The KEYNOTE-522 clinical trial showed that adding the immunotherapy drug pembrolizumab (Keytruda) to standard chemotherapy before and after surgery significantly improves outcomes for patients with early-stage triple-negative breast cancer, one of the most aggressive forms of breast cancer. After a median follow-up of about 39 months, 84.5% of patients who received pembrolizumab plus chemotherapy were alive without cancer recurrence or progression, compared with 76.8% of those who received chemotherapy alone — a 37% reduction in the risk of cancer events or death. These findings establish pembrolizumab as an important new treatment option that can help prevent recurrence in this challenging disease.
Triple-negative breast cancer (TNBC) is a subtype of breast cancer that lacks three common receptors that fuel most breast cancers: estrogen receptors, progesterone receptors, and the HER2 protein. Because these tumors do not respond to hormone therapy or HER2-targeted drugs, treatment traditionally relies on chemotherapy.
TNBC is known to be more aggressive than other breast cancer types. Even when patients receive the standard curative-intent chemotherapy regimen containing anthracyclines (such as doxorubicin or epirubicin) and taxanes (such as paclitaxel), the risk of recurrence and death remains substantial.
The numbers are sobering: among patients with stage II or III triple-negative breast cancer, approximately 71% are alive and free of cancer events at 5 years, and overall survival at 5 years is approximately 77%. For patients with early-stage disease, neoadjuvant chemotherapy — chemotherapy given before surgery — is the current standard of care.
The short-term goal of neoadjuvant therapy is to achieve a pathological complete response, meaning that no invasive cancer remains in the breast tissue and lymph nodes at the time of surgery. Patients who achieve this response tend to have better long-term outcomes. The long-term goal of combining neoadjuvant and adjuvant (post-surgery) therapy is to prevent the cancer from coming back as metastatic disease.
In recent years, researchers have explored whether immune checkpoint inhibitors — drugs that help the body's immune system recognize and attack cancer cells — could improve outcomes in TNBC. These drugs target proteins called programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1), which cancer cells use to hide from the immune system.
The KEYNOTE-522 trial was designed to answer a critical question: could adding the PD-1 inhibitor pembrolizumab to standard chemotherapy improve outcomes for patients with early-stage TNBC?
KEYNOTE-522 is a phase 3, randomized, double-blind, placebo-controlled clinical trial — considered the gold standard of medical research. In a double-blind trial, neither the patients nor their doctors know who is receiving the active drug versus the placebo, which helps eliminate bias.
The trial was conducted at 181 sites (plus 2 satellite sites) across 21 countries, making it one of the most extensive studies ever conducted in this patient population. Patients were enrolled from March 2017 through September 2018.
Each patient was randomly assigned in a 2:1 ratio — meaning for every patient who received placebo, two received pembrolizumab. In total, 1,174 patients were enrolled: 784 in the pembrolizumab–chemotherapy group and 390 in the placebo–chemotherapy group.
Before randomization, patients were stratified (grouped) according to three factors:
The trial was sponsored by Merck Sharp and Dohme, a subsidiary of Merck, and was overseen by an independent data and safety monitoring committee that periodically reviewed safety and efficacy results. All patients provided written informed consent, and the trial protocol was approved by ethics committees at each participating institution.
This report describes the results of the fourth planned interim analysis, with a data cutoff of March 23, 2021. The median follow-up at this point was 39.1 months (range, 30.0 to 48.0 months).
The study enrolled adult patients with newly diagnosed, previously untreated, nonmetastatic stage II or III triple-negative breast cancer. Triple-negative status was centrally confirmed using standard guidelines from the American Society of Clinical Oncology and the College of American Pathologists.
Eligible patients had specific tumor characteristics, including T1c N1–2 or T2–4 N0–2 disease (based on the 7th edition of the American Joint Committee on Cancer staging criteria). They also needed to have a good performance status — specifically an Eastern Cooperative Oncology Group (ECOG) performance-status score of 0 or 1, which means they were fully active or restricted only in physically strenuous activity but able to carry out work of a light or sedentary nature.
Patients were eligible for the trial regardless of their PD-L1 expression status, meaning the drug was studied in all patients with early TNBC, not just those whose tumors tested positive for PD-L1.
Importantly, at baseline, the characteristics of patients were well balanced between the two treatment groups, meaning the groups were comparable in terms of age, disease stage, and other important factors.
A total of 783 patients in the pembrolizumab–chemotherapy group and 389 in the placebo–chemotherapy group received at least one dose of trial treatment or underwent surgery (the "as-treated" population). No patients were still receiving treatment at the time of this analysis.
The treatment plan in KEYNOTE-522 was carefully structured and involved two phases: a neoadjuvant (pre-surgery) phase and an adjuvant (post-surgery) phase.
