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T-DXd yielded iDFS improvements in HER2-positive early breast cancer with residual invasive disease, irrespective of HER2 expression of neoadjuvant chemotherapy type.
Findings from subgroup analyses of the phase 3 DESTINY-Breast05 trial (NCT04622319) showed that post-neoadjuvant administration of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) led to consistent improvements in invasive disease-free survival (iDFS) vs ado-trastuzumab emtansine (T-DM1; Kadcyla) in patients with early-stage HER2-positive breast cancer with residual disease following neoadjuvant chemotherapy and HER2-targeted therapy.1,2
Data presented at the 2025 San Antonio Breast Cancer Symposium demonstrated that T-DXd yields an iDFS benefit irrespective of HER2 expression.1 In patients with HER2 immunohistochemistry (IHC) 3+ disease, the 3-year iDFS rates were 91.8% (95% CI, 88.7%-94.1%) for T-DXd (n = 676) compared with 83.2% (95% CI, 79.2%-86.5%) for T-DM1 (n = 670; HR, 0.49; 95% CI, 0.34-0.70). For patients with HER2 in situ hybridization–positive (ISH+) expression, the 3-year iDFS rates were 96.2% (95% CI, 91.0%-98.4%) for T-DXd (n = 140) vs 86.5% (95% CI, 78.1%-91.8%) for T-DM1 (n = 147; HR, 0.35; 95% CI, 0.13-0.97).
When broken down by prior neoadjuvant chemotherapy type, patients who received prior anthracyclines experienced a 3-year iDFS rate of 90.6% (95% CI, 86.1%-93.6%) with T-DXd (n = 423) vs 80.3% (95% CI, 74.8%-84.8%) with T-DM1 (n = 399; HR, 0.45; 95% CI, 0.29-0.69). For those given prior platinum-based chemotherapy, the 3-year iDFS rates were 93.9% (95% CI, 90.4%-96.1%) for T-DXd (n = 386) vs 87.3% (95% CI, 82.4%-90.9%) for T-DM1 (n = 392; HR, 0.54; 95% CI, 0.31-0.93).
“These additional analyses are very helpful to further characterize the clinical benefit and safety profile of T-DXd over T-DM1 in the post-neoadjuvant HER2-positive early breast cancer residual invasive disease setting, supporting T-DXd as the potential new standard of care,” lead study author Sibylle Loibl, MD, PhD, said in a presentation of the data. Loibl is an associate professor of obstetrics and gynecology at the Goethe University of Frankfurt, as well as chair of the German Breast Group and chief executive officer of the GBG Forschungs GmbH in Germany.
Findings from an interim analysis of DESTINY-Breast05 presented at the 2025 ESMO Congress showed that patients in the overall population treated with T-DXd (n = 818) experienced a 3-year iDFS rate of 92.4% (95% CI, 89.7%-94.4%) compared with 83.7% (95% CI, 80.2%-86.7%) for patients treated with T-DM1 (HR, 0.47; 95% CI, 0.34-0.66; P < .0001).3
The global, multicenter, open-label, randomized study enrolled patients with centrally confirmed HER2-positive (IHC 3+ or IHC ISH+) early breast cancer who had residual invasive disease in the breast or axillary lymph nodes following neoadjuvant chemotherapy and HER2-targeted therapy.1 Patients needed to have high-risk disease, defined as inoperable early breast cancer (cT4, N0-3, M0 or cT1-3, N2-3, M0) or operable early breast cancer (cT1-3, N0-1, M0) with axillary node–positive disease (ypN1-3) after neoadjuvant therapy. An ECOG performance status of 0 or 1 was also required.
Patients were randomly assigned 1:1 to receive T-DXd at 5.4 mg/kg once every 3 weeks for 14 cycles or T-DM1 at 3.6 mg/kg once every 3 weeks for 14 cycles. Key stratification factors included extent of disease at presentation (operable vs inoperable), HER2-targeted neoadjuvant therapy (single agent vs dual agent), hormone receptor status (positive vs negative), and post–neoadjuvant therapy pathologic nodal status (positive vs negative).
