FDA granted priority review to Enhertu application for previously treated HER2-positive solid tumors

Daiichi Sankyo and AstraZeneca announced that the FDA granted priority review for the supplemental BLA of trastuzumab deruxtecan (T-DXd/Enhertu; HER2 ADC) for patients with previously treated unresectable or metastatic HER2-positive (IHC 3+) solid tumors.

The application is being reviewed under the Real-Time Oncology Review (RTOR) program and Project Orbis, and the FDA has set a PDUFA date of May 30, 2024. However, under RTOR, earlier approval is probable.

Potential tumor-agnostic approval in the US would introduce a new biomarker-directed ADC competitor in 2L+ mUC. However, Enhertu threat may be moderated by indication restriction to the IHC 3+ segment, which is an estimated smaller portion of mUC (up to ~15%).

Key Highlights and Potential Implications:

• The application is based on data from the P2 DESTINY-PanTumor02 trial where Enhertu monotherapy showed durable responses and “clinically meaningful” survival benefit across multiple 2L+ HER2-expressing solid tumors including mUC
  • In mUC, Enhertu demonstrated clinically relevant ORR, PFS, and OS across both IHC 3+ and IHC 2+ populations, with generally stronger benefit observed in the IHC 3+ segment; results were comparable to or numerically higher than historical P2 benchmarks but in a very small sample (N=41)
  • Data from other supporting trials in HER2-positive (IHC 3+) tumours, including P2 DESTINY-Lung01 and P2 DESTINY-CRC02, were also included in the submission
• Priority review designation and RTOR reinforces FDA’s view of the clinical potential of Enhertu across 2L+ HER2-positive solid tumors; under RTOR, expects approval ahead of the target action date, potentially as early as Q1’24
  • AZ/Daiichi also benefit from the FDA BTD previously granted for Enhertu for this population
  • Path for confirmatory P3 approval remains unclear, with no commentary on this from AstraZeneca or Daiichi Sankyo as of yet
• If approved, Enhertu would be the first HER2-directed therapy and antibody drug conjugate with a tumour-agnostic indication
  • Approvals for tumor-agnostic approaches that enable treatment based on biomarkers rather than tumor location remain relatively rare, with only six FDA-approved tumor-agnostic products
• As a biomarker-directed ADC, Enhertu could start to carve out the 2L+ mUC market; however, restriction to an IHC 3+ population (est. ~15% mUC) may temper competitive impact
  • Based on expected indication statement and non-overlapping payload with enfortumab vedotin (EV), Enhertu could be positioned as a 2L treatment option to 1L EV+Pembro in HER2-positive patients; however, there is currently no data showing Enhertu’s efficacy and safety following EV+Pembro
  • HER2 expression is not well defined in mUC, and HER2 testing is not standard practice. Testing delaying treatment start has also been raised as a concern by some KOLs
    • AstraZeneca & Daiichi can leverage previous experience in defining HER2 expression across tumor types and supporting HER2 testing uptake
    • Note that Daiichi management has previously signalled that there are no specific plans to study Enhertu in a HER2-low pan-tumor setting, which would preclude need for testing
  • While Enhertu’s label will be specific to IHC 3+, it’s unknown if NCCN guidelines for bladder may also include IHC 2+ population, which could unlock an additional estimated ~15% of the mUC market and increase threat 
    • Guidelines for endometrial and cervical cancer, where results were particularly strong, have already been updated to list Enhertu for both IHC 3+ or IHC 2+ populations as useful in certain circumstances

Additional Information

• The FDA granted BTD for T-DXd in 2L+ unresectable or metastatic HER2-positive solid tumors in August 2023 based on results from the P2 DESTINY-PanTumor02 trial, making it the first HER2 directed therapy to demonstrate a potential benefit across a series of difficult to-treat cancers
• T-DXd has been approved for HER2-positive breast cancer, HER2-positive gastric and gastroesophageal junction adenocarcinoma, and NSCLC with HER2 mutations, showcasing its wide-ranging efficacy across various indications
• Initial results from P2 DESTINY-PanTumor02 were presented at ASCO in June 2023 (Abstract #LBA3000), followed by primary analysis results at ESMO in October 2023 (Abstract #LBA34, F. Meric-Bernstam et al.) --
  • Study Information
    • P2 DESTINY-PanTumor02 (NCT04482309; DP-02): T-DXd in 2L+ HER2-expressing (IHC 3+ or 2+ by local or central testing) solid tumors including mUC, endometrial, cervical
    • Bladder N=41 (N=268 across cohorts)
    • 1EP: ORR
    • 2EP: DOR, PFS, OS, AEs
  • Efficacy (Bladder)
    • cORR: 39%
      • IHC 3+: 56%
      • IHC 2+: 35%
    • mPFS (mos): 7.0
      • IHC 3+: 7.4
      • IHC 2+: 7.8
    • mOS (mos): 12.8
      • IHC 3+: 13.4
      • IHC 2+: 13.1
    • Safety (across cohorts)
      • Gr3+ TRAEs: 41%
      • All-grade ILD/pneumonitis: 10.5% (N=28)
        • Gr 1: 2.6% (N=7)
        • Gr 2: 6.4% (N=17)
        • Gr 3: 0.4% (N=1)
        • Gr 4: 0% (N=0)
        • Gr 5: 1.1% (N=3)
      • Discontinuation rate due to TRAEs: 9%