Neoadjuvant Pembrolizumab Combo Significantly Improves EFS in High-Risk Early-Stage TNBC


Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant single-agent pembrolizumab was found to significantly improve event-free survival over neoadjuvant chemotherapy followed by adjuvant placebo in patients with high-risk, early-stage triple-negative breast cancer.

Vicki Goodman, MD

Vicki Goodman, MD

Neoadjuvant pembrolizumab (Keytruda) plus chemotherapy followed by adjuvant single-agent pembrolizumab was found to significantly improve event-free survival (EFS) over neoadjuvant chemotherapy followed by adjuvant placebo in patients with high-risk, early-stage triple-negative breast cancer (TNBC), according to data from the fourth interim analysis of the phase 3 KEYNOTE-522 trial (NCT03036488) presented during the 2021 ESMO Virtual Plenary.1

After a median follow-up of 39.0 months, the pembrolizumab regimen resulted in a 37% reduction in the risk of EFS events vs the chemotherapy/placebo regimen (HR, 0.63; 95% CI, 0.48-0.82; P = .00031).

Additionally, the immunotherapy regimen resulted in a 28% reduction in the risk of death compared with the chemotherapy/placebo regimen (HR, 0.72; 95% CI, 0.51-1.02; P = .03214). However, these data have not crossed the boundary for statistical significance. The trial will continue to allow for follow-up of overall survival, which serves as a secondary end point.

“These highly anticipated EFS results in this TNBC population build upon earlier findings from the KEYNOTE-522 trial and further support the potential use of [pembrolizumab] in these patients,” Vicki Goodman, MD, vice president of clinical research at Merck Research Laboratories, stated in a press release. “KEYNOTE-522 is the first large, randomized phase 3 study to report a statistically significant and clinically meaningful EFS result among patients with stage II and III TNBC. We have submitted these data to the FDA and are working closely with the agency on its review of our application.”

In KEYNOTE-522, patients were randomized 2:1 to receive pembrolizumab at 200 mg every 3 weeks (n = 784) or placebo (n = 390). All participants were given 4 cycles of carboplatin plus paclitaxel, which was followed by 4 cycles of doxorubicin or epirubicin plus cyclophosphamide. After surgery, adjuvant pembrolizumab was continued for 9 cycles or until disease recurrence or intolerable toxicity.

EFS and pathologic complete response (pCR) were the dual primary end points of the study. pCR was defined as ypT0/Tis or ypN0. EFS was defined as the time from randomization to the first occurrence of either disease progression that precluded definitive surgery, a local/distant recurrence, a second primary cancer, or death from any cause.

The trial enrolled patients with node-negative and -positive disease. Tumor stage ranged from T1c N1/N2 to T2 to T4 and N0 to N2, per AJCC criteria. All participants had an ECOG performance status of 0 or 1. Stratification factors included nodal status, tumor size, and carboplatin schedule (weekly vs every 3 weeks).

Data from the first interim analysis presented during the 2019 ESMO Congress demonstrated that pCR was observed in 64.8% of patients who received the pembrolizumab regimen (n = 401) vs 51.2% in those who received chemotherapy alone (n = 201; P = .00055).2 The benefit with the immunotherapy regimen was noted, irrespective of pCR definition. However, using the definition of ypT0 ypN0, the pCR rates in the investigative and control arms were 59.9% and 45.3%, respectively. By the ypT0/Tis definition, the pCR rates with pembrolizumab and placebo were 68.6% and 53.7%, respectively.

In a subgroup of 498 patients with PD-L1 positivity, defined as a combined positive score (CPS) of 1 or greater, pembrolizumab elicited a pCR rate of 68.9% vs 54.9% with placebo; this translated to a percentage point increase of 14.2 (CI, 5.3-23.1). In 97 patients with PD-L1 negativity, defined as a CPS of less than 1, the pCR rates in the investigative and control arms were 45.3% and 30.3%, respectively: translating to an 18.3 percentage point increase (CI, -3.3 to 36.8).

