Longer follow-up data from the phase 3 KEYNOTE-522 trial presented at the 2023 San Antonio Breast Cancer Symposium continue to support the use of neoadjuvant pembrolizumab (Keytruda) plus chemotherapy followed by adjuvant pembrolizumab in patients with high-risk, early-stage triple-negative breast cancer (TNBC). The 5-year data demonstrate a sustained and clinically meaningful improvement in event-free survival (EFS) compared to placebo plus chemotherapy.
Sustained EFS Benefit
At a median follow-up of 63.1 months, the 5-year EFS rate was 81.3% in patients who received neoadjuvant pembrolizumab/chemotherapy followed by adjuvant pembrolizumab, compared with 72.3% in those who received placebo/chemotherapy plus placebo (HR, 0.63; 95% CI, 0.49-0.81). These results build upon previous interim analyses that led to the FDA approval of this regimen in July 2021.
"These results overall provide further support for pembrolizumab plus platinum-containing neoadjuvant chemotherapy followed by adjuvant pembrolizumab after surgery as a standard-of-care for patients with high-risk, early-stage triple-negative breast cancer," said lead study author Peter Schmid, FRCP, MD, PhD, professor, cancer medicine, centre lead, Centre of experimental Cancer Medicine, director, Barts Breast Cancer Centre.
Trial Design and Key Endpoints
The KEYNOTE-522 trial was a prospective, randomized, placebo-controlled, phase 3 study. Eligible patients were at least 18 years of age with newly diagnosed TNBC that was either T1c N1-N2 or T2-T4 N0-N2 and an ECOG performance status of 0 or 1. Patients were randomized 2:1 to receive either neoadjuvant pembrolizumab (200 mg every 3 weeks) plus carboplatin and paclitaxel followed by doxorubicin/epirubicin plus cyclophosphamide, or the same chemotherapy regimens plus placebo. After surgery, patients received either pembrolizumab (200 mg every 3 weeks) or placebo.
The primary endpoints of the trial were pathologic complete response (pCR; ypT0/Tis ypN0) and EFS. Secondary endpoints included pCR (ypT0 ypN0 and ypT0/Tis) and safety. Investigators also examined pCR, EFS, and OS in the PD-L1–positive population.
Subgroup Analysis
Subgroup analyses revealed consistent EFS benefits with pembrolizumab across different disease stages and nodal status. In patients with stage II disease, the 5-year EFS rates were 85.6% and 77.5% in the pembrolizumab and placebo arms, respectively (HR, 0.59; 95% CI, 0.43-0.82). In those with stage III disease, these rates were 68.2% and 57.1% (HR, 0.71; 95% CI, 0.48-1.05).
Patients with negative nodes who received the pembrolizumab regimen experienced a 5-year EFS rate of 86.3% vs 77.8% in those who received the placebo regimen (HR, 0.56; 95% CI, 0.38-0.84). In patients with positive nodes, these rates were 76.8% and 67.0%, respectively (HR, 0.67; 95% CI, 0.49-0.93).
Impact of pCR on EFS
EFS was also evaluated by baseline disease stage in patients with and without a pCR. In patients with stage II disease and a pCR, the 5-year EFS rates were 94.2% and 89.8% in the pembrolizumab and placebo arms, respectively (HR, 0.56; 95% CI, 0.30-1.06); these rates were 69.2% and 59.1%, respectively, in patients without a pCR (HR, 0.67; 95% CI, 0.46-0.97).
For those with stage III disease who had a pCR, the 5-year EFS rates were 85.1% and 81.4% with pembrolizumab and placebo, respectively (HR, 0.80; 95% CI, 0.34-1.87). In those without a pCR, these rates were 46.8% and 38.2%, respectively (HR, 0.86; 95% CI, 0.55-1.34).
Distant Recurrence and Brain Metastases
In patients who had a pCR, the distant recurrence rates were 4.4% and 6.5% in the pembrolizumab and placebo arms, respectively. In those without a pCR, these rates were 17.3% and 23.7%, respectively. The incidence of brain metastases as a first EFS event was low in both treatment groups, with a numerically lower incidence in the pembrolizumab group (2.3%) compared with the placebo group (3.3%).
Ongoing Overall Survival Analysis
Because this was an event-driven analysis, the overall survival (OS) follow-up is still ongoing. Biomarker findings from KEYNOTE-522 will be presented in 2024.
