Phase III KEYNOTE-522: Pembrolizumab Benefits Outcome in Neoadjuvant, Adjuvant Settings in Triple-Negative Breast Cancer

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In patients with triple-negative breast cancer, the addition of pembrolizumab to neoadjuvant and adjuvant chemotherapy achieves higher rates of pathologic complete response compared with placebo, according to results of the phase III KEYNOTE-522 trial presented at the 2019 San Antonio Breast Cancer Symposium.1 The benefits of pembrolizumab were consistent across subgroups regardless of programmed cell death ligand 1 (PD-L1) status, with the greatest magnitude of benefit observed in node-positive and stage IIIB disease.

“Triple-negative breast cancer is an aggressive subtype of breast cancer with a higher recurrence rate within the first 5 years of diagnosis compared to other subtypes. It has been known for some time that involvement of lymph nodes is associated with an even higher risk of recurrence in patients with triple-negative breast cancer,” said lead author Peter Schmid, MD, PhD, Professor of Cancer Medicine and Lead of the Centre of Experimental Cancer Medicine at Barts Cancer Institute, London.

“The results of KEYNOTE-522 suggest that adding pembrolizumab to neoadjuvant chemotherapy is beneficial for patients with the most aggressive disease and the highest unmet need.”
— Peter Schmid, MD, PhD

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“Patients who achieve pathologic complete response after neoadjuvant or adjuvant therapy have an improved prognosis and low rates of recurrence, particularly those with more aggressive cancers like triple-negative breast cancer. We know that if you give [a patient with triple-negative breast cancer] neoadjuvant chemotherapy consisting of an anthracycline and a taxane, the pathologic complete response rates are about 40%, and if you add in a platinum, the rate is about 50% to 55%,” Dr. Schmid explained. “There continues to be a significant need for new regimens that can increase the pathologic complete response rate and increase long-term, event-free survival for patients with triple-negative breast cancer.”

He added, “The results of KEYNOTE-522 suggest that adding pembrolizumab to neoadjuvant chemotherapy is beneficial for patients with the most aggressive disease and the highest unmet need. I think the results have the potential to be practice-changing.” 

Prior to KEYNOTE-522, smaller studies suggested that the addition of pembrolizumab and other checkpoint inhibitors to neoadjuvant chemotherapy was safe and promising in triple-negative breast cancer.

Study Details 

KEYNOTE-522 enrolled 1,174 patients with newly diagnosed, operable, stage II or III triple-negative breast cancer treated with both neoadjuvant and adjuvant systemic therapies. During the neoadjuvant phase of therapy, patients were randomly assigned 2:1 to receive pembrolizumab at 200 mg every 3 weeks vs placebo, given together with chemotherapy. All patients were administered carboplatin plus paclitaxel for 12 weeks followed by doxorubicin or epirubicin plus cyclophosphamide for an additional four cycles. After neoadjuvant therapy, patients underwent surgery and received definitive radiation therapy if indicated. Following surgery, patients received nine more cycles of adjuvant pembrolizumab or placebo.

The ongoing KEYNOTE-522 study has two co-primary endpoints: pathologic complete response and event-free survival. The data for pathologic complete response are mature and were presented in San Antonio. Event-free survival data are still not mature.

Baseline characteristics were well balanced between the two treatment groups. The median patient age was 49 years, about 75% had T1 or T2 tumors, and slightly more than half had node-positive disease. More than 80% of patients had PD-L1–positive disease, based on a combined positive score (CPS) ≥ 1 according to the pharmDx assay.

PD-L1 Expression, Nodal Status

Regardless of PD-L1 expression, more patients in the pembrolizumab arm achieved pathologic complete response: 64.8% vs 51.2% for placebo, representing an absolute difference of 13.6% (P = .00055), which Dr. Schmid called “statistically significant and clinically meaningful.”

At the first planned interim analysis with just 15.5 months of follow-up, the second primary endpoint of event-free survival based on 1,174 patients was 91.3% in the pembrolizumab groups vs 85.3% in the placebo group at 18 months.

“There is a separation of the Kaplan-Meier curves for event-free survival, but it is not statistically significant at this point, considering the stringent predesignated P value for significance,” Dr. Schmid said.

Across disease stages, pembrolizumab achieved a consistent increase in pathologic complete response, with the greatest magnitude of benefit in patients with stage IIIB disease: 48.6% vs 23.1% for the placebo group, respectively, for an absolute difference of 25.6%. In patients with stage IIIA disease, pathologic complete response rates were 66.7% vs 42.1%, respectively, for an absolute difference of 24.6%; in patients with stage IIB disease, pathologic complete response rates were 56.2% vs 48.4%, respectively, for an absolute difference of 7.8%; and for those with stage IIA disease, pathologic complete response rates were 73.1% vs 62.1%, for an absolute difference of 11.0%.

