What is the recommended approach for using immunotherapy, such as pembrolizumab (programmed death-1 (PD-1) inhibitor), in the neoadjuvant setting for patients with triple negative breast cancer?

Immunotherapy in Neoadjuvant Setting for Triple-Negative Breast Cancer

For patients with stage II or III triple-negative breast cancer (TNBC), pembrolizumab combined with platinum-containing chemotherapy in the neoadjuvant setting followed by adjuvant pembrolizumab is strongly recommended as the standard of care, regardless of PD-L1 status. 1

Recommended Treatment Protocol

Neoadjuvant Phase

• Preferred regimen (KN522 trial protocol): 1
  • Pembrolizumab 200 mg IV every 3 weeks
  • Combined with sequential chemotherapy:
    • Initial 4 cycles: Paclitaxel + Carboplatin
    • Followed by 4 cycles: Anthracycline (doxorubicin or epirubicin) + Cyclophosphamide

Surgical Phase

• Definitive surgery after completion of neoadjuvant therapy

Adjuvant Phase

• Pembrolizumab 200 mg IV every 3 weeks for up to 9 additional cycles 1, 2
• Continue regardless of pathological complete response (pCR) status 1

Evidence Supporting This Approach

The recommendation is based on robust clinical evidence demonstrating significant improvements in multiple critical outcomes:

1. Pathological Complete Response (pCR):

   • 64.8% with pembrolizumab-chemotherapy vs. 51.2% with chemotherapy alone 3
   • This represents a 13.6 percentage point improvement (p<0.001)

2. Event-Free Survival (EFS):

   • 84.5% at 36 months with pembrolizumab-chemotherapy vs. 76.8% with chemotherapy alone 4
   • Hazard ratio for event or death: 0.63 (95% CI, 0.48 to 0.82; p<0.001)

3. Overall Survival (OS):

   • 86.6% at 60 months with pembrolizumab-chemotherapy vs. 81.7% with chemotherapy alone 2
   • This represents a statistically significant improvement (p=0.002)

Important Clinical Considerations

Patient Selection

• This regimen is indicated for stage II and III TNBC 1
• The benefit is independent of PD-L1 status 1
• Younger patients (<55 years) may have higher pCR rates 5, 6

Treatment Adherence

• Completing at least 8 cycles of pembrolizumab is significantly associated with improved pCR rates 5
• Ductal histology and unifocal disease are independently associated with higher pCR rates 6

Chemotherapy Backbone

• The benefit from carboplatin is independent of germline BRCA1/2 status 1
• Standard anthracycline regimens include:
  • Doxorubicin-cyclophosphamide (AC) or epirubicin-cyclophosphamide (EC) for 4 cycles
  • Followed by taxane for 4 cycles or 8-12 weeks 1

Dose-Dense Scheduling

• There is no consensus on whether dose-dense every-2-week AC/EC regimens should be used with pembrolizumab:
  • 30% of experts support dose-dense approach
  • 38% note lack of safety/efficacy data and prefer standard 3-week schedule 1

Safety Considerations

• Adverse events occur predominantly during the neoadjuvant phase 4
• Grade 3 or higher treatment-related adverse events:
  • 78.0% with pembrolizumab-chemotherapy vs. 73.0% with chemotherapy alone
  • Treatment-related deaths: 0.4% (3 patients) vs. 0.3% (1 patient) 3
• Monitor for immune-related adverse events, particularly thyroid dysfunction 1

Post-Treatment Management

• For patients with residual disease after neoadjuvant therapy:
  • Continue pembrolizumab for nine courses (if given in neoadjuvant setting) 1
  • Consider capecitabine every 3 weeks for six or eight cycles if gBRCA1/2-wildtype 1

This approach represents a significant advancement in the management of early-stage TNBC, with consistent evidence showing improved outcomes across multiple endpoints including the critical measures of event-free survival and overall survival.