Neoadjuvant treatment with pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab, has demonstrated a statistically significant improvement in overall survival (OS) compared to neoadjuvant chemotherapy plus placebo followed by adjuvant placebo in patients with early-stage triple-negative breast cancer (TNBC). These findings come from the phase 3 KEYNOTE-522 trial, presented at the 2024 ESMO Congress, and highlight a substantial advancement in the treatment of this aggressive form of breast cancer. The perioperative pembrolizumab regimen reduced the risk of death by 34% compared with the placebo regimen (HR, 0.66; 95% CI, 0.50-0.87; P = .00150). At a median follow-up of 75.1 months, patients treated in the pembrolizumab arm (n = 784) achieved a 5-year OS rate of 86.6% (95% CI, 84.0%-88.8%) vs 81.7% (95% CI, 77.5%-85.2%) for those in the placebo arm (n = 390). The OS event rates were 14.7% and 21.8% for the pembrolizumab and placebo arms, respectively.
KEYNOTE-522 Trial Details
The KEYNOTE-522 trial is a randomized, double-blind study that enrolled patients with centrally confirmed TNBC in all foci. Eligible patients were at least 18 years old with newly diagnosed, previously untreated, nonmetastatic disease, defined as tumor stage T1c, nodal stage N1-2, or tumor stage T2-4, nodal stage N0-2. Patients also needed to have an ECOG performance status of 0 or 1 and adequate organ function. The trial included patients with bilateral or multifocal primary tumors and inflammatory breast cancers.
Patients were randomly assigned 2:1 to either the pembrolizumab arm or the placebo arm. In the neoadjuvant setting, patients received pembrolizumab at 200 mg or placebo once every 3 weeks for 4 cycles plus paclitaxel at 80 mg/m2 once weekly plus carboplatin at area under the 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. The second neoadjuvant treatment cycle consisted of pembrolizumab or placebo for 4 additional cycles plus doxorubicin at 60 mg/m2 or epirubicin at 90 mg/m2 plus cyclophosphamide at 600 mg/m2 once every 3 weeks for 12 weeks.
Following neoadjuvant therapy and surgery, patients received pembrolizumab or placebo once every 3 weeks for up to 9 cycles in the adjuvant setting. Radiation was permitted during this phase.
The trial's dual primary endpoints were pathological complete response (pCR) rate and event-free survival (EFS) in the intention-to-treat population. Secondary endpoints included pCR and EFS in patients with PD-L1–positive tumors, and OS among all patients and those with PD-L1–positive tumors.
Efficacy Outcomes
Updated efficacy analysis demonstrated that the pembrolizumab regimen maintained a significant improvement in EFS compared to the placebo regimen (HR, 0.65; 95% CI, 0.51-0.83). The 5-year EFS rates were 81.2% for the pembrolizumab arm versus 72.2% for the placebo arm. EFS events were reported in 20.3% of patients in the experimental arm versus 29.2% of patients in the control arm.
Patients who achieved a pCR on the study also experienced an OS benefit, irrespective of treatment arm. For responders, the 5-year OS rate was 95.1% for the pembrolizumab arm (n = 495) versus 94.4% for the placebo arm (n = 217; HR, 0.69; 95% CI, 0.38-1.26). In non-responders, the 5-year OS rate was 71.8% for the pembrolizumab arm (n = 289) versus 65.7% for the placebo arm (n = 173; HR, 0.76; 95% CI, 0.56-1.05).
"[KEYNOTE-522] was a positive trial for its 2 primary end points—short-term pathological complete response [(pCR) rate] and event-free survival [EFS]—and most importantly, [data] demonstrated that [the pembrolizumab regimen] reduced the risk of death by 34%," said lead study author Peter Schmid, MD, PhD, of Barts Cancer Institute at Queen Mary University in London, United Kingdom, during a press briefing at the ESMO Congress.
Regulatory Context
In July 2021, the FDA approved pembrolizumab in combination with chemotherapy as neoadjuvant treatment, followed by single-agent pembrolizumab as adjuvant treatment after surgery, for the treatment of patients with high-risk, early-stage TNBC, based on prior data from KEYNOTE-522.
