Dana-Farber Cancer Institute and Harvard Medical School, both in Boston. The results mark “a pivotal step forward and brings us closer than ever to curing the vast majority of our early-stage HER2-positive breast cancer patients, including those at the very highest risk of recurrence.”

DESTINY-Breast 05 was sponsored by Daiichi Sankyo, Inc. DESTINY-Breast 11 was sponsored by AstraZeneca. Geyer reported receiving grants or contracts from Daiichi Sankyo and AstraZeneca, Roche/Genentech, and Exact Sciences as well as support for the presentation from Daiichi Sankyo and AstraZeneca, among other disclosures. Harbeck reported receiving honoraria from AstraZeneca, Daiichi Sankyo, Gilead, Lilly, and others.Tolaney reported having a range of disclosures, including consulting or advisory roles for Daiichi Sankyo and AstraZeneca, among others.

Kate Johnson is a Montreal-based freelance medical journalist who has been writing for more than 30 years about all areas of medicine.