As reported in The New England Journal of Medicine by Peter Schmid, MD, PhD, and colleagues, a preplanned interim analysis of the phase III KEYNOTE-522 trial has shown improved event-free survival with the addition of pembrolizumab to neoadjuvant chemotherapy, followed by adjuvant pembrolizumab, in patients with early-stage triple-negative breast cancer.

The trial supported the July 2021 approval of pembrolizumab in high-risk, early-stage triple-negative breast cancer in combination with chemotherapy as neoadjuvant treatment and continued as adjuvant treatment on the basis of improved pathologic complete response rate and event-free survival. 

Peter Schmid, MD, PhD

Study Details

In the double-blind trial, 1,174 patients with previously untreated stage II or III triple-negative breast cancer (T1c, N1-2 or T2-4, N0-2) from sites in 21 countries were randomly assigned 2:1 between March 2017 and September 2018 to receive neoadjuvant pembrolizumab plus chemotherapy (n = 784) or placebo plus chemotherapy (n = 390), followed by adjuvant pembrolizumab vs placebo. Neoadjuvant treatment consisted of four cycles of pembrolizumab at 200 mg or placebo every 3 weeks plus paclitaxel at 80 mg/m² once weekly and carboplatin at area under the curve = 5 every 3 weeks, followed by four cycles of pembrolizumab or placebo plus doxorubicin at 60 mg/m² or epirubicin at 90 mg/m² plus cyclophosphamide at 600 mg/m² every 3 weeks for the next 12 weeks. After definitive surgery, patients in the pembrolizumab group received pembrolizumab, and those in the placebo group received placebo every 3 weeks for up to nine cycles.

The primary endpoints were pathologic complete response and event-free survival, defined as time to disease progression that precluded definitive surgery, local or distant recurrence, occurrence of a second primary cancer, or death from any cause. A prior report from the study showed that the addition of pembrolizumab to neoadjuvant chemotherapy resulted in a significantly higher rate of pathologic complete response.

Event-Free Survival

Median follow-up at the fourth planned interim analysis (data cutoff in March 2021) was 39.1 months (range = 30.0–48.0 months). An event-free survival event occurred in 123 patients (15.7%) in the pembrolizumab group and 93 (23.8%) in the control group (hazard ratio [HR] = 0.63, 95% confidence interval [CI] = 0.48–0.82, P < .001). Estimated event-free survival at 36 months was 84.5% (95% CI = 81.7%–86.9%) vs 76.8% (95% CI = 72.2%–80.7%). First events consisted of progression of disease that precluded definitive surgery in 1.8% vs 3.8% of patients, local recurrence in 3.6% vs 4.4%, distant recurrence in 7.7% vs 13.1%, second primary cancer in 0.8% vs 1.0%, and death from any cause in 1.9% vs 1.5%. The hazard ratio for distant progression and distant recurrence–free survival was 0.61 (95% CI = 0.46–0.82), with estimated 36-month rates of 87.0% vs 80.7%.  

In subgroup analyses, hazard ratios were: 0.65 (95% CI = 0.46–0.91) among 408 vs 196 patients with positive nodal status and 0.58 (95% CI = 0.37–0.91) among 376 vs 194 with negative nodal status, and 0.67 (95% CI = 0.49–0.92) among 656 vs 317 with PD-L1–positive disease (combined positive score ≥ 1) and 0.48 (95% CI = 0.28–0.85) among 128 vs 69 with PD-L1–negative status.

In a prespecified exploratory analysis among patients who achieved pathologic complete response, event-free survival events occurred in 27 (5.5%) of 494 (5.5%) vs 16 (7.4%) of 217 patients (HR = 0.73, 95% CI = 0.39–1.36); estimated 36-month event-free survival rates were 94.4% vs 92.5%. Among patients without pathologic complete response, events occurred in 96 (33.1%) of 290 vs 77 (44.5%) of 173 patients (HR = 0.70, 95% CI = 0.52–0.95); estimated 36-month rates were 67.4% vs 56.8%.

Data on overall survival were immature at time of analysis. Death occurred in 80 patients (10.2%) in the pembrolizumab group and 55 patients (14.1%) in the control group (HR = 0.72, 95% CI = 0.51–1.02), with an estimated 36-month overall survival rate of 89.7% (95% CI = 87.3%–91.7%) vs 86.9% (95% CI = 83.0%–89.9%).

Adverse Events

Adverse events occurred predominantly during the neoadjuvant phase. For the combined phases, treatment-related grade ≥ 3 adverse events occurred in 77.1% of patients in the pembrolizumab group vs 73.3% of the control group; the most common in both groups were neutropenia (34.5% vs 34.4%), decreased neutrophil count (18.6% vs 23.1%), and anemia (18.0% vs 14.9%). In the adjuvant phase, grade ≥ 3 treatment-related adverse events occurred in 6.3% vs 2.7%. Serious treatment-related adverse events occurred in 34.1% vs 20.1% of patients; most commonly, febrile neutropenia (15.1% vs 12.1%). Discontinuation of study treatment due to treatment-related adverse events occurred in 27.7% vs 14.1% of patients. Immune-mediated adverse events of any grade occurred in 33.5% (grade ≥ 3 in 12.9%) vs 11.3% (grade ≥ 3 in 1.0%). Treatment-related adverse events led to death in four patients (0.5%) vs one patient (0.3%).

The investigators concluded, “In patients with early triple-negative breast cancer, neoadjuvant pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab after surgery, resulted in significantly longer event-free survival than neoadjuvant chemotherapy alone.”

Dr. Schmid, of the Centre of Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, is the corresponding author for The New England Journal of Medicine article.

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