Among patients with high-risk, HER2-positive early breast cancer, presurgical, or neoadjuvant, treatment with Enhertu (fam-trastuzumab deruxtecan-nxki; T-DXd) followed by paclitaxel, Herceptin (trastuzumab) and Perjeta (pertuzumab, THP) was associated with an improvement in pathologic complete response (pCR) rate compared with dose-dense doxorubicin and cyclophosphamide plus THP (ddAC-THP), data from the phase 3 DESTINY-Breast11 trial has shown.
Findings presented at the 2025 ESMO Congress demonstrated that patients treated with Enhertu followed by THP (321 patients) experienced a pCR rate of 67.3% compared with 56.3% for those given ddAC-THP (320 patients; difference, 11.2%). Notably, the pCR benefit was observed in the hormone receptor–positive population, where the pCR rate was 61.4% in the Enhertu arm (236 patients) versus 52.3% in the ddAC-THP arm (235 patients; difference, 9.1%), as well as the hormone receptor–negative population, where the respective pCR rates for the Enhertu arm (83 patients) and ddAC-THP arm (85 patients) were 83.1% and 67.1% (difference, 16.1%).
“DESTINY-Breast11 showed the highest reported pCR rate in HER2-positive early breast cancer for a registrational study in the neoadjuvant setting, despite — if you want to do cross-trial comparisons — a high prevalence of hormone receptor–positive disease and a high-risk population,” lead study author Dr. Nadia Harbeck said in a presentation of the data.
Harbeck is director of the Breast Center and chair for Conservative Oncology at the Department of OB&GYN at LMU University Hospital in Munich, Germany.
How Was the DESTINY-Breast11 Trial Designed?
Harbeck noted that current neoadjuvant standard-of-care (SOC) regimens for HER2-positive early breast cancer have remained unchanged for more than a decade. As such, investigators sought to evaluate Enhertu–based treatment in this population with the goal of improving efficacy and safety versus the current SOC.
Patients were randomly assigned to receive Enhertu followed by THP; ddAC-THP; or Enhertu alone, followed by surgery in all arms. In the first arm, 321 patients received four cycles of Enhertu followed by four cycles of THP. In the second, ddAC was administered for four cycles, followed by four cycles of THP. In the final arm, patients received Enhertu alone for eight cycles.
Notably, the Enhertu monotherapy arm was closed in March 2024, following a recommendation from the study’s independent data monitoring committee.
After surgery, study protocols called for the following treatments, irrespective of arm:
- pCR: radiotherapy and concomitant Herceptin with or without Perjeta for up to one year
- Non-pCR: radiotherapy and Kadcyla for up to 14 cycles
- Hormone receptor–positive disease: endocrine therapy
The study’s primary end point was pCR rate. Secondary end points included event-free survival (EFS), safety, pharmacokinetics, invasive disease-free survival, overall survival and health-related quality of life. Residual cancer burden (RCB) was an additional outcome measured during the study.
At data cutoff, 16.9% of patients in the Enhertu plus THP arm discontinued a study drug, including Enhertu (2.8%) paclitaxel (14.4%) Herceptin (2.2%) and Perjeta (2.2%); 97.2% of patients in this arm proceeded to surgery. In the ddAC-THP arm, 13.8% of patients had discontinued any study treatment, including AC (2.9%) paclitaxel (12%) Herceptin (3%) and Perjeta (3.7%); 93.8% of patients in this arm underwent surgery. In the Enhertu monotherapy arm (286 patients), 18.4% of patients discontinued study treatment and 95.8% underwent surgery.
Regarding post-neoadjuvant treatments, 99.1% of evaluable patients in the Enhertu arm who achieved a pCR (226 patients) underwent any adjuvant therapy, comprising any cytotoxic chemotherapy regimen (5.8%), any Kadcyla–containing regimen (1.8%) and any Herceptin-containing regimen (94.2%). In the ddAC-THP, 98.4% of patients who achieved a pCR (190 patients) underwent any adjuvant therapy, including any cytotoxic chemotherapy regimen (5.8%), any Kadcyla–containing regimen (2.1%) and any Herceptin-containing regimen (91.6%).
For patients who did not achieve a pCR, any adjuvant therapy was administered to 89.5% of patients in the Enhertu plus THP arm (95 patients) and 82.3% of patients in the ddAC-THP arm (130 patients). In the experimental group, adjuvant therapies included any cytotoxic chemotherapy regimen (10.5%) any Kadcyla–containing regimen (52.6%) and any Herceptin-containing regimen (38.9%). These respective rates were 9.2%, 56.9% and 26.2% in the control group.
In the Enhertu plus THP and ddAC-THP arms, the median age was 50 years and 50 years, respectively. All patients in both arms were female. The highest proportion of patients in each arm was from Asia (Enhertu plus THP, 47.4%; ddAC-THP, 47.5%) and were Asian (49.8%; 49.1%). Most patients had an ECOG performance status of 0 (86.6%; 87.5%) had immunohistochemistry 3+ HER2-positive disease (87.2%; 88.4%) had cT0-2 tumors (54.8%; 58.8%) and had positive lymph nodes (89.4%; 87.8%).
