Updated results from the phase 3 KEYNOTE-522 trial reveal that neoadjuvant pembrolizumab (Keytruda) combined with chemotherapy, followed by adjuvant pembrolizumab, significantly improves overall survival (OS) in patients with early-stage triple-negative breast cancer (TNBC). The findings, presented at the 2024 European Society of Medical Oncology (ESMO) Congress, highlight a substantial reduction in the risk of death associated with the pembrolizumab regimen.
Significant Survival Improvement
The study demonstrated that 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 with pembrolizumab (n = 784) achieved a 5-year OS rate of 86.6% (95% CI, 84.0%-88.8%) compared to 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.
According to lead study author Dr. Peter Schmid from Barts Cancer Institute, Queen Mary University in London, the KEYNOTE-522 trial met its two primary endpoints—pathological complete response (pCR) rate and event-free survival (EFS)—and, most importantly, demonstrated a significant reduction in the risk of death with the pembrolizumab regimen.
Trial Design and Key Endpoints
The KEYNOTE-522 trial was a randomized, double-blind study involving patients with centrally confirmed TNBC in all foci. Eligible patients had 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 were randomized in a 2:1 ratio to receive either pembrolizumab or placebo.
In the neoadjuvant setting, patients received pembrolizumab at 200 mg or placebo every 3 weeks for 4 cycles, plus paclitaxel at 80 mg/m2 weekly and carboplatin at AUC of 5 mg/mL per minute every 3 weeks or 1.5 mg/mL per minute weekly for the first 12 weeks. This was followed by 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 every 3 weeks for 12 weeks. In the adjuvant setting, patients received pembrolizumab or placebo every 3 weeks for up to 9 cycles. Radiation was permitted.
The trial's dual primary endpoints were pCR rate and 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.
Impact of Pathological Complete Response
Further analysis revealed that patients who achieved a pCR also experienced an OS benefit, irrespective of the treatment arm. Among 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).
Regulatory Context
In July 2021, the FDA approved pembrolizumab in combination with chemotherapy as neoadjuvant treatment, followed by adjuvant pembrolizumab monotherapy after surgery, for high-risk early-stage TNBC based on earlier KEYNOTE-522 data.
