FDA Approves T-DXd for 2 New Indications in Early-Stage HER2-Positive Breast Cancer

The FDA approved fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for 2 separate indications in adults with HER2-positive early-stage breast cancer: one in the neoadjuvant setting and one in the post-neoadjuvant adjuvant setting.¹

Concurrent with the drug approvals, the FDA also authorized 2 companion diagnostic devices for identifying HER2-positive (IHC 3+ or ISH+) patients eligible for treatment with T-DXd under the new indications: the PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody and the VENTANA HER2 Dual ISH DNA Probe Cocktail.

The 2 trials supporting these approvals, DESTINY-Breast11 and DESTINY-Breast05, were presented together as back-to-back Presidential Symposium abstracts at the 2025 ESMO Annual Congress in Berlin and were simultaneously published in major peer-reviewed journals.

“HER2-positive breast cancer is an aggressive disease, and our goal is to reduce the risk of recurrence for patients as early as possible to achieve the best long-term outcomes. The neoadjuvant setting offers the earliest opportunity to improve outcomes, while the adjuvant setting provides another important chance to prevent recurrence for patients with residual disease after surgery. These 2 new indications in HER2-positive early breast cancer will evolve how we treat patients in these settings and support trastuzumab deruxtecan as a potential new standard of care in early-stage disease,” Shanu Modi, MD, Medical Oncologist, Memorial Sloan Kettering Cancer Center, stated in a news release.²

Neoadjuvant Indication: T-DXd Followed by THP (DESTINY-Breast11)

Efficacy and Safety

Among patients with HER2-positive, high-risk early-stage breast cancer who received neoadjuvant T-DXd for 4 cycles followed by paclitaxel, trastuzumab, and pertuzumab (THP) for 4 cycles in the phase 3 DESTINY-Breast11 trial, the pathologic complete response rate pCR was 67.3% (95% CI, 61.9%-72.4%), compared with 56.3% (95% CI, 50.6%-61.8%) with dose-dense doxorubicin and cyclophosphamide followed by THP (ddAC-THP), a statistically significant difference (P =.003). The pCR benefit was consistent regardless of hormone receptor status. Event-free survival data were not mature at the time of the primary data cutoff in March 2025, though a positive trend favoring T-DXd-THP was observed.

The tolerability profile of T-DXd-THP was favorable compared with the anthracycline-containing control arm. Grade 3 or higher adverse events occurred in 37.5% of T-DXd-THP patients versus 22.6% in the T-DXd monotherapy arm and were lower than the 64.4% grade 3 or higher rate historically observed with the TCHP regimen in the KRISTINE phase 3 study.³ Serious adverse events were similarly low, occurring in 10.6% and 10.2% of patients in the T-DXd-THP and T-DXd monotherapy arms, respectively.³

Adjudicated drug-related ILD or pneumonitis occurred in 4.4% of patients in the T-DXd-THP arm (including 2 patients with grade ≥3 events, one of which was a grade 5 event) and 5.1% in the ddAC-THP arm (including 6 patients with grade ≥3 events, including one fatality). Left ventricular dysfunction occurred in 1.3% of T-DXd-THP patients versus 6.1% of ddAC-THP patients, underscoring the cardiac safety advantage of the anthracycline-free regimen. The prescribing information includes a boxed warning for ILD and pneumonitis, and warnings and precautions for neutropenia and left ventricular dysfunction.¹

Study Design and Patient Characteristics

DESTINY-Breast11 (NCT05113251) was a randomized, 3-arm, open-label, multicenter phase 3 trial conducted across 147 sites in 18 countries. The trial enrolled 927 adult female patients with HER2-positive, high-risk early-stage breast cancer, defined as stage ≥cT3cN0 or cT0–4cN1–3. Patients were randomized 1:1:1 between October 2021 and March 2025 to T-DXd for 8 cycles (n = 286), T-DXd-THP for 4+4 cycles (n=321), or ddAC-THP for 4+4 cycles (n = 320). Enrollment in the T-DXd monotherapy arm was closed early following a recommendation from the Independent Data Monitoring Committee. The primary end point was centrally assessed pCR (ypT0/is ypN0) in the intent-to-treat population; secondary endpoints included EFS and safety. The recommended neoadjuvant dosage is 5.4 mg/kg every three weeks for four cycles, followed by the THP regimen for four cycles.

Adjuvant Indication: Post-Neoadjuvant Residual Disease (DESTINY-Breast05)

Efficacy and Safety

Among 1635 patients with HER2-positive breast cancer and residual invasive disease following neoadjuvant therapy randomized in DESTINY-Breast05, adjuvant T-DXd produced a dramatic and statistically significant improvement in invasive disease-free survival compared with ado-trastuzumab emtansine (T-DM1; Kadcyla). The 3-year IDFS rate was 92.4% (95% CI, 89.7%-94.4%) with T-DXd versus 83.7% (95% CI, 80.2%-86.7%) with T-DM1, representing a 53% reduction in the risk of invasive disease recurrence or death (HR, 0.47; 95% CI, 0.34-0.66; P <.0001).¹ Disease-free survival results were concordant, with 3-year DFS rates of 92.3% (95% CI, 89.5%-94.3%) and 83.5% (95% CI, 79.9%-86.4%) in the T-DXd and T-DM1 arms, respectively (HR, 0.47; 95% CI, 0.34-0.66; P <.0001).¹

At the time of the IDFS analysis, 47 patients (2.9%) had died across both arms, with OS data still immature. The nearly 9-percentage-point absolute improvement in 3-year IDFS over T-DM1 surpassed the benefit that had established T-DM1 as the standard of care following the KATHERINE trial, in which T-DM1 reduced the risk of invasive disease recurrence or death by 50% compared with trastuzumab.

