In a randomised, double-blind, placebo-controlled phase III study, neoadjuvant pembrolizumab combined with chemotherapy followed by adjuvant pembrolizumab resulted in a significant improvement, as compared with neoadjuvant chemotherapy alone, in event-free survival among patients with previously untreated stage II or III triple-negative breast cancer (TNBC). The risk of disease progression that precluded definitive surgery, local or distant recurrence, occurrence of a second primary cancer, or death from any cause was 37% lower with pembrolizumab–chemotherapy than with placebo–chemotherapy. The addition of pembrolizumab before and after surgery for a total duration of approximately 1 year led to a lower risk of distant recurrence. Findings from the KEYNOTE-522 study are published by Prof. Peter Schmid of the Barts Cancer Institute, Queen Mary University of London in London, UK and colleagues in the 10th February 2022 issue of The New England Journal of Medicine.

The authors wrote in the background that addition of pembrolizumab to neoadjuvant chemotherapy led to a significantly higher percentage of patients with early TNBC having a pathological complete response (pCR), defined as no invasive cancer in the breast and negative nodes, at definitive surgery in an earlier analysis of this phase III study of neoadjuvant and adjuvant therapy. Now, the KEYNOTE-522 study investigators report the results for the other primary endpoint, event-free survival, as well as additional efficacy endpoints and updated safety data. The primary results regarding event-free survival in this study have not been previously reported.

The study team randomly assigned, in a 2:1 ratio, patients with previously untreated stage II or III TNBC to receive neoadjuvant therapy with 4 cycles of pembrolizumab or placebo every 3 weeks plus paclitaxel and carboplatin, followed by 4 cycles of pembrolizumab or placebo plus doxorubicin–cyclophosphamide or epirubicin–cyclophosphamide. After definitive surgery, patients received adjuvant pembrolizumab in the pembrolizumab–chemotherapy group or placebo in the placebo–chemotherapy group every 3 weeks for up to 9 cycles. The primary endpoints were pCR and event-free survival, defined as the time from randomisation to the date of disease progression that precluded definitive surgery, local or distant recurrence, occurrence of a second primary cancer, or death from any cause. Safety was also assessed.

In total 1174 patients underwent randomisation, of whom 784 were assigned to the pembrolizumab–chemotherapy group and 390 to the placebo–chemotherapy group. The median follow-up at this 4th planned interim analysis with data cut-off date of 23 March 2021 was 39.1 months.

The estimated event-free survival at 36 months was 84.5% (95% confidence interval [CI] 81.7 to 86.9) in the pembrolizumab–chemotherapy group, as compared with 76.8% (95% CI 72.2 to 80.7) in the placebo–chemotherapy group (hazard ratio for event or death 0.63; 95% CI 0.48 to 0.82; p < 0.001).

The prolongation of event-free survival with pembrolizumab was observed across all the subgroups. The higher percentage of patients with a pCR with the addition of pembrolizumab to neoadjuvant chemotherapy was independent of PD-L1 expression.

Adverse events occurred predominantly during the neoadjuvant phase and were consistent with the established safety profiles of pembrolizumab and chemotherapy. The higher incidence of immune-mediated adverse events in the pembrolizumab–chemotherapy group than in the placebo–chemotherapy group was driven primarily by endocrinopathies and skin reactions, which occurred mostly during the neoadjuvant phase, with a very low incidence during the adjuvant phase. 

The authors commented that a key strength of their study was the inclusion of a control group of patients who received standard-of-care platinum-, taxane-, and anthracycline-containing chemotherapy, which permitted the direct comparison of the pembrolizumab–chemotherapy combination with the neoadjuvant chemotherapy regimen that has been associated with high response among patients with early TNBC. Although the duration of follow-up at the time of this analysis precludes the assessment of mature data regarding overall survival, double-blinding was maintained to permit ongoing follow-up.

The results of this study support the use of pembrolizumab plus platinum-, taxane-, and anthracycline-containing neoadjuvant chemotherapy, followed by adjuvant pembrolizumab after surgery, as a treatment regimen for patients with high-risk, early TNBC, regardless of tumour PD-L1 expression status.

The study was funded by Merck Sharp and Dohme, a subsidiary of Merck.


Schmid P, Cortes J, Dent R, et al. for the KEYNOTE-522 Investigators. Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer. N Engl J Med 2022; 386:556-567.