FDA Approves Enhertu for 2 New Indications for Patients With HER2+ Early Breast Cancer

The FDA has approved 2 new indications for trastuzumab deruxtecan (T-DXd; Enhertu) in HER2-positive early breast cancer.¹ This decision moves T-DXd further into the curative-intent setting after its rapid expansion across metastatic HER2-positive disease.

Neoadjuvant and Adjuvant Approvals Expand T-DXd's Role

In the neoadjuvant setting, T-DXd followed by paclitaxel, trastuzumab, and pertuzumab (THP) was approved for patients with high-risk HER2-positive stage II/III early breast cancer, supported by findings from the phase 3 DESTINY-Breast11 trial, which demonstrated significantly improved pathologic complete response (pCR) rates compared with standard chemotherapy-based regimens.² In the adjuvant setting, T-DXd was approved for patients with HER2-positive breast cancer who have residual invasive disease following neoadjuvant trastuzumab and taxane-based treatment, based on results from the phase 3 DESTINY-Breast05 trial.

T-DXd, an antibody-drug conjugate jointly developed by AstraZeneca and Daiichi Sankyo, has already reshaped treatment for HER2-positive metastatic breast cancer and HER2-low disease. T-DXd received rapid approval in HER2-low breast cancer in 2022,³ just months after the results of the DESTINY-Breast04 trial caused a buzz at the American Society of Clinical Oncology.⁴ The findings were groundbreaking because they meant that the pathology of breast cancer needed to be redefined.

“No longer can we simply say that someone is HER2-positive or HER2-negative, but the appreciation of HER2 low becomes really important as these patients clearly benefit from therapeutic intervention,” Debra Patt, MD, PhD, MBA, executive vice president for policy and strategic initiatives at Texas Oncology, told The American Journal of Managed Care^® at the time.

This expansion could alter the standard neoadjuvant approach for patients with high-risk localized disease across both the neoadjuvant and adjuvant settings.

DESTINY-Breast11: Improved pCR Rates in the Neoadjuvant Setting

DESTINY-Breast11 evaluated neoadjuvant T-DXd followed by THP in patients with high-risk HER2-positive early breast cancer. Patients were randomized to receive either the investigational T-DXd–containing regimen or standard anthracycline-based chemotherapy. The primary end point was pCR, a commonly used surrogate marker associated with improved long-term outcomes in HER2-positive breast cancer.⁵

According to results presented at the 2025 European Society for Medical Oncology Congress, the T-DXd-based regimen achieved a statistically significant improvement in pCR rates versus standard treatment. Investigators also reported encouraging early event-free survival trends, though longer follow-up will be needed to determine durability and overall survival impact.

DESTINY-Breast05: Cutting Recurrence Risk in the Adjuvant Setting

In DESTINY-Breast05, T-DXd significantly reduced the risk of invasive disease recurrence or death by 53% compared to trastuzumab emtansine (T-DM1) in patients with residual invasive disease following neoadjuvant therapy, with a three-year invasive disease-free survival rate of 92.4% versus 83.7% with T-DM1. Based on these results, T-DXd has been included in the National Comprehensive Cancer Network Guidelines as a Category 1 recommended treatment in the adjuvant setting for eligible patients.

Personalized Treatment and the Push Toward Earlier-Stage Use

Both trials build on growing momentum for antibody-drug conjugates in breast oncology, particularly as investigators explore moving highly active metastatic therapies into earlier-stage disease. “I think overall moving antibody-drug conjugates into the localized and curative setting is where the field of breast oncology is heading as we have seen great activity of these drugs in the metastatic setting,” said Rani Bansal, MD, medical oncologist at Duke Cancer Center Breast Clinic.

Bansal noted that while DESTINY-Breast11 showed improved pCR rates, patient selection will remain important. "I think there are definitely patients who will benefit from this regimen, however it is complicated as not all patients may need an escalated regimen to achieve a great response for their HER2-positive breast cancer," she said. "I think we need a more personalized approach in treating HER2-positive disease and I think the technology is coming where we can test a patient's tumor to help guide us on if we need to escalate or can actually de-escalate the treatment they receive."

Safety Considerations: ILD and Pneumonitis Remain Key Concerns

Furthermore, safety considerations remain central to discussions surrounding wider adoption. Interstitial lung disease (ILD) and pneumonitis are recognized toxicities associated with T-DXd and can be fatal in rare cases.

"We do need to be mindful of the potential for pneumonitis or ILD with T-DXd as this can be a fatal complication of this drug so as this drug is utilized more for our patients in the curative setting, we will need to weigh the risks and benefits," Bansal said. "Overall, I feel these trials are moving the field forward in regards to curing more of our patients."

References

1. Daiichi Sankyo. Enhertu approved in the U.S. for two new indications for patients with HER2 positive early breast cancer. Business Wire. Published May 13, 2026. Accessed May 18, 2026. https://www.businesswire.com/news/home/20260513022601/en/Enhertu-Approved-in-the-U.S.-for-Two-New-Indications-for-Patients-with-HER2-Positive-Early-Breast-Cancer
2. Bradbury H. ESMO 2025: DESTINY-Breast11 trial results revealed. EMJ Reviews. Published October 18, 2025. Accessed May 14, 2026.
3. Caffrey M. Trastuzumab deruxtecan wins rapid approval for HER2-low breast cancer. AJMC^®. August 6, 2022. Accessed May 18, 2026. https://www.ajmc.com/view/trastuzumab-deruxtecan-wins-rapid-approval-for-her2-low-breast-cancer
4. Caffrey M. Trastuzumab deruxtecan cuts risk of disease progression or death by 50% for patients with HER2-low metastatic breast cancer. AJMC. June 5, 2022. Accessed May 18, 2026. https://www.ajmc.com/view/trastuzumab-deruxtecan-cuts-risk-of-disease-progression-or-death-by-50-for-patients-with-her2-low-metastatic-breast-cancer
5. Harbeck N, Modi S, Pusztai L, et al; and the DESTINY-Breast11 Trial Investigators. 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. 2026;37(2):166-179. doi:10.1016/j.annonc.2025.10.019
6. Loibl S, Park YH, Shao Z, et al; and the DESTINY-Breast05 Trial Investigators. Trastuzumab deruxtecan in residual HER2-positive early breast cancer. N Engl J Med. 2026;394(9):845-857. doi:10.1056/NEJMoa2514661