Two pivotal studies of fam-trastuzumab deruxtecan-nxki (T-DXd) in early HER2-positive breast cancer suggest this antibody-drug conjugate (targeting the HER2 protein) may be moving into the curative setting after having shown benefit in metastatic disease in multiple previous trials. The new findings were presented at the Presidential Symposium of the European Society for Medical Oncology (ESMO) Congress 2025.
DESTINY-Breast05
Findings from the phase III DESTINY-Breast05 trial1 are positioning T-DXd as a new standard of care for patients treated with neoadjuvant therapy for HER2-positive early breast cancer wth residual invasive cancer after neoadjuvant therapy and at high risk for recurrence. A planned interim analysis of the study of 1,635 high-risk patients found that treatment with T-DXd led to a statistically significant and clinically meaningful improvement in invasive disease–free survival—meeting the primary endpoint—over the current standard, ado-trastuzumab emtansine (T-DM1), also an antibody-drug conjugate.
Charles Geyer, MD
The approval of T-DM1 for patients with residual disease after neoadjuvant therapy was based on a 50% reduction in the risk of invasive disease recurrence or death, compared with trastuzumab, in the KATHERINE trial2 and was considered a major treatment advance at the time. In DESTINY-Breast05, treatment with T-DXd yielded nearly a 9% absolute improvement in 3-year invasive disease–free survival over T-DM1, reflecting a 53% reduction in risk (hazard ratio [HR] = 0.47; P <. 0001), reported Charles Geyer, MD, Professor of Medicine at the University of Pittsburgh, noting that the figure “easily beat the early reporting stopping boundary of 0.0183.”
“Adjuvant T-DXd demonstrated superior efficacy, with manageable safety, in patients with high-risk HER2-positive early breast cancer and residual invasive disease after neoadjuvant therapy and represents a potential new standard of care in this postneoadjuvant setting,” Dr. Geyer said.
Jame Abraham, MD, FACP,
“This is a practice-changing finding,” said Jame Abraham, MD, FACP, Chairman and Professor of the Department of Hematology and Medical Oncology at the Cleveland Clinic, and Study Chair for the NSABP Foundation’s involvement in DESTINY-Breast05. He also noted encouraging evidence that T-DXd offered some reduction in the risk for central nervous system (CNS) recurrences. “I think oncologists will be ready to use this regimen as soon as T-DXd is approved for this indication.”
DESTINY-Breast11
Also reported at the Presidential Symposium were the results of DESTINY-Breast11,3 which evaluated T-DXd even earlier, as neoadjuvant therapy, in 927 patients. “In DESTINY-Breast11, T-DXd–THP (paclitaxel, trastuzumab, pertuzumab) showed the highest reported pathologic complete response rate in HER2-positive early breast cancer for a registrational study in the neoadjuvant setting, despite a high prevalence of hormone receptor–positive disease and a high-risk population,” said Nadia Harbeck, MD, PhD, of LMU University Hospital and CCC Munich.
Patients with HER2-positive, high-risk breast cancer received neoadjuvant T-DXd followed by THP or T-DXd alone for eight total cycles (T-DXd alone was discontinued early and will be reported on at a later date). The control arm was standard dose-dense anthracycline plus cyclophosphamide followed by THP (AC-THP) for eight total cycles. High risk was defined as ≥ cT3 and N0–3 or cT904 and N1–3 tumors or inflammatory breast cancer.
Nadia Harbeck, MD, PhD
The study’s primary endpoint, pathologic complete response rate, was achieved by 67.3% in the T-DXd arm and 56.3% in the control arm, an increase of 11.2% with T-DXd (P = .003), with benefit observed across most prespecified subgroups. At data cutoff, with patients followed a median of about 24 months, a favorable trend in event-free survival had also emerged with T-DXd, with 96.9% vs 93.1% of patients event-free (HR = 0.56; 95% confidence interval [CI] = 0.26–1.17).
“These results support neoadjuvant T-DXd–THP as a potential new anthracycline-free regimen with improved efficacy and less toxicity as compared with dose-dense AC-THP for patients with high-risk, HER2-positive early breast cancer,” Dr. Harbeck said.
DESTINY-Breast05: Other Key Findings
DESTINY-Breast05 randomly assigned 1,635 patients with HER2-positive disease who had high-risk, residual invasive disease in the breast and/or axillary nodes after neoadjuvant chemotherapy with HER2-directed therapy to T-DXd at 5.4 mg/kg or T-DM1 at 3.6 mg/kg every 3 weeks for 14 cycles. Adjuvant radiotherapy was allowed per local practice and could be delivered concurrent with initiation of study therapy or prior to initiation of study therapy (sequential). The primary endpoint was invasive disease–free survival.
