Addition of ICIs to Neoadjuvant Chemotherapy in High-Risk Breast Cancer Supported by Results of Phase 3 Trial

In Clinical Studies News by Barbara Jacoby

By: Susan Moench, PhD, PA-C


The pathologic complete response (pCR) rate was nearly 14% higher for women with high-risk nonmetastatic triple-negative breast cancer (TNBC) treated with a neoadjuvant treatment regimen including chemotherapy plus an immune checkpoint inhibitor (ICI) compared with chemotherapy alone, according to results of a phase 3 study published in the New England Journal of Medicine.1

Promising results were observed with the addition of ICI therapy to neoadjuvant chemotherapy in 2 previously conducted studies of women with high-risk, early-stage breast cancer. Specifically, early results from the phase Ib KEYNOTE-173 study showed antitumor activity and reasonable tolerability in women with locally advanced TNBC who were treated with the programmed cell death-1 (PD-1) inhibitor, pembrolizumab, in combination with platinum-based chemotherapy.2  Those results were supported by findings from the adaptively designed, phase 2 I-SPY2 trial, which evaluated standard chemotherapy with or without pembrolizumab in the neoadjuvant treatment of women with HER2-negative breast cancer.3

In this randomized, double-blind, placebo-controlled clinical trial (KEYNOTE-522; Identifier: NCT03036488), patients with triple-negative stage II or III breast cancer were randomly assigned in a 2:1 ratio to receive neoadjuvant treatment with either pembrolizumab plus carboplatin chemotherapy followed by pembrolizumab plus anthracycline-based chemotherapy or placebo plus carboplatin chemotherapy followed by placebo plus anthracycline-based chemotherapy, respectively.

Following surgery, patients were treated with up to 9 cycles of single-agent pembrolizumab or placebo. Although programmed cell death ligand-1 (PD-L1) expression was evaluated in tumor specimens of all patients, tumor PD-L1–positivity was not a criterion for study inclusion. The 2 primary endpoints of the study were pCR rate and event-free survival, both in the intention-to-treat population.

Regarding this study design, the study authors commented that “a key strength of our trial is the inclusion of a control group of patients who received platinum therapy; this permits the direct comparison of the pembrolizumab–chemotherapy combination with the neoadjuvant chemotherapy regimen that has been associated with the highest rate of pathological complete response among patients with early triple-negative breast cancer.”

Of the 1174 patients who underwent study randomization, 784 received pembrolizumab-based therapy and 390 received chemotherapy alone. At baseline, more than 80% of patients had tumors classified as PD-L1–positive, nearly 90% of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0, and approximately three-quarters of patients had stage II disease.

At the time of the first interim analysis, pCR rates were 64.8% for patients receiving pembrolizumab plus chemotherapy compared with 51.2% for those treated with chemotherapy alone (P <.001). Respective pCR rates were higher for those classified as having PD-L1–positive disease (68.9% vs 54.9%) compared with those with disease classified as PD-L1–negative (45.3% vs 30.3%), although similar percentage differences between the 2 study arms were observed in both cases.

At a median follow-up of 15.5 months, significantly fewer events defined as disease progression, local or distant recurrence/a second primary tumor, or death from any cause were observed for those enrolled in the pembrolizumab-containing arm compared with the chemotherapy alone arm (hazard ratio [HR], 0.63; 95% CI, 0.43-0.93).

Regarding safety, the rates of treatment-related grade 3 or 4 adverse events exceeded 70% in both study arms across all treatment phases, although the rate of serious adverse events was higher in the pembrolizumab-containing arm (32.5% vs 19.5%). Grade 3 or higher immune-related adverse events included skin reactions, infusion reactions, and adrenal insufficiency in 3.8%, 2.6%, and 1.3%, respectively, of patients receiving pembrolizumab-based therapy.

However, the study authors noted that “this did not hamper the ability to administer neoadjuvant chemotherapy, which is important, since administration of fewer doses of neoadjuvant chemotherapy than planned is associated with worse long-term outcomes.”

Treatment-related death occurred in 3 patients (0.4%) receiving pembrolizumab plus chemotherapy and 1 patient (0.3%) treated with chemotherapy alone.

Disclosure: This study was supported by Merck Sharp & Dohme, a subsidiary of Merck. For a full list if disclosures, please refer to the original study.


  1. Schmid P, Cortes J, Pusztai L, et al Pembrolizumab for early triple-negative breast cancer. N Engl J Med [published online February 27, 2020]. DOI: 10.1056/NEJMoa1910549
  2. Schmid P, Park YH, Muñoz-Couselo E, et al. Pembrolizumab (pembro) + chemotherapy (chemo) as neoadjuvant treatment for triple negative breast cancer (TNBC): preliminary results from KEYNOTE-173. J Clin Oncol 2017; 35:(15_suppl): Abstract 556.
  3. Nanda R, Liu M, Yau C, et al. Effect of Pembrolizumab plus neoadjuvant chemotherapy on pathologic complete response in women with early-stage breast cancer: An analysis of the ongoing phase 2 adaptively randomized I-SPY2 trial. Lancet Oncol [published online February 20, 2020]. DOI: 10.1001/jamaoncol.2019.6650