What Were the Other Efficacy Outcomes for Enhertu Plus THP Versus ddAC-THP?
Findings also showed that 81.3% of patients in the Enhertu plus THP arm had no RCB (RCB-0) or minimal RCB (RCB-1) in resected breast or lymph node tissue compared with 69.1% in the ddAC-THP arm (difference, 12.2%). In the hormone receptor–positive population, the RCB-0 plus RCB-1 rates were 78% for Enhertu plus THP versus 64.7% for ddAC-THP; these respective rates were 90.4% and 81.2% in the hormone receptor–negative population.
Investigators also reported an EFS trend favoring Enhertu plus THP, with data at 4.5% maturity. Maturity for the data cutoff of the trial’s final analysis is predicted at approximately 10%. The 24-month EFS rates were 96.9% in the Enhertu plus THP arm versus 93.1% in the ddAC-THP arm.
What Is the Side Effect Profile of Enhertu Plus THP?
Any-grade side effects occurred in 98.1% of patients in the Enhertu plus THP arm compared with 98.7% of patients in the ddAC-THP arm. The respective rates of grade 3 (severe) or higher side effects were 37.5% and 55.8%. Any-grade serious side effects were reported in 10.6% and 20.2% of patients, respectively.
In the Enhertu plus THP arm, side effects led to dose any dose reduction, any drug interruption and any treatment discontinuation in 18.1%, 37.8% and 14.1% of patients, respectively. In the ddAC-THP group, these rates were 19.2%, 54.5% and 9.9%, respectively. Side effects led to death in 0.6% of patients in both arms. Side effects led to delays in surgery in 3.4% of patients in the experimental arm versus 2.6% of patients in the control arm.
Regarding side effects of special interest, any-grade drug-related adjudicated interstitial lung disease (ILD) was 4.4% in the Enhertu plus THP arm versus 5.1% in the ddAC-THP arm. The rates of grade 3 or higher ILD were 0.6% and 1.9%, respectively. Grade 5 (fatal) ILD occurred in one patient (0.3%) in both groups. Any-grade left ventricular dysfunction occurred in 1.3% of patients in the experimental arm versus 6.1% of patients in the control arm. The rates of grade 3 or higher left ventricular dysfunction were 0.3% and 1.9%, respectively, although no grade 5 events were reported in either group.
Any-grade treatment-emergent side effects reported in at least 20% of patients in either arm included nausea (Enhertu plus THP, 64.7%; ddAC-THP, 51.6%) diarrhea (58.8%; 54.2%) alopecia (47.5%; 49.0%) fatigue (41.3%; 54.8%) increased transaminase levels (34.4%; 33.7%) neutropenia (29.1%; 44.2%) constipation (29.1%; 24.4%) vomiting (28.8%; 21.2%) peripheral neuropathy (25.9%; 20.8%) anemia (22.8%; 49.7%) stomatitis (18.4%; 27.9%) and leukopenia (17.2%; 23.4%).
What Data Were Reported for Enhertu Monotherapy in HER2+ Early Breast Cancer?
In the Enhertu monotherapy arm, patients were allowed to remain on therapy or immediately switch to local SOC. If patients switched therapy, they were classified as having a non-pCR.
Findings from the monotherapy arm showed that 286 patients achieved a pCR rate of 43% at the primary analysis and 51.4% at a prespecified supplementary analysis. EFS data were similar between Enhertu monotherapy and ddAC-THP, and the 24-month EFS rate in the Enhertu monotherapy group was 94.4%.
Regarding safety, 97.5% of patients treated with Enhertu alone (283 patients) experienced any-grade side effects, 22.6% had grade 3 or higher side effects, and 10.2% had any-grade serious side effects. Side effects led to dose reduction, drug interruption and treatment discontinuation in 6.7%, 18% and 7.8% of patients, respectively. One patient (0.4%) experienced a side effect that led to death. Side effects led to surgical delay in 6.4% of patients.
The rate of any-grade drug-related adjudicated ILD was 4.9% in the Enhertu monotherapy arm, although all instances were grade 1 (mild) or 2 (moderate). Left ventricular dysfunction occurred in 0.7% of patients, all at grade 1 or 2.
What’s Next for Enhertu Plus THP?
Based on data from DESTINY-Breast11, the U.S. Food and Drug Administration (FDA) accepted a supplemental biologics license application seeking the approval of neoadjuvant Enhertu followed THP for the treatment of adult patients with high-risk HER2-positive (IHC 3+ or in situ hybridization–positive) stage 2/3 breast cancer.
The FDA has assigned a target action date of May 18, 2026, under the Prescription Drug User Fee Act.
“DESTINY-Breast11 results support [Enhertu plus] THP as a more effective and less toxic neoadjuvant treatment compared with ddAC-THP, and it may become the preferred regimen for patients with high-risk HER2-positive early breast cancer,” Harbeck concluded in her presentation.
References
- “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),” by Dr. Nadia Harbeck et al., presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract 291O.
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