T-DXd Regimens Show Better Tolerability, Manageable Safety in High-Risk, HER2-Positive Early Breast Cancer

Trastuzumab deruxtecan-based (T-DXd; Enhertu; AstraZeneca) regimens helped maintain physical functioning in patients, reduced their symptom burden, and demonstrated manageable safety while improving outcomes in high-risk, HER2-positive early breast cancer, according to data from 2 abstracts presented during yesterday’s “Rapid Fire 6” session at the San Antonio Breast Cancer Symposium (SABCS).1,2

As announced in October, the phase 3 DESTINY-Breast11 study (NCT05113251) demonstrated that neoadjuvant treatment with T-DXd followed by paclitaxel plus trastuzumab and pertuzumab (THP) produced a statistically significant and clinically meaningful improvement in pathologic complete response and had a more favorable safety profile compared with dose-dense doxorubicin plus cyclophosphamide followed by THP (ddAC-THP) in high-risk, HER2-positive early-stage breast cancer.3

Building on these findings, 2 abstracts presented yesterday at SABCS further examined the patient-reported outcomes and safety results from the DESTINY-Breast11 trial.1.2

New findings from 2 abstracts presented at SABCS reveal T-DXd regimens enhance outcomes and tolerability for patients with high-risk HER2-positive early breast cancer. | Image Credit: ST.art - stock.adobe.com

Patient-Reported Outcomes Reveal Better Tolerability With Regimens Containing T-DXd

One abstract, “Patient-Reported Outcomes (PROs) in DESTINY-Breast11: Neoadjuvant Treatment (NAT) With Trastuzumab + Pertuzumab (THP) vs Dose-Dense Doxorubicin + Cyclophosphamide Followed by THP (ddAC-THP) in High-Risk, HER2+ Early-Stage Breast Cancer (eBC)," reported on physical functioning and patient-reported tolerability during NAT.1

Presented by Shanu Modi, MD, the analysis included all patients with high-risk, HER2-positive early breast cancer, who were randomized to receive neoadjuvant T-DXd (8 cycles), T-DXd-THP (4+4 cycles), or ddAC-THP (4+4 cycles). The patient-reported outcomes evaluated included physical functioning, 20 symptomatic adverse events, and overall treatment tolerability.

The T-DXd, T-DXd-THP, and ddAC-THP arms comprised 283, 320, and 321 treated patients, respectively. Modi reported that a greater proportion of patients maintained or improved physical functioning with T-DXd (range across weeks, 42.7%-75.5%) or T-DXd-THP (43.7%-75.7%) than with ddAC-THP (24.0%-62.4%).

Overall adverse-effect bother was also generally lower with T-DXd (45.8%) and T-DXd-THP (43.0%) vs ddAC-THP (49.5%), with fewer patient-weeks marked by high adverse-effect burden. Of the 20 symptomatic adverse events assessed, Modi noted that 14 were improved with T-DXd and 13 with T-DXd-THP. Both regimens were associated with improvements in the following adverse effects: diarrhea, loss of appetite, taste changes, mouth/throat sores, numbness/tingling, muscle pain, joint pain, chest pain, cough, dyspnea, rash, insomnia, and hot flashes. However, improvements in nosebleeds were seen only with T-DXd.

In contrast, 5 adverse events were generally worse with T-DXd and/or T-DXd-THP, namely hair loss, headaches, nausea, and vomiting. Patients on T-DXd also experienced worse constipation, whereas those on T-DXd-THP experienced more nosebleeds. Despite the presence of these adverse events, Modi emphasized that symptomatic adverse events that impact daily life had limited interference on patients across all arms.

“Taken together, these findings, along with the favorable effect and safety, do support T-DXd followed by THP as a tolerable treatment option for patients with high-risk, early-stage HER2-positive breast cancer,” Modi concluded.

