Destiny – Breast 02 Trial – Rodrigo Arrangoiz MS, MD, FACS, FSSO

Is a randomized phase III trial:
- That established trastuzumab deruxtecan (T-DXd) as the preferred therapy for patients with HER2-positive metastatic breast cancer:
  - Previously treated with trastuzumab emtansine (T-DM1)
Population:
- HER2-positive unresectable or metastatic breast cancer
- Prior therapy:
  - Trastuzumab + taxane and T-DM1
- Randomization: T
  - DXd vs Investigator’s choice (trastuzumab + capecitabine or lapatinib + capecitabine)
- Primary endpoint:
  - Progression-free survival (PFS, BICR)
- Key secondary endpoints:
  - Overall survival (OS), ORR, duration of response, safety
Mechanism of Action (Why T-DXd Is Different):
- Trastuzumab deruxtecan is a next-generation antibody–drug conjugate (ADC) with:
  - High drug-to-antibody ratio (≈8:1)
  - Cleavable linker membrane-permeable topoisomerase I payload bystander effect:
    - Enabling killing of adjacent tumor cells with heterogeneous HER2 expression:
      - This design explains its activity after T-DM1 failure, where resistance commonly develops.
Efficacy Results:
- Progression-Free Survival (Primary Endpoint):
  - Median PFS:
    - T-DXd:
      - ~17.8 months
    - Control:
      - ~6.9 months
    - Hazard ratio:
      - ~0.36
    - Risk reduction:
      - ~64% reduction in progression or death
  - Clinically transformative improvement in disease control
- Overall Survival:
  - Median OS:
    - T-DXd:
      - ~39.2 months
    - Control:
      - ~26.5 months
    - Hazard ratio:
      - ~0.66
  - Statistically significant and clinically meaningful OS benefit, uncommon in heavily pretreated HER2-positive MBC trials
- Objective Response Rate:
  - T-DXd:
    - ~69%
  - Control:
    - ~29%
  - Complete responses:
    - Observed with T-DXd
Safety Profile:
- Common Adverse Events (T-DXd):
  - Nausea
  - Fatigue
  - Alopecia
  - Vomiting
  - Neutropenia
  - Anemia
  - Interstitial Lung Disease (ILD) / Pneumonitis:
    - Any-grade ILD:
      - ~10%
    - Grade ≥3 ILD:
      - ~1–2%
    - Fatal events:
      - Rare but reported
Key clinical takeaway:
- Early recognition, prompt drug interruption, and steroid initiation are essential
- Patient education and routine symptom monitoring are mandatory
How DESTINY-Breast 02 Changed Practice:
- Before DESTINY-Breast 02:
  - Post-T-DM1 options relied on capecitabine-based combinations:
    - Limited durability and modest survival benefit
- After DESTINY-Breast 02:
  - T-DXd is the standard of care after T-DM1:
    - Supported by PFS + OS superiority:
      - Endorsed by NCCN, ASCO, ESMO
- Represents a paradigm shift in the HER2-positive metastatic sequence
Treatment Sequencing (Current Standard):
- First line:
  - Trastuzumab + pertuzumab + taxane
- Second line:
  - T-DXd
- Later lines:
  - Tucatinib-based regimens
  - Clinical trials
  - Other HER2-targeted agents
Surgical and Multidisciplinary Relevance:
- Durable systemic control increases:
  - Consideration of local therapies for oligoprogression
  - Delayed need for palliative surgery
- Highlights importance of:
  - Early referral to medical oncology
  - Coordinated surveillance for pulmonary toxicity
Key Take-Home Messages:
- DESTINY-Breast 02 firmly establishes T-DXd as best-in-class post-T-DM1 therapy:
  - Demonstrates both PFS and OS benefit in a refractory population
- ILD monitoring is critical to safe delivery
- Confirms the power of ADC engineering in overcoming resistance