Previous data showed that the addition of pembrolizumab to neoadjuvant chemotherapy led to a significantly higher percentage of patients with early triple-negative breast cancer (TNBC) having a pathological complete response; however, at that moment the question remained: pathological complete response translate into a better survival endpoint?
On February 10, the primary results regarding event-free survival in the KEYNOTE-522 trial (NCT03036488) were published in the New England Journal of Medicine. KEYNOTE-522 is a randomized, double-blind, placebo-controlled and multicenter trial that randomly assigned, in a 2:1 ratio, patients with previously untreated stage II or III TNBC to receive neoadjuvant therapy with four cycles of pembrolizumab 200 mg or placebo every 3 weeks plus paclitaxel and carboplatin, followed by four cycles of pembrolizumab or placebo plus doxorubicin–cyclophosphamide or epirubicin–cyclophosphamide. After definitive surgery, patients received adjuvant pembrolizumab or placebo every 3 weeks for up to nine cycles. In the adjuvant phase, patients received radiation therapy as indicated and either pembrolizumab or placebo, administered once every 3 weeks for up to nine cycles. Adjuvant pembrolizumab or placebo could be started either concurrently with radiation therapy or 2 weeks after the completion of radiation therapy. Adjuvant therapy with capecitabine was not allowed. The primary endpoints were pathological complete response and event-free survival, defined as the time from randomization 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.
Of the 1174 patients who underwent randomization, 784 were assigned to the immunotherapy group and 390 to the placebo group. The median follow-up at this planned interim analysis (data cutoff, March 23, 2021) was 39.1 months.
The estimated event-free survival at 36 months was 84.5% (CI 95%, 81.7 to 86.9) in the pembrolizumab group versus 76.8% (95% CI, 72.2 to 80.7) in the placebo group (HR 0.63; 95% CI, 0.48 to 0.82; P < 0.001). The most common event in the analysis of event-free survival was distant recurrence, which occurred in 60 patients (7.7%) in the pembrolizumab–chemotherapy group and in 51 (13.1%) in the placebo–chemotherapy group. The prolongation of event-free survival with immunotherapy was observed across all the subgroups and the higher percentage of patients with a pathological complete response with the addition of pembrolizumab to neoadjuvant chemotherapy was independent of PD-L1 expression. Data on overall survival were immature at that time. Adverse events occurred predominantly during the neoadjuvant phase and were consistent with the established safety profiles of pembrolizumab and chemotherapy. According to the authors, these results support the use of pembrolizumab plus neoadjuvant chemotherapy, followed by adjuvant pembrolizumab after surgery, as a treatment regimen for patients with high-risk, early triple-negative breast cancer, regardless of tumor PD-L1 expression status. Reference:
1. Schmid P, et al. Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer. N Engl J Med 2022; 386:556-567.