FDA approval for trastuzumab deruxtecan for adult patients with unresectable or metastatic HR positive, HER2-low or HER2-ultralow breast cancer

On January 27, 2025, Daiichi Sankyo (DS) and AstraZeneca (AZ) announced the US approval for trastuzumab deruxtecan (T-DXd, Enhertu; HER2-ADC) for adult patients with unresectable or metastatic hormone receptor (HR)-positive, HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer, as determined by an FDA-approved test, that has progressed on one or more endocrine therapies in the metastatic setting. 

Highlights and Implications

• This label expansion, occurring slightly ahead of the set PDUFA date of Feb 1, 2025, is based on PFS results from the Phase 3 DESTINY-Breast06 trial of T-DXd in HR+/HER2-low mBC post-ET, presented at ASCO 2024 
  • T-DXd significantly improved PFS vs TPC in HER2-low patients (HR: 0.62; median PFS: 13.2 vs 8.1 mo); ITT results (HER2-low and ultralow) were numerically consistent with the HER2-low group (HR:0.64)  
    • In an exploratory analysis of the HER2-ultralow subgroup (n=153), median PFS was 15.1 mo, for T-DXd vs. 8.3mo. for TPC (HR: 0.76) though this population was not powered for significance; At time of PFS final analysis OS was still immature
    • Safety was consistent with previous breast cancer trials including a black box warning for ILD and embryo-fetal toxicity
  • The approval was granted by the FDA after securing Priority Review in Oct 2024 and Breakthrough Therapy Designation in Aug 2024
• T-DXd’s US label is in line with expectation and continues to represent a high competitive threat into the post ET (chemo-naïve) HR+/HER2- mBC population based on the Phase 3 ASCENT-07 due to the overlapping patient populations and its earlier approval timeline 
• With this approval, T-DXd moved into an earlier line of treatment and also broadened its eligible patient population as the first HER2-targeted treatment in the newly established “HER2-ultralow” BC segment 
  • AZ estimates that “Approximately 85-90% of patients with HR+/HER2 mBC patients were determined to have actionable levels of HER2-expression…with nearly 2/3 …previously assessed as IHC 0 at a local laboratory were classified as HER2-low or HER2-ultralow upon central analysis of the tumor sample”
  • Per the PI, HER2-ultralow (IHC 0 with membrane staining), is defined as membrane staining that is seen in >0% and ≤10% of tumor cells and was determined in the trial by Ventana’s PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody assay and evaluated at a central laboratory
  • KOLs have expressed a strong need for improved and standardized patient classification of HER2 expression in BC and  AZ/DS will likely need to increase educational efforts for both oncologist and pathologists to facilitate uptake of T-DXd in this newly defined patient population 
    • Ahead of this approval, both AZ and DS have been messaging around the importance of “ the spectrum” of HER2 expression in oncology at key medical conference exhibit booths, publications, and educational sessions
  • Note, AZ/DS are also evaluating T-DXd in HER2-0 mBC patients in the Phase 3b DESTINY-Breast15 trial 

Additional Background

• T-DXd’s Type II Variation application has also been validated by the EMA for HER2-low or HER2-ultralow mBC post ET in Aug 2024 and EU approval is guided for H1 2025
• T-DXd is currently approved in the US and EU for the treatment of HER2-low mBC post chemotherapy based on the results of the Phase 3 DESTINY-Breast04 trial, which was presented at ASCO 2022 Annual Meeting and published in the NEJM
• The trial demonstrated that T-DXd had statically significant and clinically meaningful benefit in PFS and OS compared to standard of care regardless of HR status
• The safety profile of T-DXd was consistent with previous clinical trials with no new safety concerns identified