FDA Grants Priority Review to T-DXd in HER2+ Early Breast Cancer

The FDA accepted a supplemental biologics license application and granted priority review for fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) as a treatment for adult patients with HER2-positive early breast cancer who had residual invasive disease following neoadjuvant systemic therapy.¹

This regulatory action, was based on results from the phase 3 DESTINY-Breast05 trial (NCT04622319), which demonstrated that T-DXd significantly improved invasive disease-free survival (iDFS) compared with trastuzumab emtansine (T-DM1; Kadcyla).² The FDA assigned a Prescription Drug User Fee Act date within the third quarter of 2026, reflecting the potential for the agent to provide a significant improvement over available therapies for this patient population.

DESTINY-Breast05 Trial Data Supporting the Findings

At the prespecified interim analysis of the DESTINY-Breast05 trial, T-DXd demonstrated a statistically significant and clinically meaningful improvement in the primary end point of iDFS. Treatment with T-DXd reduced the risk of invasive disease recurrence or death by 53% compared with T-DM1 (HR, 0.47; 95% CI, 0.34-0.66; P <.001).

The 3-year iDFS rate was 92.4% (95% CI, 89.7%-94.4%) for patients receiving T-DXd and 83.7% (95% CI, 80.2%-86.7%) for those receiving T-DM1. Key secondary end points also favored the T-DXd arm. The 3-year disease-free survival (DFS) rates were 92.3% (95% CI, 89.5%-94.3%) and 83.5% (95% CI, 79.9%-86.4%), respectively.

Furthermore, T-DXd was associated with a 51% reduction in the risk of distant disease recurrence and a 36% reduction in the risk of brain metastases. Overall survival (OS) data were not mature at the time of the interim analysis (2.9% maturity), though the HR was 0.61 (95% CI, 0.34-1.10).

Trial Design

DESTINY-Breast05 was a global, randomized, open-label, active-controlled phase 3 trial evaluating the efficacy and safety of post-neoadjuvant T-DXd vs T-DM1.

The trial randomly assigned 1635 patients in a 1:1 ratio to receive either T-DXd (n = 818) at 5.4 mg/kg or T-DM1 (n = 817) at 3.6 mg/kg every 3 weeks. Adult patients with HER2-positive early breast cancer who had residual invasive disease in the breast or axillary lymph nodes following neoadjuvant systemic therapy were eligible to enroll on the trial. The study population was characterized as high-risk, including patients with inoperable disease at baseline and those who were node-positive at the time of surgery. All patients had an ECOG performance-status score of 0 or 1.

The primary end point was iDFS, defined as the time from randomization to the first occurrence of local or regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, or death. Secondary end points included DFS, OS, DRFI, BMFI, and safety.

Adverse Effects Noted Between T-DXd and T-DM1

The safety profile of T-DXd was consistent with previous reports. Grade 3 or higher adverse effects (AEs) occurred in 50.6% of patients in the T-DXd arm and 51.9% in the T-DM1 arm. The most common AEs in patients receiving T-DXd included nausea (71.3%), constipation (32.0%), decreased neutrophil count (31.6%), and vomiting (31.0%). For the T-DM1 group, the most common AEs were increased aspartate aminotransferase (50.2%), decreased platelet count (49.8%), and increased alanine aminotransferase (45.3%).

Adjudicated drug-related interstitial lung disease (ILD) or pneumonitis occurred in 9.6% (n = 78) of patients treated with T-DXd, compared with 1.6% (n = 13) in the T-DM1 group. Most ILD events were low-grade; in the T-DXd arm, these included grades 1 (2.0%), grade 2 (6.5%), and grade 3 (0.9%) events.

References

1. Enhertu granted Priority Review in the US as post-neoadjuvant treatment for patients with HER2-positive early breast cancer. News release. March 9, 2026. Accessed March 9, 2026. https://tinyurl.com/yeyjtx7h
2. Loibl S, Park YH, Shao Z, et al. Trastuzumab deruxtecan in residual HER2-positive early breast cancer. N Engl J Med. 2026;394(9):845-857. doi:10.1056/NEJMoa2514661