Enhertu Improves Survival Over Kadcyla In Early Stage HER2+ Breast Cancer

Data from the subgroup analyses of the phase 3 DESTINY-Breast05 trial demonstrated that post-neoadjuvant administration of Enhertu (T-DXd; fam-trastuzumab deruxtecan-nxki) led to consistent improvements in invasive disease-free survival (iDFS) versus Kadcyla (T-DM1; ado-trastuzumab emtansine) in patients with early-stage HER2-positive breast cancer with residual disease following neoadjuvant chemotherapy and HER2-targeted therapy.

Data presented at the 2025 San Antonio Breast Cancer Symposium demonstrated that Enhertu yields an iDFS benefit irrespective of HER2 expression. In patients with HER2 immunohistochemistry (IHC) 3+ disease, the 3-year iDFS rates were 91.8% for Enhertu (676 patients) compared with 83.2% for Kadcyla (670 patients). For patients with HER2 in situ hybridization–positive (ISH+) expression, the 3-year iDFS rates were 96.2% for Enhertu (140 patients) versus 86.5% for Kadcyla (147 patients).

When broken down by prior neoadjuvant chemotherapy type, patients who received prior anthracyclines experienced a 3-year iDFS rate of 90.6% with Enhertu (423 patients) versus 80.3% with KADCYLA (399 patients). For those given prior platinum-based chemotherapy, the 3-year iDFS rates were 93.9% for Enhertu (386 patients) versus 87.3% for Kadcyla (392 patients).

“These additional analyses are very helpful to further characterize the clinical benefit and safety profile of Enhertu over Kadcyla in the post-neoadjuvant HER2-positive early breast cancer residual invasive disease setting, supporting Enhertu as the potential new standard of care,” lead study author Dr. Sibylle Loibl, 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.

What was previously reported from DESTINY-Breast05?

Findings from an interim analysis of DESTINY-Breast05 presented at the 2025 ESMO Congress showed that patients in the overall population treated with Enhertu (818 patients) experienced a 3-year iDFS rate of 92.4% compared with 83.7% for patients treated with Kadcyla.

How was DESTINY-Breast05 designed?

Patients were randomly assigned 1 to 1 to receive Enhertu at 5.4 mg per kg once every three weeks for 14 cycles or Kadcyla at 3.6 mg/kg once every three weeks for 14 cycles. Key stratification factors included extent of disease at presentation (operable versus inoperable), HER2-targeted neoadjuvant therapy (single agent versus dual agent), hormone receptor status (positive versus negative), and post–neoadjuvant therapy pathologic nodal status (positive versus 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.

What was found regarding ILD and radiation pneumonitis in DESTINY-Breast05?

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. Enhertu was allowed to resume if ILD resolved to grade 0. For patients with grade 2 or higher ILD, Enhertu 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 Enhertu arm (806 patients), any-grade drug-related ILD occurred in 9.6% of patients compared with 1.6% of patients in the Kadcyla arm (801 patients). For patients who received sequential radiation and Enhertu (319 patients), 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 days. In those given concurrent Enhertu and radiation (438 patients), 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.

In the Kadcyla arm, patients who received sequential treatment (270 patients) experienced ILD at any grade (2.6%), grade 1 (1.5%), and grade 2 (1.1%). These respective rates were 1%, 0.6% and 0.4% in those given concurrent treatment (480 patients). No grade 3 or higher ILD was reported in the Kadcyla arm as a whole.

Regarding investigator-reported radiation-induced pneumonitis, no grade 3 or higher events were reported in either arm. In the Enhertu 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 Enhertu/radiation. In the Kadcyla 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.

References

1. “Trastuzumab deruxtecan in residual HER2-positive early breast cancer” by Dr. Loibl, et al., New England Journal of Medicine
2. “Trastuzumab deruxtecan versus trastuzumab emtansine in patients with high-risk HER2-positive primary breast cancer with residual invasive disease after neoadjuvant therapy: interim analysis of DESTINY-Breast05” by Dr. Loibl, et al., Annals of Oncology
3. “Trastuzumab deruxtecan versus trastuzumab emtansine in patients with high-risk HER2-positive primary breast cancer with residual invasive disease after neoadjuvant therapy: interim analysis of DESTINY-Breast05” by Dr. Loibl, et al., 2025 San Antonio Breast Cancer Symposium

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