FDA Priority Review for Post-Neoadjuvant T-DXd in HER2+ Early BC

On March 9, 2026, researchers of early stage HER2-positive breast cancer learned more recent information on the development progress of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for treatment of early stage HER2-positive breast cancer as the U.S. Food and Drug Administration (FDA) announced that they have accepted for review of a supplemental Biologics License Application (sBLA) for potential new indication. The sBLA will receive Priority Review, which is given to applications for new drugs, or treatments for serious, life-threatening, or debilitating illnesses and clinical entities, that, if approved, would offer significant improvements in the safety or effectiveness of treatment, diagnosis, or prevention of serious disease or conditions. In December 2025, the FDA granted Breakthrough Therapy Designation for Enhertu for this patient population.

Regulatory Milestone and Strategic Overview

The submission is seeking treatment indication of T-DXd for the post-neoadjuvant treatment of patients with HER2-positive early breast cancer who have residual invasive disease in the breast and/or sous-serosal tissues. This is distinct from the patients with metastatic disease or the so-called “curative intent” setting. The standard of care for these highly aggressive patients with residual disease after preoperative (neoadjuvant) therapy is ado-trastuzumab emtansine (T-DM1). There will be significant interest in this data as this would be a shift in approach to treatment. The PDUFA target action date for approval of T-DXd for this new indication is July 7, 2026.

Why It Matters

Management of HER2-positive early breast cancer, both from the patient’s and physician’s perspective, occurs in the post-neoadjuvant setting. The majority of patients with early HER2-positive breast cancer undergo neoadjuvant (preoperative) systemic therapy using a combination of chemotherapy and HER2-targeted therapies such as trastuzumab and pertuzumab, followed by surgical therapy. Pathological complete response (pCR) (i.e., the absence of any residual tumor within both the breast and lymph nodes at time of surgery) serves as a surrogate end point for effective cancer therapy.

However, for a significant proportion of patients invasive tumour will be found at surgery. These patients are at very high risk of recurrence and are in need of effective adjuvant treatment. While T-DM1 is currently the standard of care for these patients, there remains a high risk of relapse. With the next generation of ADCs, T-DXd aims to provide a more effective treatment for patients with residual disease left in situ.

Bridging the Gap in High-Risk Early Disease

This meeting highlight reinforces the notion that addressing an important unmet need in the curative intent setting is an important goal of this approach. It is exciting that an approach already shown to revolutionize treatment in the metastatic setting is now being targeted in the early-stage setting to prevent metastatic disease in patients most at risk for relapse and who could potentially benefit from a cure.

The Clinical Evidence: Deep Dive into DESTINY-Breast05

The application is mainly supported by data from the global, open-label, multicenter Phase 3 DESTINY-Breast05 trial (NCT04622319), in which Dxdicabazexin (T-DXd; trastuzumab dysprosium hafnium-176 immunoconjugate, experimental HER2-targeted therapy) was compared with T-DM1 (trastuzumab emtansine; Kadcyla), for use in early breast cancer with HER2-positive (high-risk) disease.

Trial Design and Patient Population:

This trial aims to explore the efficacy and safety of detargeted tracer conjugate DS-8201a (T-DXd), which consists of a HER2-targeting antibody of trastuzumab (T) linked with a topoisomerase II inhibitor, DXD. Patients (≥18 years of age) with previously untreated or treated infeasible for further surgery invasive carcinoma (T1-4) with lymph node involvement (N0-3) without distant metastases (M0) with HER2-positive breast cancer (BC) will be enrolled. All patients have residual invasive cancer in the breast or lymph nodes after neoadjuvant therapy with a taxane and a drug for targeting HER2 (trastuzumab or pertuzumab in addition to trastuzumab), thus considered to be a high-risk patient for early-stage BC. Patients receive T-DXd (5.4 mg/kg) or T-DM1 (3.6 mg/kg) by IV over 1-2 minutes on Day 1 of a 21-day cycle for 14-24 doses.

Efficacy Results:

This data was highly statistically significant and clinically meaningful according to the investigators.