“We also saw a significant benefit in the important endpoint of distant recurrence–free interval. CNS metastases and deaths were numerically fewer, and the overall safety profile was manageable, without new safety signals,” Dr. Geyer said.
Dr. Geyer noted that in KATHERINE, adjuvant T-DM1 had failed to reduce the risk for CNS recurrences.4In DESTINY-Breast05, recurrences within the CNS were observed in 26 patients treated with T-DM1 and in 17 patients treated with T-DXd, providing early evidence that T-DXd may reduce the risk for recurrences in the CNS. Distant recurrence–free survival rates were 93.9% with T-DXd and 86.1% with T-DM1 (HR = 0.49; 95% CI = 0.34–0.71). Overall survival is immature, but a favorable trend was seen at this interim analysis, with rates of 97.4% and 95.7%, respectively (HR = 0.61; 95% CI = 0.43–1.10).
Rates of grade ≥ 3 treatment-emergent adverse events were 50.6% with T-DXd and 51.9% with T-DM1. “However, we do have to acknowledge that adjudicated drug-related interstitial lung disease was present in 9.6% of patients [with two deaths]. Fortunately, most of these cases were reversible discontinuation of T-DXd and prompt initiation of systemic steroids. We are working to provide details on interstitial lung disease recovery on the trial for the San Antonio Breast Cancer Symposium,” Dr. Geyer commented.
In addition, he acknowledged that among patients receiving T-DXd, grade 2/3 nausea occurred in 27.8%/4.5% and grade 2/3 vomiting, in 10.9%/1.1%, emphasizing the need for prophylactic antiemetics, appropriate for management of this highly emetogenic agent. Prophylactic antiemetics were recommended but not mandatory on the trial. Dr. Geyer also noted that the relatively high rate of radiation pneumonitis (28.8% with T-DXd and 27.0% with T-DM1) was a consequence of the serial imaging following radiation therapy with low-dose chest CT scans used to monitor for interstitial lung disease on the trial. The majority were grade 1 (24.2% with T-DXd and 20.8% with T-DM1), with grade 2 in 4.6% and 6.1%, respectively, and no cases of ≥ grade 3 in either arm.
DESTINY-Breast11: Other Key Findings
As Dr. Harbeck noted, there have been no new neoadjuvant therapies for HER2-positive breast cancer in more than a decade. With existing regimens, pathologic complete response rates remain low in patients with hormone receptor–positive disease, large tumors, or extensive nodal involvement.
“The achievement of a pathologic complete response allows for less burdensome subsequent treatment and less toxic postneoadjuvant therapy, but standard-of-care regimens have acute and long-term sequelae,” she said. “Based on improved survival outcomes seen with T-DXd in the metastatic setting, DESTINY-Breast11 aimed to bring T-DXd to the neoadjuvant setting to determine whether this would improve efficacy and safety for patients with high-risk, HER2-positive early breast cancer.”
Here are some other key findings from DESTINY-Breast11:
- By hormone receptor status, pathologic complete response rates were 61.4% after T-DXd–THP vs 52.3% after dose-dense AC-THP in the hormone receptor–positive subset and 83.1% vs 67.1%, respectively, in the hormone receptor–negative group.
- Residual cancer burden (RCB) was minimal after T-DXd–THP treatment. RCB is a marker of residual cancer in the resected breast and nodes that correlates with clinical outcomes. Low RCB class (RCB-0 and RCB-1), which herald “good outcomes,” were documented in 81.3% of the T-DXd–THP arm vs 69.1% of the dose-dense AC-THP arm. Almost 80% of patients with hormone receptor–positive disease had RCB-0 or RCB-1.
- The overall safety profile of T-DXd–THP was favorable as compared with dose-dense AC-THP, with reduced rates of grade ≥ 3 adverse events, serious adverse events, treatment interruptions, and left ventricular dysfunction.
Grade ≥ 3 adverse events were reported in 37.5% of patients in the T-DXd–THP arm compared with 55.8% in the dose-dense AC-THP arm. Less any-grade left ventricular dysfunction was observed with T-DXd–THP (1.3% vs 6.1%), but more grade ≥ 3 nausea was reported in this arm (1.9% vs 0.3%). The incidence of interstitial lung disease was low and similar between the arms (4.4% and 5.1%, respectively). Interstitial lung disease grade ≥ 3 was more common with dose-dense AC-THP (1.9% vs 0.6%), and there was one grade 5 event in each arm. Patients treated with T-DXd–THP experienced fewer any-grade and grade ≥ 3 hematologic events and fatigue than those receiving dose-dense AC-THP, Dr. Harbeck reported.
