KEYNOTE-522 Meets EFS End Point in High-Risk, Early TNBC

Pembrolizumab plus chemotherapy as neoadjuvant therapy followed by adjuvant monotherapy in patients with early triple-negative breast cancer was superior in terms of event-free survival versus matched placebo.

The phase 3 KEYNOTE-522 trial (NCT03036488) of neoadjuvant chemotherapy plus either pembrolizumab (Keytruda) or placebo followed by single-agent adjuvant therapy for high-risk, early triple-negative breast cancer (TNBC) met its dual primary end point of event-free survival (EFS), according to the company responsible for developing the PD-1 inhibitor, Merck.1

An interim analysis by the independent Data Monitoring Committee indicated a statistically significant improvement in EFS with the experimental versus the control regimen, featuring a safety profile that was consistent with the known effects of pembrolizumab.

“Keytruda is the first immunotherapy to show positive results for event-free survival in patients with high-risk early-stage TNBC, a particularly aggressive form of breast cancer,” Roy Baynes, MD, PhD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said in a press release.

Pathologic complete response (pCR) data, the other dual primary end point of the trial, were previously reported in the New England Journal of Medicine and presented at the European Society for Medical Oncology 2019 Congress.2,3

The investigators enrolled 1174 patients in the study and randomized them 2:1 to either the experimental or control arms. Pembrolizumab was administered every 3 weeks plus paclitaxel weekly and carboplatin (weekly or every 3 weeks) for 4 cycles, followed by pembrolizumab plus cyclophosphamide every 3 weeks and either doxorubicin or epirubicin for 4 cycles as neoadjuvant therapy prior to surgery, followed by 9 cycles of pembrolizumab every 3 weeks as adjuvant therapy post-surgery. Those in the control arm received matching placebo and the same regimen of chemotherapy.

The proportion of patients achieving pCR with pembrolizumab was 64.8% (95% CI, 59.9%-69.5%) versus 51.2% (95% CI, 44.1%-58.3%) in the placebo/chemotherapy group (estimated treatment difference, 13.6 percentage points; 95% CI, 5.4-21.8; P <.001). These results were generally consistent across subgroups. At 18 months, patients who were alive without disease progression precluding definitive surgery, without local or distant recurrence, and with a second primary tumor comprised 91.3% (95% CI, 88.8%-93.3%) of patients in the pembrolizumab arm versus 85.3% (95% CI, 80.3%-89.1%) of patients with placebo. The risk of death or disease progression that would preclude definitive surgery, local or distant recurrence, or a second or primary tumor was reduced by 37% with pembrolizumab (HR, 0.63; 95% CI, 0.43-0.93).

“The improvement in pathological complete response rates initially observed following pre-operative treatment was encouraging, and now that we are seeing the data mature after 4 years to include a statistically significant improvement in event-free survival,” Barnes said. “[W]e look forward to working with the FDA and other global authorities to bring this new option to patients as quickly as possible.”

In March 2021, a complete response letter was issued by the FDA for the biologics license application pursuing approval for pembrolizumab as adjuvant/neoadjuvant therapy for patients with high-risk, early TNBC. The application was based on the trial’s pCR results and early EFS data, with the FDA Oncologic Drugs Advisory Committee voting to defer a regulatory decision until more information was available.


1. Merck Announces Phase 3 KEYNOTE-522 Trial Met Dual Primary Endpoint of Event-Free Survival (EFS) in Patients With High-Risk Early-Stage Triple-Negative Breast Cancer (TNBC). News release. Merck. May 13, 2021. Accessed May 13, 2021.

2. Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382(9):810-821. doi:10.1056/NEJMoa1910549

3. Schmid P, Cortés J, Dent R, et al. 1812 - KEYNOTE-522: Phase 3 study of pembrolizumab (pembro) + chemotherapy (chemo) vs placebo (pbo) + chemo as neoadjuvant treatment, followed by pembro vs pbo as adjuvant treatment for early triple-negative breast cancer (TNBC). Ann Oncol. 2019;30(suppl 5):v851-v934. doi: 10.1093/annonc/mdz394