Pembrolizumab for Early Triple-Negative Breast Cancer

• High-risk early triple-negative breast cancer:
  • Is frequently associated with early recurrence and high mortality
• Neoadjuvant chemotherapy:
  • Is the preferred treatment approach
• In addition to potentially increasing the likelihood of tumor resectability and breast conservation:
  • Patients who have a pathological complete response after neoadjuvant therapy:
    • Have longer event-free survival:
      • Defined as the time from randomization to the date of disease progression that precluded definitive surgery, the date of local or distant recurrence or the occurrence of a second primary tumor, or the date of death from any cause
    • Have longer overall survival:
      • Accordingly, regulatory guidance supports the use of the pathological complete response as an end point for clinical testing of neoadjuvant treatment in patients with early triple-negative breast cancer
• Pembrolizumab (Keytruda, Merck Sharp & Dohme):
  • An anti–programmed death 1 (PD-1) monoclonal antibody:
    • Has been shown to have antitumor activity and a range of mainly low-grade toxic effects in patients with metastatic triple-negative breast cancer, especially when used as first-line treatment
  • Immune checkpoint inhibition:
    • May enhance endogenous anticancer immunity:
      • After increased release of tumor-specific antigens with chemotherapy
• Preliminary results from the phase 1b KEYNOTE-173 trial:
  • Showed that pembrolizumab plus neoadjuvant chemotherapy, with or without carboplatin:
    • Had promising antitumor activity:
      • Without a major increase in serious toxic effects in patients with locally advanced triple-negative breast cancer
• In the phase 2 I-SPY2 trial:
  • The estimated percentage of patients with human epidermal growth factor receptor 2 (HER2)–negative breast cancers:
    • Who had a pathological complete response was:
      • Higher among those who received pembrolizumab combined with neoadjuvant chemotherapy than among those who received neoadjuvant chemotherapy alone
• The phase 3 KEYNOTE-522 trial:
  • Evaluated the efficacy and safety of neoadjuvant pembrolizumab–chemotherapy as compared with neoadjuvant placebo–chemotherapy, followed by adjuvant pembrolizumab or placebo in patients with early triple-negative breast cancer
• Methods of the Keynote 522 trial:
  • In this phase 3 trial, they randomly assigned (in a 2:1 ratio) patients with previously untreated stage II or stage III triple-negative breast cancer:
    • To receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) every 3 weeks plus paclitaxel and carboplatin (784 patients; the pembrolizumab–chemotherapy group) or placebo every 3 weeks plus paclitaxel and carboplatin (390 patients; the placebo–chemotherapy group)
    • The two groups then received an additional four cycles of pembrolizumab or placebo, and both groups received doxorubicin–cyclophosphamide or epirubicin–cyclophosphamide
    • After definitive surgery, the patients received adjuvant pembrolizumab or placebo every 3 weeks for up to nine cycles
    • The primary end points were a pathological complete response at the time of definitive surgery and event-free survival in the intention-to-treat population
• Results of the Keynote 522 trial:
  • At the first interim analysis, among the first 602 patients who underwent random- ization, the percentage of patients with a pathological complete response was 64.8% (95% confidence interval [CI], 59.9 to 69.5) in the pembrolizumab–chemotherapy group and 51.2% (95% CI, 44.1 to 58.3) in the placebo–chemotherapy group (esti- mated treatment difference, 13.6 percentage points; 95% CI, 5.4 to 21.8; P<0.001). After a median follow-up of 15.5 months (range, 2.7 to 25.0), 58 of 784 patients (7.4%) in the pembrolizumab–chemotherapy group and 46 of 390 patients (11.8%) in the placebo–chemotherapy group had disease progression that precluded definitive surgery, had local or distant recurrence or a second primary tumor, or died from any cause (hazard ratio, 0.63; 95% CI, 0.43 to 0.93). Across all treatment phases, the incidence of treatment-related adverse events of grade 3 or higher was 78.0% in the pembrolizumab–chemotherapy group and 73.0% in the placebo–chemotherapy group, including death in 0.4% (3 patients) and 0.3% (1 patient), respectively.

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