The safety profile of T-DXd in DESTINY-Breast05 was consistent with its known profile, with no new safety signals identified.^4,5 Grade 3 or higher treatment-emergent adverse event rates were comparable between the two treatment arms, occurring in 50.6% of T-DXd patients and 51.9% of T-DM1 patients.⁵ ILD was the most clinically monitored adverse event of special interest. ILD events were reported in 9.6% of T-DXd patients and 1.6% of T-DM1 patients.⁵ The majority were low grade, with grade 1 events in 2.0% and grade 2 events in 6.5% of T-DXd patients.

In the T-DXd arm, 7 patients experienced grade 3 ILD events (0.9%), no grade 4 events occurred, and 2 grade 5 ILD events (0.2%) were identified by an independent adjudication committee. No grade 3 or higher ILD events occurred in the T-DM1 arm. The prescribing information carries a boxed warning for ILD and pneumonitis, and warnings and precautions for neutropenia and left ventricular dysfunction.¹

Study Design and Patient Characteristics

DESTINY-Breast05 (NCT04622319) was a randomized, two-arm, open-label, multicenter phase 3 trial enrolling 1635 adults with HER2-positive breast cancer who had residual invasive disease in the breast and/or axillary lymph nodes after neoadjuvant chemotherapy and HER2-targeted therapy.^1,4 The trial enrolled a notably high-risk population: approximately twice as many patients had inoperable disease at baseline compared with prior post-neoadjuvant trials, nearly twice as many were node-positive at surgery, and 80% had received dual HER2-directed therapy preoperatively. Patients were randomized 1:1 to T-DXd (n = 818) or T-DM1 (n = 817) for a maximum of 14 cycles or until disease recurrence or unacceptable toxicity.

The primary endpoint was investigator-assessed IDFS; key secondary endpoints included DFS and OS. Results were first presented at ESMO 2025 as abstract LBA1 and simultaneously published in the New England Journal of Medicine. The recommended adjuvant dosage is 5.4 mg/kg every three weeks for a maximum of 14 cycles unless disease recurrence or unacceptable toxicity occurs.¹

“Providing patients with early breast cancer more options to help prevent progression to metastatic disease can lead to improved outcomes. Progression and recurrence remain among the most significant unmet needs for those diagnosed with early breast cancer, and continued advances in treatment bring new hope to patients and families facing this disease,” Victoria Smart, senior vice president, Mission, Susan G. Komen, stated in the news release.²

References

1. U.S. Food and Drug Administration. FDA approves two separate indications for fam-trastuzumab deruxtecan-nxki in HER2-positive early-stage breast cancer. FDA. May 15, 2026. Accessed May 15, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-two-separate-indications-fam-trastuzumab-deruxtecan-nxki-her2-positive-early-stage

2. AstraZeneca/Daiichi Sankyo. ENHERTU (fam-trastuzumab deruxtecan-nxki) approved in the US for two new indications for patients with HER2-positive early breast cancer. News release. AstraZeneca/Daiichi Sankyo; May 15, 2026. Accessed May 15, 2026. https://www.astrazeneca-us.com/media/press-releases/2026/ENHERTU-fam-trastuzumab-deruxtecan-nxki-approved-in-the-US-for-two-new-indications-for-patients-with-HER2-positive-early-breast-cancer.html

3. Harbeck N, Rastogi P, Semiglazov V, et al. Neoadjuvant trastuzumab deruxtecan alone or followed by paclitaxel, trastuzumab, and pertuzumab for high-risk HER2-positive early breast cancer (DESTINY-Breast11): a randomised, open-label, multicentre, phase III trial. Ann Oncol. 2025;36(12):1087-1099. doi:10.1016/j.annonc.2025.10.019

4. Loibl S, Park YH, Shao Z, et al. Trastuzumab deruxtecan in residual HER2-positive early breast cancer. N Engl J Med. Published online December 10, 2025. doi:10.1056/NEJMoa2514661

5. Daiichi Sankyo/AstraZeneca. ENHERTU reduced the risk of disease recurrence or death by 53% vs. T-DM1 in patients with high-risk HER2-positive early breast cancer following neoadjuvant therapy in DESTINY-Breast05 Phase III trial. News release. Daiichi Sankyo/AstraZeneca; October 18, 2025. Accessed May 15, 2026. https://www.astrazeneca.com/media-centre/press-releases/2025/enhertu-reduced-the-risk-of-disease-recurrence-or-death-by-53-vs-t-dm1-in-patients-with-high-risk-her2-positive-early-breast-cancer.html