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Adding Pembrolizumab to Neoadjuvant Chemotherapy Improves Outcome in Early TNBC

Neoadjuvant therapy with pembrolizumab plus chemotherapy provides greater anti-tumour activity than placebo plus chemotherapy in patients with early stage triple negative breast cancer
29 Sep 2019
Immunotherapy;  Cytotoxic Therapy
Breast Cancer

The addition of pembrolizumab to standard neoadjuvant chemotherapy provided greater rates of pathological complete response (pCR) in patients with early triple negative breast cancer (TNBC), according to findings from the phase III KEYNOTE-522 trial that were presented at the ESMO Congress 2019  in Barcelona, Spain.

Peter Schmid of the Barts Cancer Institute-Queen Mary University of London in London, United Kingdom noted that the phase Ib KEYNOTE-173 and phase II I-SPY 2 clinical trials demonstrated promising anti-tumour activity and a manageable safety profile with neoadjuvant pembrolizumab in combination with chemotherapy in patients with early TNBC.

Professor Schmid and colleagues conducted the international KEYNOTE-522 study (NCT03036488) of neoadjuvant pembrolizumab with chemotherapy followed by adjuvant pembrolizumab to further define the activity of the regimen in patients with early stage TNBC.

The placebo-controlled phase III study enrolled patients with previously untreated, non-metastatic, centrally confirmed TNBC, defined as stage T1c N1-2, or T2-4 N0-2 according to American Joint Committee on Cancer criteria. Of these patients, 784 were randomly assigned to receive pembrolizumab at 200 mg every 3 weeks (q3w) and 390 were assigned to placebo, each delivered with neoadjuvant chemotherapy consisting of 12 weeks of paclitaxel plus carboplatin followed by of 4 cycles of doxorubicin or epirubicin plus cyclophosphamide. After undergoing definitive surgery, all patients received pembrolizumab or placebo during the adjuvant phase for an additional 9 cycles or until recurrence or unacceptable toxicity. The patients were stratified by nodal status (positive versus negative), tumour size (T1/T2 versus T3/T4), and carboplatin schedule (q3w versus weekly [qw]).

KEYNOTE-522 had two primary endpoints of pathological complete response (pCR), defined as ypT0/Tis ypN0, and event-free survival (EFS). The secondary endpoints included pCR, defined as ypT0 ypN0 and ypT0/Tis, overall survival (OS), and efficacy in the PD-L1-positive population.

With median follow-up of 15.5 (range, 2.7 to 25.0) months, 602 patients were evaluable for the definitive pCR analysis. Among these patients, those receiving pembrolizumab/chemotherapy demonstrated a statistically significant improvement in pCR defined as ypT0/Tis ypN0 compared to patients receiving placebo plus chemotherapy. The pCR rate was 64.8% (95% confidence interval [CI], 59.9-69.5) with the pembrolizumab/chemotherapy regimen compared to 51.2% (95% CI, 44.1-58.3) with placebo plus chemotherapy (treatment difference, 13.6 percentage points; 95% CI, 5.4-21.8; p = 0.00055).

Regarding the secondary pCR endpoints, the pCR rates of ypT0 ypN0 were 59.9% versus 45.3% and the pCR rates of ypT0/Tis were 68.6% versus 53.7% with the pembrolizumab combination versus placebo plus chemotherapy, respectively.

Schmid Image-1 ESMO 2019 News

Pathological complete response at IA1.

© Peter Schmid.

Greater anti-tumour activity of pembrolizumab plus chemotherapy observed regardless of PD-L1 status

Analysis of data based on PD-L1 status showed that pCR defined as ypT0/Tis ypN0 was higher with the pembrolizumab regimen in both the PD-L1-positive and PD-L1-negative subgroups. The pCR rates were 68.9% versus 54.9% in the PD-L1-positive cohort and 45.3% versus 30.3% in the PD-L1-negative population in patients receiving chemotherapy plus pembrolizumab or placebo, respectively. 

Patients treated with neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab also showed a favourable trend in EFS compared to patients on the neoadjuvant placebo plus chemotherapy followed by adjuvant placebo treatment (hazard ratio [HR] 0.63; 95% CI, 0.43-0.93).

Schmid Image-2 ESMO 2019 News

Event-free survival at IA2.

© Peter Schmid.

Adverse event rates were similar between treatment arms and consistent with the known safety profiles of each

The grade 3 or higher treatment-related adverse event (AE) rates were 78.0% with neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared to 73.0% with neoadjuvant placebo plus chemotherapy followed by adjuvant placebo. The incidence of death was 0.4% versus 0.3% with the respective
treatment regimens.


Based upon data presented at ESMO 2019 Congress the investigators were able to conclude that pembrolizumab plus chemotherapy as neoadjuvant treatment significantly increased the pCR rate over neoadjuvant chemotherapy plus placebo in patients with early TNBC. In addition, a favourable trend in EFS was observed with the neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab regimen.


This trial was sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. 


LBA8_PR – Schmid P, Cortés J, Dent R, et al. 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).

Last update: 29 Sep 2019

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