Pembrolizumab Achieves Prespecified Event-Free Survival in High-Risk TNBC

Patients with high-risk, early-stage triple-negative breast cancer (TNBC) in the phase 3 KEYNOTE-522 trial (NCT03036488) of pembrolizumab (Keytruda) plus chemotherapy after surgery demonstrated statistically significant event-free survival (EFS), according to a press release from Merck.1

When compared with pre-operative chemotherapy, an interim analysis by the Data Monitoring Committee revealed that neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab monotherapy had a statistically significant and clinically meaningful improvement in EFS. This met one of the dual primary end points of the trial, the other primary end point, pathologic complete response (pCR), was already met.

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

“The improvement in pCR 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 EFS, we look forward to working with the FDA and other global authorities to bring this new option to patients as quickly as possible. We are grateful to the study participants who are critical to our efforts to advance potential treatment options for patients with TNBC,” Baynes concluded.

In this 2:1 randomized, double-blind trial, 784 patients received 200 mg of pembrolizumab every 3 weeks combined with paclitaxel and carboplatin for 4 cycles, followed by pembrolizumab plus cyclophosphamide and doxorubicin or epirubicin prior to surgery, then after surgery, pembrolizumab alone every 3 weeks for up to 9 cycles. Placebo was given with chemotherapy in the same design as the pembrolizumab group to 390 patients.

During the European Society for Medical Oncology (ESMO) 2019 meeting and subsequently in the New England Journal of Medicine, an interim analysis of pCR for these patients were presented and published. There was a statistically significant increase in pCR for those receiving pembrolizumab among the 602 patients evaluated, with a pCR of 64.8% (95% CI, 59.9%-69.5%) versus 51.2% (95% CI, 44.1%-58.3%) in patients receiving placebo. The estimated difference was 13.6 percentage points (95% CI, 5.4-21.8; P < .001).2

At median follow-up of 15.5 months (range, 2.7-25.0 months) in the published data, 7.4% (n = 58/784) of patients receiving pembrolizumab and chemotherapy versus 11.98% (n = 46/390) of those receiving placebo and chemotherapy had disease progression that died from any cause, had local or distant recurrence or a second primary tumor, or precluded surgery (HR, 0.63; 95% CI, 0.43-0.93).

There were no new safety signals in the analysis of EFS and the safety profile of pembrolizumab remained consistent with previously reported studies.1 In the published data, the incidence of grade 3 or higher treatment-related adverse events was 78.0% and 73.0% in patients given pembrolizumab and placebo, respectively; this included the death in 3 patients in the pembrolizumab arm and 1 patient in the placebo arm.2

In a subgroup analysis of KEYNOTE-522, a presentation at the ESMO Asia Virtual Congress 2020 showed that the combination of pembrolizumab and chemotherapy significantly increased pCR in Asian patients with TNBC.3 Of the 215 Asian patients enrolled, 136 were given the pembrolizumab regimen. At median follow-up of 13.0 months, the pCR rate among the first 125 Asian patients was 59% (95% CI, 47%-70%) in the 75 patients receiving pembrolizumab versus 40% (95% CI, 26%-55%) in those receiving placebo.

After a vote of 10 to 0 by the FDA’s Oncologic Drugs Advisory Committee that a regulatory decision should be deferred until more data came out of KEYNOTE-522, the FDA gave Merck a Complete Response Letter in March 2021 for their supplemental Biologics License Application for the approval of pembrolizumab in patients with high-risk, early-stage TNBC based on the pCR and early interim EFS findings.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. Published May 13, 2021. Accessed May 13, 2021.

Schmid P, Cortes J, Pusztai L, et al; KEYNOTE-522 Investigators. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382(9):810-821. doi:10.1056/NEJMoa1910549

Dent R, Cortes J, Pusztai L, et al. KEYNOTE-522 Asian subgroup: phase 3 study of neoadjuvant pembrolizumab (pembro) vs placebo (pbo) + chemotherapy (chemo) followed by adjuvant pembro vs pbo for early triple-negative breast cancer (TNBC). Presented at: ESMO Asia Virtual Congress 2020; November 20-22, 2020. Accessed May 13, 2021.