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) 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 vs 56.3% in the standard therapy arm, representing a statistically significant improvement.¹

“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, said in a news release. Modi is a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York.⁴

Neoadjuvant therapy achieving pCR has been associated with reduced recurrence risk and improved survival outcomes in HER2-positive disease.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 vs 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 postneoadjuvant 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 patients with 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 1 in 4 patients still experience disease recurrence, underscoring the need for new options in this setting,” Dave Fredrickson, executive vice president at AstraZeneca, 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 boxed warnings for interstitial lung disease and pneumonitis, as well as warnings for 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 on treatment expectations, adherence, and adverse event monitoring as T-DXd moves 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. 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. 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. 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. 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. 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