As reported in The New England Journal of Medicine by Peter Schmid, MD, PhD, and colleagues, interim analyses of the phase III KEYNOTE-522 trial have shown that the addition of pembrolizumab to neoadjuvant chemotherapy and use of adjuvant pembrolizumab vs placebo resulted in improvements in pathologic complete response rate and event-free survival in women with early triple-negative breast cancer.

Peter Schmid, MD, PhD

Study Details

In the trial, 1,174 patients from 181 sites in 21 countries with previously untreated stage II or III triple-negative breast cancer were randomly assigned 2:1 to the pembrolizumab/chemotherapy group (n = 784) or the placebo/chemotherapy group (n = 390). Neoadjuvant therapy consisted of four cycles of pembrolizumab at 200 mg or placebo every 3 weeks plus paclitaxel (80 mg/m² once weekly) and carboplatin (at a dose based on an area under the concentration–time curve of 5 mg/mL per minute once every 3 weeks or 1.5 mg/mL per minute once weekly in the first 12 weeks) for the first 12 weeks followed by four cycles of pembrolizumab or placebo plus doxorubicin (60 mg/m²) or epirubicin (90 mg/m²) plus cyclophosphamide (600 mg/m²) once every 3 weeks for the subsequent 12 weeks. After definitive surgery, patients received adjuvant pembrolizumab or placebo every 3 weeks for up to nine cycles. The primary endpoints were pathologic complete response at the time of definitive surgery and event-free survival in the intention-to-treat population. Event-free survival events consisted of disease progression precluding definitive surgery, local or distant recurrence or second primary tumor, and death from any cause.

Efficacy Outcomes

At the first interim analysis, among the first 602 randomly assigned patients (401 in pembrolizumab group, 202 in placebo group), pathologic complete response was achieved in 64.8% of patients in the pembrolizumab group vs 51.2% of the placebo group (estimated treatment difference = 13.6%, 95% confidence interval [CI] = 5.4%–21.8%, P < .001). The benefit of pembrolizumab was generally consistent across subgroups, including programmed cell death ligand 1 expression subgroups.

At the first event-free survival assessment (second interim analysis) after median follow-up of 15.5 months (range = 2.7–25.0 months) among all patients in the intent-to-treat population, median event-free survival had not been reached in either group. Event-free survival events had occurred in 58 (7.4%) of 784 patients in the pembrolizumab group vs 46 (11.8%) of 390 patients in the placebo group (hazard ratio = 0.63, 95% CI = 0.43–0.93). At 18 months, estimated event-free survival was 91.3% in the pembrolizumab group vs 85.3% in the placebo group.

Adverse Events

In the neoadjuvant phase, treatment-related grade ≥ 3 adverse events occurred in 76.8% of the pembrolizumab group vs 72.2% of the placebo group. Serious treatment-related adverse events occurred in 32.5% vs 19.5%. In the adjuvant phase, treatment-related adverse events of any grade occurred in 48.1% vs 43.0% of patients. Across all phases, treatment-related grade ≥ 3 adverse events occurred in 78.0% vs 73.0%. Treatment-related adverse events led to death in three patients (0.4%) in the pembrolizumab group (one from pulmonary embolism, one from sepsis and multiple organ dysfunction syndrome, and one from pneumonitis) and one patient (0.3%) in the placebo group (septic shock).

The investigators concluded, “Among patients with early triple-negative breast cancer, the percentage with a pathologic complete response was significantly higher among those who received pembrolizumab plus neoadjuvant chemotherapy than among those who received placebo plus neoadjuvant chemotherapy.”

Disclosure: The study was funded by Merck Sharp & Dohme. For full disclosures of the study authors, visit nejm.org.