Neoadjuvant phase:
Glucocorticoids could be used to prevent allergic reactions before chemotherapy and to manage immune-related side effects.
After completing the neoadjuvant phase, patients underwent definitive surgery — either breast-conserving surgery or mastectomy, with sentinel lymph-node evaluation or axillary dissection — at 3 to 6 weeks after their last neoadjuvant treatment cycle.
Adjuvant phase: After surgery, patients received radiation therapy as clinically indicated, plus either pembrolizumab (the pembrolizumab–chemotherapy group) or placebo (the placebo–chemotherapy group) once every 3 weeks for up to nine additional cycles. Adjuvant pembrolizumab or placebo could begin either at the same time as radiation therapy or 2 weeks after completing radiation. Notably, adjuvant treatment with capecitabine (another chemotherapy drug) was not allowed in this trial.
Patients stopped treatment if their disease progressed in a way that prevented surgery, if the cancer recurred, or if they experienced unacceptable side effects.
The trial had two primary endpoints (the main outcomes used to determine whether the treatment worked):
Secondary endpoints included:
An exploratory endpoint was distant progression–free or distant recurrence–free survival, defined as the time from randomization to distant cancer spread, distant recurrence, or death from any cause.
How patients were monitored: After completing neoadjuvant therapy, patients were followed for disease status and survival every 3 months for the first 2 years after randomization, then every 6 months for years 3 through 5, and annually thereafter.
PD-L1 testing: Tumor samples were tested at a central laboratory using the PD-L1 IHC 22C3 pharmDx assay. PD-L1 expression was measured using the combined positive score (CPS), which is the number of PD-L1–positive cells (tumor cells, lymphocytes, and macrophages) divided by the total number of tumor cells, multiplied by 100. A CPS of 1 or higher was considered PD-L1–positive.
The results of this fourth planned interim analysis were striking. A total of 123 patients (15.7%) in the pembrolizumab–chemotherapy group experienced an event or died, compared with 93 patients (23.8%) in the placebo–chemotherapy group.
The hazard ratio for an event or death was 0.63 (95% confidence interval [CI], 0.48 to 0.82; P<0.001). In plain language, this means patients who received pembrolizumab had a 37% lower risk of experiencing a cancer event or dying during the follow-up period compared with patients who received chemotherapy alone.
The estimated event-free survival at 36 months (3 years) was:
This means that at 3 years, about 84 out of every 100 patients who received pembrolizumab were alive and free of cancer events, compared with about 77 out of every 100 who received chemotherapy alone — a difference of 7.7 percentage points in favor of pembrolizumab.
The median event-free survival was not reached in either group, which means that at the time of this analysis, more than half of the patients in both groups were still event-free, so researchers could not yet calculate an "average" survival time — a good sign.
The statistical threshold for significance at this interim analysis was P<0.01034 (a two-sided alpha level), and the result easily crossed that threshold, confirming that the improvement in event-free survival was statistically significant and not due to chance.
Researchers also examined the specific types of events that occurred first in each group. Understanding these details helps doctors know exactly what benefit pembrolizumab provides.
Here is the breakdown of first events in the trial:
Notably, 13 patients in the pembrolizumab group and 9 in the placebo group who had a local recurrence subsequently developed a distant recurrence.
The most important observation here is that the largest gap between groups was in distant recurrence — the type of recurrence that is most dangerous because it means the cancer has spread to other parts of the body. The pembrolizumab group had nearly half the rate of distant recurrence (7.7% vs. 13.1%).
The event-free survival benefit was consistent across all prespecified patient subgroups, including subgroups defined by PD-L1 expression and lymph-node involvement. This means the benefit was seen regardless of whether a patient's tumor tested positive or negative for PD-L1, and regardless of whether the cancer had spread to lymph nodes.
Overall survival — the ultimate measure of whether a treatment helps patients live longer — showed a promising trend, though the data were still immature at the time of this analysis.
In other words, at 3 years, approximately 90% of patients who received pembrolizumab were still alive, compared with approximately 87% of those who received chemotherapy alone. The researchers note that follow-up for overall survival is ongoing, and these numbers may change as more events occur.
Distant progression–free or distant recurrence–free survival — the measure of how long patients lived without the cancer spreading to distant organs — showed a hazard ratio of 0.61 (95% CI, 0.46 to 0.82) in favor of the pembrolizumab group. This translates to a 39% reduction in the risk of distant spread or death.
Exploratory analysis by pathological complete response: The researchers also looked at whether achieving a pathological complete response (pCR) affected event-free survival, recognizing that this was a non-randomized, exploratory analysis:
This suggests that even among patients who achieved a complete response to neoadjuvant therapy, those who received pembrolizumab also tended to have slightly better event-free survival, although this difference was not statistically significant in this exploratory analysis.