Safety Outcomes Highlight Manageable Adverse Events Across Treatment Arms

Another abstract, “DESTINY-Breast11 (DB-11) Safety: Neoadjuvant Trastuzumab Deruxtecan (T-DXd) Alone or Followed by Paclitaxel + Trastuzumab + Pertuzumab (THP) vs Dose-Dense Doxorubicin + Cyclophosphamide Followed by THP (ddAC-THP) in High Risk, HER2+ Early-Stage Breast Cancer (eBC),” offered additional detail on clinically relevant adverse events.2

Presented by Giuseppe Curigliano, MD, PhD, the analysis compared adverse events across the 3 treatment arms, with high-resolution CT scans performed every 6 weeks. Adverse events of special interest included adjudicated interstitial lung disease (ILD)/pneumonitis and left ventricular dysfunction (LVD). The abstract also described clinically relevant adverse events, namely nausea/vomiting, neutropenia, and peripheral neuropathy.

At primary analysis, Curigliano noted that all-grade adjudicated drug-related ILD/pneumonitis rates were low in all groups and were either stable (T-DXd-THP) or higher (ddAC-THP) during cycles 5 through 8 compared with cycles 1 through 4. He added that rates of serious adverse events, grade 3 or higher adjudicated drug-related ILD/pneumonitis, and all-grade or grade 3 or higher LVD were highest in the ddAC-THP arm.

Of the patients with adjudicated drug-related ILD/pneumonitis, 71.4% of the T-DXd arm, 64.3% of the T-DXd-THP arm, and 56.3% of the ddAC-THP arm received steroids. Among these arms, 57.1%, 71.4%, and 81.3% of cases resolved, respectively.

Regarding clinically relevant adverse events, Curigliano highlighted that nausea/vomiting was more frequent with T-DXd and TDX-THP than with ddAC-THP, although the use of 3 recommended prophylactic antiemetics before cycle 1 was lower in the T-DXd and T-DXd-THP arms. Meanwhile, the use of 2 recommended antiemetics occurred in 57.2% of the T-DXd-THP arm, 55.5% of the T-DXd arm, and 40.4% of the ddAC-THP arm. He noted that these events were mostly low-grade and nonserious, with decreasing rates after the first 4 cycles.

Meanwhile, neutropenia was most common with ddAC-THP, consistent with the arm's higher use of granulocyte colony-stimulating factor (87.2%) vs the T-DXd (16.1%) and T-DXd-THP (22.7%) arms. Lastly, although peripheral neuropathy rates were lowest with T-DXd, Curigliano highlighted that events were largely low-grade and nonserious across all arms, occurring primarily during cycles 1 through 4.

“DESTINY-Breast11 safety results support, in my opinion, T-DXd-THP as a potential neoadjuvant treatment option for patients with high-risk HER2-positive early breast cancer,” he concluded.

References

1. Modi S, Boileau JF, Wu J, et al. Patient-reported outcomes (PROs) in DESTINY-Breast11: neoadjuvant treatment (NAT) with trastuzumab + pertuzumab (THP) vs dose-dense doxorubicin + cyclophosphamide followed by THP (ddAC-THP) in high-risk, HER2+ early-stage breast cancer (eBC). Presented at: San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, Texas. Poster RF6-06.
2. Curigliano G, Harbeck N, Boileau JF, et al. DESTINY-Breast11 (DB-11) safety: neoadjuvant trastuzumab deruxtecan (T-DXd) alone or followed by paclitaxel + trastuzumab + pertuzumab (THP) vs dose-dense doxorubicin + cyclophosphamide followed by THP (ddAC-THP) in high-risk, HER2+ early-stage breast cancer (eBC). Presented at: San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, Texas. Poster RF6-02.
3. Enhertu followed by THP before surgery resulted in a pathologic complete response in 67% of patients with high-risk HER2-positive early-stage breast cancer in DESTINY-Breast11 phase III trial. News release. AstraZeneca. October 18, 2025. Accessed December 11, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/enhertu-followed-by-thp-before-surgery-resulted-in-a-pcr-in-67-of-patients-in-db11.html