Lymph node–positive patients had a greater pathologic complete response benefit if they received pembrolizumab vs placebo: 64.8% and 44.1%, for an absolute difference of 20.6%. Node-negative patients also benefited from the addition of pembrolizumab, but the magnitude of benefit was smaller: 64.9% vs 58.6%, for an absolute difference of 6.3%.

PD-L1 status was not associated with a tumor response. “This is different from metastatic breast cancer, where there is a vast difference in patients with PD-L1–positive tumors and PD-L1–negative tumors in terms of the benefit from immune therapy,” said Dr. Schmid. “We don’t see this association in early breast cancer. My personal theory is that the reason for these differences is due to the increased tumor plasticity and the tumor biology dynamics in early disease.”

In patients with a PD-L1 CPS < 1, the pembrolizumab-treated group had pathologic complete response rates of 45.3% vs 30.3% in the chemotherapy-alone group, for an absolute difference of 18.3%. For CPS ≥ 1, pathologic complete response rates were 68.9% vs 54.9%, respectively, for an absolute difference of 14.2%. In patients with CPS ≥ 10, rates were 77.9% vs 59.8%, for an absolute difference of 17.5%; and in patients with CPS ≥ 20, rates were 81.7% vs 62.5%, respectively, for an absolute difference of 18.5%.

“The absolute difference between chemotherapy alone and the pembrolizumab combination was consistent whether you used a CPS cutoff of 1, 10, or 20,” Dr. Schmid said. “Of note, if you look at the patients with inflamed tumors with a CPS ≥ 10, we see pathologic complete response rates that we have never seen in such an aggressive disease group.”

Regardless of exposure to chemotherapy, patients treated with pembrolizumab had an improved pathologic complete response compared with the chemotherapy/placebo group. Full exposure to chemotherapy plus pembrolizumab led to a pathologic complete response rate of 69.7% vs 55.3% in the chemotherapy/placebo group, for an absolute difference of 14.4%. In those who received less than the full chemotherapy dose, the pathologic complete response rate was 51.5% with pembrolizumab vs 35.7% with placebo, for an absolute difference of 15.4%.

Dr. Schmid noted that further biomarker analysis will continue, including analysis of tumor-infiltrating lymphocytes and BRCA-­mutational status, to determine if particular subgroups will have greater benefit from pembrolizumab.

Comments on the Study

“Pembrolizumab will be an important addition to our treatment options, and these results will be practice-changing.”
— C. Kent Osborne, MD, FASCO

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“KEYNOTE-522 is promising. Pembrolizumab will be an important addition to our treatment options, and these results will be practice-changing,” stated C. Kent Osborne, MD, FASCO, Director of the Dan L. Duncan Comprehensive Cancer Center, Professor of Medicine, and the Dudley and Tina Sharp Chair for Cancer Research at Baylor College of Medicine, Houston.

“The use of immunotherapy is still young in breast cancer, and there are lots of unanswered questions. For example, can we identify those patients who will benefit? For checkpoint inhibitors focused on triple-negative breast cancer, a number of us think that estrogen receptor–positive patients will benefit,” Dr. Osborne said.

“The thinking behind this is that estrogen ­receptor–positive tumors are ‘cold’ and do not have a lot of [tumor-infiltrating lymphocytes]. The new approach [of checkpoint inhibitor therapy] may ‘turn on’ the [tumor-infiltrating lymphocytes]. Immunotherapy in breast cancer is still in its infancy,” Dr. Osborne emphasized.  

DISCLOSURE: KEYNOTE-522 was sponsored by Merck Sharp & Dohme. Dr. Schmid has received research support from AstraZeneca, Genentech, Roche, OncoGenex Pharmaceuticals, Novartis, Astellas, and Medivation and honoraria or consultation fees from Pfizer, AstraZeneca, Novartis, Roche, Merck, Boehringer Ingelheim, Bayer, Eisai, Celgene, and Puma. Dr. Osborne has served on advisory boards for Genentech and AstraZeneca; has been a consultant for Tolmar Pharma; and owns stock in GeneTex.


1. Schmid P, Park YH, Ferreira M, et al: KEYNOTE-522: Phase 3 study of neoadjuvant pembrolizumab + chemotherapy versus placebo + chemotherapy, followed by adjuvant pembrolizumab versus placebo for early triple-negative breast cancer: Pathologic complete response in key subgroups and by treatment exposure and residual cancer burden. 2019 San Antonio Breast Cancer Symposium. Abstract GS3-03. Presented December 12, 2019.