FDA Expands T-DXd With 2 New Indications in HER2-Positive Early Breast Cancer

The FDA has approved 2 new indications for fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu; Daiichi Sankyo, Inc/AstraZeneca) in adults with HER2-positive early-stage breast cancer, significantly expanding the role of the antibody-drug conjugate (ADC) in earlier lines of treatment.¹ The approvals include neoadjuvant use of T-DXd followed by a taxane, trastuzumab (Herceptin; Genentech), and pertuzumab (Perjeta; Genentech) (THP) regimen for patients with stage 2 or 3 HER2-positive disease, as well as adjuvant use for patients with residual invasive disease following neoadjuvant trastuzumab-based and taxane-based therapy.¹

The approvals further establish T-DXd as a key therapy across the HER2-positive breast cancer treatment continuum and may reshape standards of care for patients with high-risk early-stage disease.^2,3

DESTINY-Breast11 Demonstrates Improved Pathologic Complete Response

The neoadjuvant indication was supported by results from the phase 3 DESTINY-Breast11 trial (NCT05113251), which enrolled 927 adults with HER2-positive, high-risk, early-stage breast cancer. Patients received either T-DXd for 4 cycles followed by THP, standard dose-dense doxorubicin (Adriamycin; Pfizer)/cyclophosphamide (Cytoxan; Pfizer) followed by THP, or an investigational regimen.¹

The primary end point was pathologic complete response (pCR), defined as the absence of invasive cancer in the breast and axillary lymph nodes after surgery. Investigators reported a pCR rate of 67.3% in the T-DXd-THP arm compared with 56.3% in the standard therapy arm, representing a statistically significant improvement.¹

“These two 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,” said Shanu Modi, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, in an AstraZeneca news release.⁴

Neoadjuvant therapy achieving pCR has been associated with reduced recurrence risk and improved survival outcomes in HER2-positive diseases.³ Investigators noted the results could help support earlier intervention strategies aimed at preventing disease recurrence before surgery.

DESTINY-Breast05 Shows Superior Disease-Free Survival

The adjuvant approval was based on findings from the phase 3 DESTINY-Breast05 trial (NCT04622319), which evaluated T-DXd in patients with residual invasive disease after neoadjuvant therapy.^1,3 Residual disease following neoadjuvant treatment is associated with a higher likelihood of recurrence and poorer long-term outcomes.²

In the trial, 1635 patients were randomly assigned to receive either T-DXd or trastuzumab emtansine (Kadcyla; Genentech; T-DM1) for up to 14 cycles. The primary efficacy end point was invasive disease-free survival (IDFS).¹

The 3-year IDFS rate was 92.4% with T-DXd compared with 83.7% with T-DM1 (HR, 0.47; 95% CI, 0.34-0.66; P < .0001). Similar improvements were observed in disease-free survival outcomes.¹

Prior to approval, the FDA granted breakthrough therapy designation to T-DXd in the post-neoadjuvant setting based on emerging evidence of clinical benefit in this high-risk population.²

Expanding T-DXd’s Role Across Breast Cancer

T-DXd is a HER2-directed ADC that combines trastuzumab with a topoisomerase I inhibitor payload through a cleavable linker. The treatment has demonstrated efficacy across HER2-positive metastatic breast cancer, HER2-low breast cancer, gastric cancer, and non–small cell lung cancer.³

The FDA previously approved T-DXd in combination with pertuzumab for first-line treatment of unresectable or metastatic HER2-positive breast cancer, reflecting the therapy’s growing role across multiple disease settings.⁵

“HER2-positive early disease is considered highly curable, however up to one in four patients still experience disease recurrence, underscoring the need for new options in this setting,” Dave Fredrickson, executive vice president of AstraZeneca’s Oncology Haematology Business Unit, said in the news release.⁴

Concurrent with the approvals, the FDA also authorized companion diagnostic assays, including the PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody and the VENTANA HER2 Dual ISH DNA Probe Cocktail, to identify eligible HER2-positive patients.¹

Implications for Pharmacists

The expanded indications carry important implications for oncology pharmacists involved in treatment selection, patient counseling, and toxicity management. T-DXd includes a boxed warning for interstitial lung disease and pneumonitis, along with warnings regarding neutropenia and left ventricular dysfunction.¹ Early recognition and multidisciplinary management of these toxicities remain critical.

Pharmacists also play a central role in patient education surrounding treatment expectations, adherence, and adverse event monitoring as T-DXd continues moving into earlier treatment settings. The approvals reinforce the growing importance of ADCs in curative-intent breast cancer therapy and highlight the need for continued pharmacist engagement in evolving oncology practice.

REFERENCES

1. FDA approves two separate indications for fam-trastuzumab deruxtecan-nxki in HER2-positive early-stage breast cancer. News release. FDA. Published May 16, 2026. Accessed May 18, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-two-separate-indications-fam-trastuzumab-deruxtecan-nxki-her2-positive-early-stage

2. Valletti D. T-DXd Granted Breakthrough Therapy Designation in Post-Neoadjuvant HER2-Positive Early Breast Cancer. Pharmacy Times. Published December 22, 2025. Accessed May 18, 2026. https://www.pharmacytimes.com/view/t-dxd-granted-breakthrough-therapy-designation-in-post-neoadjuvant-her2-positive-early-breast-cancer

3. Valletti D. T-DXd Demonstrates Superior Outcomes in Early HER-2-Positive Breast Cancer Across Phase 3 DESTINY Trials. Pharmacy Times. Published September 30, 2025. Accessed May 18, 2026. https://www.pharmacytimes.com/view/fam-t-dxd-demonstrates-superior-outcomes-in-early-her2-positive-breast-cancer-across-phase-3-destiny-trials

4. ENHERTU (fam-trastuzumab deruxtecan-nxki) approved in the US for two new indications for patients with HER2-positive early breast cancer. News release. AstraZeneca. Published May 15, 2026. Accessed May 18, 2026. https://www.astrazeneca-us.com/content/az-us/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

5. McGovern G. FDA Approves T-DXd With Pertuzumab for First-Line Treatment of Advanced HER2+ Breast Cancer. Pharmacy Times. Published December 15, 2025.Accessed May 18, 2026. https://www.pharmacytimes.com/view/fda-approves-t-dxd-with-pertuzumab-for-first-line-treatment-of-advanced-her2-breast-cancer