Who is this trial for?
This trial was for adults with newly diagnosed, early-stage triple-negative breast cancer (TNBC) that had not yet been treated — cancer that was large or had reached nearby lymph nodes, but had not spread to distant organs.
People in the trial had:
- Triple-negative breast cancer (TNBC) — breast cancer that lacks estrogen receptors, progesterone receptors, and HER2, which removes the usual hormonal and HER2-targeted treatment options and leaves chemotherapy as the mainstay.
- Stage II or stage III disease — a tumor large enough or with enough lymph-node involvement to carry a meaningful risk of returning (about half the patients had cancer in the lymph nodes).
- No previous treatment for the breast cancer, and no distant spread (non-metastatic).
- Patients were included regardless of PD-L1 status — a protein that, in advanced disease, helps predict response to immunotherapy.
What kind of trial is this?
This trial tested whether adding immunotherapy to standard treatment could shrink the cancer more completely before surgery and stop it from coming back — the central goals when treating early-stage breast cancer with the aim of cure.
Background: why researchers asked this question
Triple-negative breast cancer is the most aggressive common subtype. Because it lacks the hormone and HER2 targets that other breast cancers can be treated against, chemotherapy has long been the backbone of treatment. For larger or node-positive tumors, that chemotherapy is usually given before surgery (neoadjuvant) — this shrinks the tumor and, importantly, shows whether the cancer has been wiped out by the time of surgery.
That last point matters enormously. Patients whose tumor has completely disappeared at surgery — a pathological complete response — have far better long-term outcomes than those with cancer still remaining. So researchers look for treatments that increase the chance of a complete response.
Pembrolizumab had already shown it could help in advanced, metastatic triple-negative breast cancer. Researchers asked: if we add it to chemotherapy before surgery in early-stage disease — while the immune system can still “see” the whole tumor — and then continue it after surgery, can we clear more tumors completely and keep the cancer from coming back?
The trial: what was tested and how
KEYNOTE-522 enrolled 1,174 people with untreated stage II or III triple-negative breast cancer across 21 countries. They were randomly assigned 2:1 to one of two groups, both of which received the same chemotherapy. The only difference was whether pembrolizumab or a placebo was added:
- Pembrolizumab + chemotherapy, then pembrolizumab (784 patients): immunotherapy added to chemo before surgery, then continued alone after surgery.
- Placebo + chemotherapy, then placebo (390 patients): the same chemotherapy with a placebo instead of pembrolizumab — the standard of care at the time.
Treatment came in three parts: chemotherapy plus pembrolizumab (or placebo) before surgery, then surgery — where the tumor is examined to see if any cancer remains — then pembrolizumab (or placebo) alone after surgery. In total, pembrolizumab was given for about a year.
The trial had two main goals: the pathological complete response rate (the share of patients with no invasive cancer left at surgery) and event-free survival (how long patients stayed free of the cancer returning, progressing, or death).
A note before the results
Triple-negative breast cancer has always been the most devastating type of breast cancer that we see in our practices. So to find a drug that helps chemotherapy work better is something to celebrate. Checkpoint inhibitor therapies are now ubiquitous in cancer treatment, and we have become good at recognizing their side effects.
However, many of these side effects can be long-lasting and permanent, and even fatal, as this trial demonstrated. We are therefore extra cautious in monitoring patients on this regimen.
Results: what they found
Adding pembrolizumab cleared more tumors completely at surgery, kept significantly more patients free of their cancer returning, and — with longer follow-up — ultimately helped more of them live longer. The benefit came at the cost of more immune-related side effects, some of which can be lasting.
Pembrolizumab + chemotherapy vs placebo + chemotherapy
Nearly two-thirds of patients given pembrolizumab had no invasive cancer left at surgery, compared with about half on chemotherapy alone — a 13.6 percentage-point improvement. The gain was seen whether or not the tumor was PD-L1 positive.