Although data for T-DXd monotherapy will be detailed at a later date, Dr. Harbeck reported that in March 2024, the independent data monitoring committee recommended that patients on this arm could continue on T-DXd alone or immediately switch to local standard-of-care therapy. Analysis at that time found the pathologic complete response rate was 43.0% or 51.4%, depending on the methodology and classifications. “T-DXd alone showed inferior but still robust pathologic complete response compared with the five-agent dose-dense AC-THP,” Dr. Harbeck noted.
DISCLOSURE: Dr. Geyer has received grants from Daiichi Sankyo, AstraZeneca, Roche/Genetech, and Exact Sciences; and has reported a financial relationship with Exact Sciences, Merck, Daiichi Sankyo, and AstraZeneca. Dr. Abraham has received clinical research support or served on a data safety board for Daiichi Sankyo. Dr. Harbeck has reported financial relationships with AstraZeneca, Daiichi Sankyo, Gilead Sciences, Lilly, Stemline Therapeutics, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Viatris, Zuellig Pharma, Exact Sciences, and Sandoz.
REFERENCES
1. Geyer CE, et al: ESMO Congress 2025. Abstract LBA1. Presented October 18, 2025.
2. von Minckwitz G, et al. N Engl J Med 380:617-628, 2019.
3. Harbeck N, et al: ESMO Congress 2025. Abstract 291O. Presented October 18, 2025.
4. Mamounas EP, et al: Ann Oncol 32:1005-1014, 2021.
EXPERT POINT OF VIEW
“The significant reduction in recurrences seen with adjuvant T-DXd [fam-trastuzumab deruxtecan-nxki] in DESTINY-Breast05 marks a pivotal step forward—bringing us closer than ever to curing the vast majority of our early-stage, HER2-positive breast cancer patients,” said the study’s invited discussant Sara M. Tolaney, MD, MPH, FASCO, Chief of the Division of Breast Oncology at Dana-Farber Cancer Institute, and Associate Professor of Medicine at Harvard Medical School.
Sara M. Tolaney, MD, MPH, FASCO
“Adjuvant T-DXd reduces the risk of recurrence by half when compared with T-DM1 [ado-trastuzumab emtansine] and should be adopted as the standard of care for patients with HER2-positive breast cancer who have residual disease after HER2-directed preoperative therapy and who are node-positive at the time or surgery or inoperable at baseline (T3/T4 or N2/N3).” Outside of these criteria, for patients with operable disease at baseline and residual node-negative disease, T-DM1 should remain the standard, she said.
In 2019, the KATHERINE trial led to a paradigm shift in early-stage, HER2-positive breast cancer by demonstrating a 50% reduction in recurrence, then a 34% increase in overall survival,1 with adjuvant T-DM1 over trastuzumab in patients with residual disease. “This solidified how critical it is for us to administer neoadjuvant therapy to adapt treatment based on response. We did, however, still see room for improvement, as there were some high-risk patients who still had substantial risk of recurrence,” she said.
“It seemed logical that T-DXd [because of its mechanism of action] could potentially improve upon these outcomes,” she said. “DESTINY-Breast05, therefore, was designed to specifically target those patients with a high risk of recurrence in KATHERINE. In fact, the study did enroll a much higher-risk population, and the results were remarkable.”
According to Dr. Tolaney, the control arm performed exactly as anticipated: T-DXd outperformed expectations, yielding an almost 9% difference in 3-year invasive events and reducing the risk of recurrence by 53%. “We do have to balance the very impressive efficacy with toxicity,” she acknowledged, pointing to more serious adverse events, more dose interruptions, more early discontinuations due to toxicity, and more interstitial lung disease with T-DXd.
Balancing Risks and Benefits in Practice
“So how do we balance the risks and benefits of treatment with T-DXd?” Dr. Tolaney asked. On the “benefits” side, she listed the halving in recurrence risk (mostly in distant sites), the consistent benefit across subgroups, the potential reduction in central nervous system relapse, a similar ability to complete therapy as T-DM1, and the similar risk of radiation pneumonitis (no greater than with T-DM1). On the “risks” side, she cited the threat of interstitial lung disease, the need for CT monitoring, and the frequent dose holds/discontinuations. Unknown at this time are the drug’s impact on quality of life, the generalizability of the results (North American enrollment was limited), and the overall survival benefit. “In balance, however, benefits far outweigh risks in high-risk patients,” Dr. Tolaney concluded.