The trial’s primary end point was iDFS, and DFS was a key secondary end point. Other secondary end points included overall survival, brain metastases–free interval, distant relapse–free survival, and safety.
To monitor for interstitial lung disease (ILD) and radiation-induced pneumonitis during the study, investigators screened all patients at baseline via chest CT. For patients who received sequential adjuvant radiotherapy after randomization, study treatment was intended to start no later than 21 days after the final dose of radiotherapy, and an additional chest CT was required after the completion of radiation and the first dose of study drug. For patients who received sequential or concurrent radiotherapy, chest CTs were also indicated at cycles 3, 7, and 11, then at 40 (+7) days of follow-up. Additional CT scans were recommended for patients with any signs or symptoms of drug-related ILD or radiation-induced pneumonitis.
For patients who experienced drug-related ILD, the trial’s protocol called for dose interruption and systemic steroids in the event of grade 1 ILD. T-DXd was allowed to resume if ILD resolved to grade 0. For patients with grade 2 or higher ILD, T-DXd was permanently discontinued, and steroids were initiated.
Those with grade 1 radiation-related pulmonary toxicity were allowed to maintain drug dose and schedule in the event of grade 1 toxicity. Those with grade 2 toxicities had treatment interrupted until recovery to baseline or grade 1 or less, and they received standard-of-care support, such as steroids. Those with grade 3 or 4 radiation-induced pulmonary toxicity discontinued study treatment.
In the T-DXd arm (n = 806), any-grade drug-related ILD occurred in 9.6% of patients compared with 1.6% of patients in the T-DM1 arm (n = 801). For patients who received sequential radiation and T-DXd (n = 319), ILD was reported at any grade (10.7%), grade 1 (1.9%), grade 2 (7.5%), grade 3 (0.9%), and grade 5 (0.3%); the median time to onset of ILD was 122.0 days (range, 36-350). In those given concurrent T-DXd and radiation (n = 438), ILD was reported at any grade (9.6%), grade 1 (2.3%), grade 2 (6.2%), grade 3 (0.9%), and grade 5 (0.2%), with a median onset of 124.5 days (range, 37-326).
In the T-DM1 arm, patients who received sequential treatment (n = 270) experienced ILD at any grade (2.6%), grade 1 (1.5%), and grade 2 (1.1%). These respective rates were 1.0%, 0.6%, and 0.4% in those given concurrent treatment (n = 480). No grade 3 or higher ILD was reported in the T-DM1 arm as a whole.
Regarding investigator-reported radiation-induced pneumonitis, no grade 3 or higher events were reported in either arm. In the T-DXd arm, those given sequential radiation and study treatment experienced pneumonitis at grade 1 (30.4%) and grade 2 (4.1%). These respective rates were 23.7% and 5.5% for concurrent T-DXD/radiation. In the T-DM1 arm, sequential treatment was associated with grade 1 (30.4%) and grade 2 (7.0%) pneumonitis. These rates were 19.8% and 6.9%, respectively, for concurrent treatment.
“While differences were observed in ILD and radiation-induced pneumonitis time to onset, duration, and outcomes between the sequential and concurrent radiotherapy groups, further analysis is needed to assess the impact of potential confounders such as race, comorbidities, regional variability in radiotherapy application, the time of radiotherapy application, and the use of steroids for managing ILD and radiation pneumonitis,” Loibl concluded.
Disclosures: Loibl reported receiving Grants and/or honorarium for advisory boards and/or contracts from AstraZeneca, AbbVie, Agendia, Amgen, BionTech, Celgene, Bristol Meyers Squibb, Daiichi Sankyo, Exact Science, Gilead, GSK, Incyte, Lilly, Medscape, Molecular Health, MSD, Novartis, Pierre Fabre, Pfizer, Relay, Roche, Sanofi, Seagen, Stemine/Menarini, Olema, Bayer, Bicycle, JAZZ Pharma, and BeiGene; receiving meeting and/or travel support from Daiichi Sankyo, European Society of Medical Oncology, St. Gallen Breast Cancer Conference, American Society of Clinical Oncology, and AGO Kommission Mamma; and receiving royalties from VM Scope.
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