At 3 years, 84.5% of patients who received pembrolizumab plus chemotherapy were alive and had not experienced an EFS event vs 76.8% of those who received chemotherapy alone.

Moreover, in a prespecified exploratory subgroup analysis of EFS, the benefit achieved with the pembrolizumab regimen was observed, independent of PD-L1 expression. Among 973 patients with PD-L1 positivity, pembrolizumab/chemotherapy reduced the risk of EFS by 33% vs chemotherapy alone (HR, 0.67; 95% CI, 0.49-0.92). Among 197 patients with PD-L1 negativity, the pembrolizumab regimen reduced the risk of EFS events by 52% vs chemotherapy alone (HR, 0.48; 95% CI, 0.28-0.85).

The most frequent treatment-related adverse effects (TRAEs) reported with pembrolizumab and placebo, respectively, during the neoadjuvant phase of the trial included nausea (62.7% vs 63.2%), alopecia (60.3% vs 56.6%), anemia (55.1% vs 55.3%), neutropenia (46.7% vs 47.0%), fatigue (41.1% vs 37.8%), diarrhea (29.4% vs 23.7%), alanine aminotransferase increase (25.5% vs 24.7%), vomiting (25.5% vs 21.9%), asthenia (24.5% vs 25.4%), constipation (23.7% vs 21.1%), neutrophil count decrease (23.7% vs 28.8%), rash (21.8% vs 15.2%), and peripheral neuropathy (19.7% vs 21.1%). Fewer TRAEs were observed in the adjuvant phase of the trial.

TRAEs that were grades 3 to 5 in severity were reported in 5.7% of those on the investigative arm and 1.9% of those on the control arm. The most common TRAEs in the pembrolizumab and placebo arms included arthralgia (7.9% vs 6.7%, respectively), rash (4.9% vs 2.2%), and pruritus (4.2% vs 2.2%).

The toxicity profile of the regimen at the updated analysis proved to be consistent with what has been seen with each regimen utilized. No new safety signals were reported.

“Given the high rates of recurrence within the first 5 years of diagnosis, patients with high-risk early-stage TNBC need new treatment options,” Peter Schmid, FRCP, MD, PhD, lead of the Centre for Experimental Cancer Medicine at Barts Cancer Institute, stated in the press release. “KEYNOTE-522 was designed to study whether the combined neoadjuvant and adjuvant regimen with [pembrolizumab] could help treat the cancer earlier. Now, with more than 3 years of follow-up, we see the potential of this approach. These EFS data are encouraging for patients…”

In November 2020, the FDA granted an accelerated approval to pembrolizumab for use in combination with chemotherapy in the treatment of patients with locally recurrent, unresectable or metastatic TNBC whose tumors express PD-L1 (CPS of 10 or higher), as determined by an FDA-approved test.3

The decision was supported by data yielded from the phase 3 KEYNOTE-355 trial (NCT02819518), which showed that the regimen resulted in a median progression-free survival of 9.7 months (95% CI, 7.6-11.3) vs 5.6 months (95% CI, 5.3-7.5) with chemotherapy alone (HR, 0.65; 95% CI, 0.49-0.86; P = .0012).


  1. KEYTRUDA (pembrolizumab) plus chemotherapy before surgery and continued as a single agent after surgery showed statistically significant event-free survival (EFS) result versus neoadjuvant chemotherapy alone in high-risk early-stage TNBC. News release. Merck. July 15, 2021. Accessed July 15, 2021.
  2. Schmid P, Cortés J, Dent R, et al. KEYNOTE-522: phase III 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):V853-V854. doi:10.1093/annonc/mdz394.003
  3. FDA grants accelerated approval to pembrolizumab for locally recurrent unresectable or metastatic triple negative breast cancer. News release. FDA. November 13, 2020. Accessed July 15, 2021.

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