DESTINY-Breast11: Valuable Neoadjuvant Therapy
Invited discussant Sara A. Hurvitz, MD, FACP, the Smith Family Endowed Chair in Women’s Health at Fred Hutch Cancer Center, Seattle, and Senior Vice President and Director of the Clinical Research Division, shared these comments about DESTINY-Breast11. “It is the first phase III evidence that replacing chemotherapy with an antibody-drug conjugate in the neoadjuvant setting improves pathologic complete response,” she said.
Sara A. Hurvitz, MD, FACP
DESTINY-Breast11 also confirmed the observation that anthracyclines are generally more toxic than nonanthracycline regimens, she said. However, adverse events leading to drug discontinuations and surgical delays were more common in the T-DXd arm. She noted that the rates of interstitial lung disease were similar and lower than in T-DXd–treated metastatic breast cancer (perhaps because only four to eight doses were given).
However, Dr. Hurvitz questioned the use of an anthracycline-based control arm and suggested that docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) would have been a more contemporary choice, may have achieved more pathologic complete responses, and thus may have produced a truer signal of the benefit of neoadjuvant T-DXd–THP. “It’s unknown how the safety of TCHP would have compared with that of T-DXd–THP,” she added.
Also unknown is whether the neoadjuvant use of T-DXd will yield improvements in long-term outcomes. Dr. Hurvitz noted a promising trend in event-free survival (hazard ratio = 0.56), though this endpoint is only 4.5% mature. Preliminary findings suggest T-DXd monotherapy is “inadequate” as the sole neoadjuvant treatment for high-risk disease, she added.
Should T-DXd Be Given in the Adjuvant or Neoadjuvant Setting?
T-DXd now has proven benefits in pivotal adjuvant and neoadjuvant trials, begging the question of which setting its use is preferable. The discussants agreed that this issue is far from settled.
Dr. Tolaney sees some factors that favor its use preoperatively. It significantly improves pathologic complete response rates, and this could result in much less axillary surgery. It exposes patients to a shorter dose of T-DXd (just 4 cycles), which would likely be associated with less toxicity and better quality of life, than the 14 cycles that would be needed in the adjuvant setting. On the other hand, if patients could receive a de-escalated regimen preoperatively (ie, taxane plus dual HER2 blockade) and still achieve a pathologic complete response, they could be spared T-DXd entirely.
Both Dr. Tolaney and Dr. Hurvitz described predictive biomarker tests, such as HER2DX, being evaluated for such purposes, and they may help to achieve this de-escalation. Dr. Tolaney also envisions moving toward a more response-guided approach in the preoperative setting. Responders to THP would move on to surgery, whereas those with less response would be escalated to receive T-DXd preoperatively. “Biomarker-driven trials are needed to help us personalize therapies to the individual patient,” Dr. Tolaney said.
DISCLOSURE: Dr. Tolaney reported personal financial relationships with Aadi Bioscience, Ambrx, Artios Biopharmaceuticals, Arvinas, AstraZeneca, Bayer, BeiGene, Bicycle Therapeutics, BioNTech, Blueprint Medicines, Bristol Myers Squibb, Circle Pharma, Cullinan Oncology, Daiichi Sankyo, eFFECTOR Therapeutics, Eisai, Genentech, Hengrui Pharmaceutical (USA), Immunomedics/Gilead, Incyte, Jazz Pharmaceuticals, Johnson & Johnson, Launch Therapeutics, Lilly, Menarini Group, Merck, Mersana, Natera, Novartis, Pfizer, Reveal Genomics, Sanofi, Seagen, Sumitovant Biopharma, Summit Therapeutics, SystImmune, Tango Therapeutics, Zentalis Pharmaceuticals, Zuellig Pharma, and Zymeworks. Dr. Hurvitz has received research funding from AstraZeneca, Bayer, Daiichi Sankyo, Genentech (Roche), G1 Therapeutics, Gilead Sciences, GSK, Immunomedics, Eli Lilly, Loxo Oncology, MacroGenics, Novartis, Pfizer, Sanofi, and Seagen; has received royalties from McGraw Hill, Sage Publications, Wiley, and Wolters Kluwer; has served on the data and safety monitoring board for Alliance Foundation Trials, Atossa Therapeutics, and the Quantum Leap Healthcare Collaborative; and has received honoraria from the Vaniam Group and OncLive. Her spouse owns stock in ROMTech.
REFERENCE
1. von Minckwitz G, Huang CS, Mano MS, et al: Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med 380:617-628, 2019.