Pembrolizumab lowered the risk of the cancer returning, progressing, or death by about 35% (HR 0.65). This benefit, first seen early and holding up at more than 6 years, is what established the regimen as a new standard of care.
With longer follow-up (a median of about 6 years), adding pembrolizumab also helped patients live longer — a significant improvement in overall survival (P=0.002). This is the capstone result, confirming the benefit goes beyond keeping the cancer away.
More patients had severe (grade 3 or higher) immune-related effects — most often involving the thyroid, skin, or adrenal glands. Some of these can be permanent, such as an underactive thyroid needing lifelong hormone replacement. Four patients (0.5%) died from treatment-related causes.
One of the most important findings was that the benefit appeared regardless of PD-L1 status. In advanced, metastatic triple-negative breast cancer, immunotherapy mainly helps patients whose tumors are PD-L1 positive. Here, in early-stage disease, both PD-L1-positive and PD-L1-negative tumors benefited — which is why this treatment is offered to people with early TNBC without needing a PD-L1 test first.
With longer follow-up — a median of about six years — the addition of pembrolizumab produced a significant improvement in overall survival: an estimated 86.6% of patients were alive at five years, compared with 81.7% on chemotherapy alone (P=0.002). Because triple-negative breast cancer tends to come back early, this durable survival benefit is especially meaningful.
What is a “pathological complete response,” and why does it matter?
When chemotherapy (and immunotherapy) is given before surgery, the surgeon removes whatever tissue is left, and a pathologist examines it under the microscope. If no invasive cancer remains in the breast or lymph nodes, that is called a pathological complete response (pCR). It matters because patients who achieve a pCR tend to have much better long-term outcomes — lower chances of the cancer returning — than those with cancer still present. A higher pCR rate is an early signal that a treatment is working, though it is not a guarantee for any one person.
What are immune-related side effects, and why can some be permanent?
Immunotherapy works by taking the brakes off the immune system — but a freed-up immune system can sometimes attack healthy organs as well as the cancer. These “immune-related” side effects most often involve the thyroid, skin, adrenal and pituitary glands, bowel, liver, or lungs. Many are mild and reversible, but some — particularly to hormone-producing glands like the thyroid or adrenal glands — can be permanent, meaning a person may need to take replacement hormones for life. This is why these effects are watched for closely and why it is important to report new symptoms promptly, since early treatment (often with steroids) can limit the damage.
The bottom line
For early-stage triple-negative breast cancer, adding pembrolizumab to chemotherapy before surgery — and continuing it afterward — cleared more tumors completely (64.8% vs 51.2%), reduced the risk of the cancer returning (about 35% lower risk; 81.2% vs 72.2% cancer-free at 5 years), and — with longer follow-up — helped patients live longer (86.6% vs 81.7% alive at 5 years). The benefit held regardless of PD-L1 status. The cost is a higher rate of immune-related side effects, some of which can be permanent. This regimen is now a standard of care for stage II–III triple-negative breast cancer.
What this could mean for you
- It applies broadly. Because the benefit did not depend on PD-L1 status, this treatment is generally offered to people with stage II–III triple-negative breast cancer without needing a PD-L1 test first.
- Timing is part of the strategy. The immunotherapy is given both before and after surgery. Giving it while the tumor is still present may help the immune system build a stronger response.
- Know the side effects. Immune-related effects can involve the thyroid, adrenal glands, skin, bowel, and other organs — and some are lasting. Report new symptoms (unusual fatigue, rashes, diarrhea, breathlessness) to your team promptly.
- A complete response is encouraging but not the whole story. Even some patients without a complete response at surgery benefit, and the after-surgery phase contributes too.
- It helps people live longer. With longer follow-up, the regimen significantly improved overall survival — not just the chance of staying cancer-free.
Questions & comments
Have a question about this trial? Ask below. Questions are read and answered by the site. We can’t give personal medical advice, but we’re glad to explain the research more clearly.