Safety findings were consistent with what researchers already knew about pembrolizumab and chemotherapy from earlier phases of this trial and other studies. Adverse events occurred predominantly during the neoadjuvant phase of treatment.
The most common treatment-related adverse events of any grade (ranging from mild to severe) were nausea, hair loss (alopecia), and anemia — side effects commonly associated with the chemotherapy backbone used in this trial.
Key safety data from this analysis:
Adverse events were monitored throughout treatment and for 30 days after discontinuation, with serious adverse events tracked for 90 days after discontinuation. They were graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0. Immune-mediated adverse events — side effects caused by the immune system becoming overactive — were identified using a predefined list of medical terms.
It is worth noting that while pembrolizumab increased the risk of certain immune-related side effects, the overall balance strongly favored the pembrolizumab group because of the substantial reduction in cancer recurrence — the event that matters most to patients.
Strengths of this trial:
Limitations of this trial:
These results provide strong evidence that adding pembrolizumab to standard chemotherapy for early-stage triple-negative breast cancer significantly reduces the risk of cancer recurrence and death. For patients and their doctors, this study helps guide treatment decisions in several important ways:
For patients newly diagnosed with early-stage triple-negative breast cancer, this study offers genuine hope. The combination of immunotherapy with modern chemotherapy — before and after surgery — represents a meaningful advance in the treatment of a cancer subtype that has historically been among the most difficult to treat.
Triple-negative breast cancer (TNBC) is a breast cancer subtype that lacks estrogen receptors, progesterone receptors, and HER2 protein. It does not respond to hormone therapy or HER2-targeted drugs, so treatment traditionally relies on chemotherapy. TNBC is known to be more aggressive than other breast cancer types, with a substantial risk of recurrence and death.
In the KEYNOTE-522 trial, after a median follow-up of 39.1 months, patients with early-stage triple-negative breast cancer who received pembrolizumab plus chemotherapy had a 37% lower risk of cancer events or death compared with chemotherapy alone. Event-free survival at 3 years was 84.5% with pembrolizumab versus 76.8% with chemotherapy alone.
The trial enrolled adults with newly diagnosed, previously untreated, nonmetastatic stage II or III triple-negative breast cancer. Patients were eligible regardless of their PD-L1 expression status. They needed a good performance status (ECOG score 0 or 1) and specific tumor characteristics such as T1c N1–2 or T2–4 N0–2 disease.
The KEYNOTE-522 treatment plan had a neoadjuvant phase followed by an adjuvant phase. Initially, patients received pembrolizumab or placebo with paclitaxel and carboplatin for four cycles, then with doxorubicin or epirubicin plus cyclophosphamide for four more cycles. After surgery, they received radiation if indicated and pembrolizumab or placebo for up to nine additional cycles.
The most common treatment-related side effects were nausea, hair loss, and anemia. Serious treatment-related side effects occurred in 34.1% of the pembrolizumab group versus 20.1% with chemotherapy alone. More patients in the pembrolizumab group stopped treatment due to side effects, but treatment-related deaths were rare in both groups.
Yes. In the KEYNOTE-522 trial, patients were eligible regardless of PD-L1 expression, and the event-free survival benefit was consistent across all prespecified subgroups, including those defined by PD-L1 expression and lymph-node involvement. So the benefit was seen whether or not the tumor tested positive for PD-L1.
Overall survival data were immature, with a favorable trend that did not reach statistical significance. Confidence intervals for secondary endpoints were not adjusted for multiple comparisons. Analysis of event-free survival by pathological complete response was exploratory and non-randomized. The trial was sponsored by the drug's manufacturer, and adjuvant capecitabine was not allowed.
Original Article: "Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer"
Authors: P. Schmid, J. Cortes, R. Dent, L. Pusztai, H. McArthur, S. Kümmel, J. Bergh, C. Denkert, Y.H. Park, R. Hui, N. Harbeck, M. Takahashi, M. Untch, P.A. Fasching, F. Cardoso, J. Andersen, D. Patt, M. Danso, M. Ferreira, M.-A. Mouret-Reynier, S.-A. Im, J.-H. Ahn, M. Gion, S. Baron-Hay, J.-F. Boileau, Y. Ding, K. Tryfonidis, G. Aktan, V. Karantza, and J. O'Shaughnessy, for the KEYNOTE-522 Investigators
Publication: The New England Journal of Medicine, 2022; Volume 386, pages 556–567
DOI: 10.1056/NEJMoa2112651
Funding: Merck Sharp and Dohme, a subsidiary of Merck
ClinicalTrials.gov number: NCT03036488
This patient-friendly article is based on peer-reviewed research published in The New England Journal of Medicine. It is intended for educational purposes and does not constitute medical advice. Patients should discuss their individual treatment options with their healthcare provider.
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