Neoadjuvant Immunotherapy Plus Chemotherapy Active in Women With Early Triple-Negative Breast Cancer

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Immunotherapy has changed the treatment paradigms for melanoma, lung cancer, bladder cancer, and renal cancer. Now, checkpoint inhibitor therapy is making inroads in triple-negative breast cancer—one of the most difficult-to-treat aggressive types of breast cancer.

Late-breaking results of the KEYNOTE-522 trial presented at the ESMO Congress 2019, showed that the addition of the checkpoint inhibitor pembrolizumab to chemotherapy boosted pathologic complete response rates compared with chemotherapy alone.1 KEYNOTE-522 is the first phase III trial to demonstrate that anti–programmed cell death protein 1 therapy significantly improves pathologic complete response rates, regardless of programmed cell death ligand 1 (PD-L1) status, when combined with chemotherapy as neoadjuvant therapy for triple-negative breast cancer.

Peter Schmid, MD, PhD

Peter Schmid, MD, PhD

An interim analysis showed that at a median follow-up of 15.5 months, pathologic complete response rates were 64.8% for pembrolizumab plus chemotherapy vs 51.2% for chemotherapy alone (P = .00055).

“This 13.6% difference is clinically meaningful,” stated lead author Peter Schmid, MD, PhD, of Barts Institute, Queen Mary University, London. “If patients with triple-negative breast cancer get neoadjuvant therapy, those with a pathologic complete response have a clinical benefit. There is a strong association between pathologic complete response after neoadjuvant chemotherapy and survival. With taxanes and anthracyclines, the pathologic complete response rate is about 40%, and if platinum is added, it is increased to about 50% to 55%. With the addition of pembrolizumab, it is up to 64.5%.”

Study Details

KEYNOTE-522 included women with early triple-negative breast cancer and randomly assigned them 2:1 to receive neoadjuvant therapy with four cycles of carboplatin/paclitaxel, followed by four cycles of doxorubicin/epirubicin with or without pembrolizumab. After surgery, patients received nine cycles of adjuvant pembrolizumab or placebo, depending on their assigned group.

The first interim analysis included 602 patients. Both PD-L1–positive and PD-L1–negative patients achieved pathologic complete response. In PD-L1–positive patients, pathologic complete response rates were 68.9% vs 54.9%, respectively. In PD-L1–negative patients, pathologic complete response rates were 45.3% vs 30.3%, respectively.

Pembrolizumab also improved event-free survival at this early time point. There was a favorable trend in estimated event-free survival. The rate was 91.3% for the pembrolizumab arm vs 85.3% for the placebo arm—a 37% improvement. Events were reported in 7.4% of the pembrolizumab arm vs 11.8% of the placebo arm.


  • KEYNOTE-522 showed that the combination of pembrolizumab plus chemotherapy improved pathologic complete response rate in early triple-negative breast cancer.
  • This is the first phase III evidence supporting neoadjuvant immunotherapy plus chemotherapy in triple-negative breast cancer, regardless of PD-L1 status.
  • Longer follow-up is needed to confirm these results and determine which patients should receive this regimen.

Side effects in the two groups of patients were mostly comparable and attributable to chemotherapy, with no new safety signals related to pembrolizumab or the combination. Slightly more rash occurred with pembrolizumab than placebo prior to surgery.

Grade 3 or higher treatment-related adverse events were reported in 78% of the pembrolizumab arm and 73% of the placebo arm. Immune-related adverse events occurred in 42% vs 21%, respectively. After surgery, low rates of toxicity were seen in both treatment arms, with little difference between them.

In the KEYNOTE-119 trial, which was also reported at the ESMO Congress 2019,2 no survival benefit was seen for -pembrolizumab monotherapy vs single-agent chemotherapy in metastatic triple-negative breast cancer. This open-label phase III study randomly assigned 622 patients with metastatic triple-negative breast cancer to pembrolizumab or single-agent chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine) as second- or third-line treatment. A trend was observed for increasing survival benefit with pembrolizumab in patients with increased expression of PD-L1. Pembrolizumab did not improve median progression-free survival compared with chemotherapy.

Clinical Perspective

Expert Giuseppe Curigliano, MD, PhD, of the University of Milan and European Institute of Oncology, Italy, put these results into perspective at a press conference.“Pathologic complete response is a surrogate for overall survival. The combination of pembrolizumab

Giuseppe Curigliano, MD, PhD

Giuseppe Curigliano, MD, PhD

plus chemotherapy in the neoadjuvant setting increased pathologic complete response from 51% to 64%, and this is a great result. If you increase pathologic complete response, you potentially increase disease-free survival and overall -survival,” he said.

Dr. Curigliano said that tumor biopsies will be analyzed to determine which patients are more likely to respond to a checkpoint inhibitor and to characterize resistance more fully.

“The combination of immunotherapy and chemotherapy for early triple-negative breast cancer could become a new standard of care if approved,” he stated. 


DISCLOSURE: Dr. Schmid has received honoraria from and is an advisor or consultant for Pfizer, AstraZeneca, Novartis, Roche, Merck, Boehringer Ingelheim, Bayer, Eisai, Puma, and Celgene; has received institutional research support from AstraZeneca, Genentech/Roche, Oncogenex, Novartis, and Astellas; and his spouse is a consultant for Genentech/Roche. Dr. Curigliano has received honoraria from Ellipses Pharma; had a consulting/advisory role with Roche/Genentech, Pfizer, Novartis, Lilly, Foundation Medicine, Bristol-Myers Squibb, and Samsung; was on a speakers bureau for Roche/Genentech, Pfizer, Novartis, Lilly, Foundation Medicine, and Samsung; and has received travel expenses from Roche/Genentech and Pfizer.


1. Schmid P, Cortés J, Dent R, et al: KEYNOTE-522: Phase III study of pembrolizumab + chemotherapy vs placebo + chemo as neoadjuvant treatment, followed by pembrolizumab vs placebo as adjuvant treatment for early triple-negative breast cancer. ESMO Congress 2019. Abstract LBA8_PR. Presented September 29, 2019.

2. Cortés J, Lipatov O, Im S-A, et al: KEYNOTE-119: Phase III study of pembrolizumab versus single-agent chemotherapy for metastatic triple-negative breast cancer. ESMO Congress 2019. Abstract LBA21. Presented September 28, 2019.