FDA granted priority review for T-DXd (Enhertu) for the treatment of HER2-low or HER2-ultralow mBC after at least one ET in the metastatic setting

 AstraZeneca (AZ) and Daiichi Sankyo (DS) announced that the FDA granted priority review for T-DXd (Enhertu, HER2-ADC) for the treatment of HER2-low (IHC 1+ or IHC2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) mBC after at least one ET in the metastatic setting with a PDUFA date set to Feb 1, 2025. 

• These regulatory updates are based on 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) while ITT and HER2-ultralow results were numerically consistent with the HER2-low group
• While PDUFA data is set for Q1 2025, approval could be granted as early as Q4 2024 given the breakthrough designation and priority review
  • For reference, DB-04 for T-DXd was granted priority review in July 2022 with a PDUFA set in Q4 2022 though approval was granted in August 2022 through the RTOR process
• DESTINY-Breast06 represents a high competitive threat to label expansion into the post ET (chemo-naïve) HR+/HER2- mBC population based on the Phase 3 ASCENT-07 due to the overlapping patient populations
  • T-DXd’s expected to move into the HR+/HER2-ultralow population and increase pool of  HR+ patients potentially  eligible for T-DXd beyond what was established through DESTINY-Breast04 (HER2-low mBC post-chemo)
  • T-DXd will likely become the first HER2-targeted treatment option in the newly established “HER2-ultralow” BC classification, though KOLs have expressed a strong need for improved and standardized patient classification
• The indication listed for priority review matches that of the Type II Variation Application validated by the EMA in Aug 2024; both are vague in whether they exclude HR-/HER2-low or -ultralow patients (who can also be categorized as TNBC) suggesting the potential for a higher threat upon approval
  • The label does not specify HR+ mBC patients; however, requirement for prior ET in the metastatic setting may preclude the use of T-DXd in HR- patients 
  • Note that DESTINY-Breast06 dataset did not include patients with HR- disease while DESTINY-Breast04 did; Moreover, the language around LoT and definition of HER2-ultralow submitted to the FDA for approval differs slightly than what was granted BTD in Aug 2024 
  • Indication listed for the FDA BTD: “unresectable or metastatic HR+, HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC >0 <1+) BC patients who have received either two lines of ET in the metastatic setting, or one line of ET if they had demonstrated disease progression within six months of starting 1 LoT with ET + CDK4/6i or within 24 months of the start of adjuvant ET”