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Adding Keytruda to Chemotherapy Before Surgery for Early-Stage, Triple-Negative Breast Cancer Improves Response to Treatment

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The combination of the immunotherapy Keytruda (chemical name: pembrolizumab) and chemotherapy before surgery to remove early-stage, triple-negative breast cancer led to a better pathologic complete response than chemotherapy alone, according to results from the KEYNOTE-522 study.

Treatment given to weaken and destroy breast cancer before surgery is called neoadjuvant treatment. One way for doctors to judge the effectiveness of neoadjuvant treatment is to look at the tissue removed during surgery to see if any active cancer cells are present. If no active cancer cells are present, doctors call it a “pathologic complete response.”

The research was presented at the European Society for Medical Oncology (ESMO) 2019 Congress in Barcelona, Spain, on Sept. 29, 2019. Read the media release about and abstract of "KEYNOTE-522: Phase 3 study of pembrolizumab (pembro) + chemotherapy (chemo) vs placebo (pbo) + chemo as neoadjuvant treatment, followed by pembro vs pbo as adjuvant treatment for early triple-negative breast cancer (TNBC)."

Listen to a podcast episode about the KEYNOTE-522 study with lead author Peter Schmid, M.D., Ph.D., of the Barts Cancer institute at Queen Mary University of London.

About triple-negative breast cancer

Triple-negative breast cancer is breast cancer that is:

  • estrogen-receptor-negative
  • progesterone-receptor-negative
  • HER2-negative

Triple-negative breast cancers are usually more aggressive, harder to treat, and more likely to come back (recur) than cancers that are hormone-receptor-positive or HER2-positive. Triple-negative breast cancers don't usually respond to hormonal therapy medicines or the medicines that target the HER2 protein, such as Herceptin (chemical name: trastuzumab), Kadcyla (chemical name: T-DM1 or ado-trastuzumab emtansine), Nerlynx (chemical name: neratinib), Tykerb (chemical name: lapatinib), or Perjeta (chemical name: pertuzumab).

About Keytruda

Keytruda (chemical name: pembrolizumab) is a type of immunotherapy known as an immune checkpoint inhibitor. To start an immune system response to a foreign invader, the immune system has to be able to tell the difference between cells or substances that are “self” (part of you) vs. “non-self” (not part of you and possibly harmful). Your body’s cells have proteins on their surfaces or inside them that help the immune system recognize them as “self.”

Some of these proteins that help your immune system recognize “self” cells are called immune checkpoints. Cancer cells sometimes find ways to use these immune checkpoint proteins as a shield to avoid being identified and attacked by the immune system.

Immune system cells called T cells roam throughout the body looking for signs of disease or infection. When T cells meet another cell, they analyze certain proteins on the cell’s surface, which helps the T cell identify the cell. If the surface proteins signal that the cell is normal and healthy, the T cell leaves it alone. If the surface proteins suggest the cell is cancerous or unhealthy in another way, the T cell starts an attack against it. Once T cells start an attack, the immune system begins to make more specialized proteins that prevent this attack from damaging normal cells and tissues in the body. These specialized proteins that keep healthy cells and tissues safe are called immune checkpoints.

Immune checkpoint inhibitors target these immune checkpoint proteins and help the immune system recognize and attack cancer cells. Immune checkpoint inhibitors essentially take the brakes off the immune system by blocking checkpoint inhibitor proteins on cancer cells or on the T cells that respond to them.

For example, PD-1 is a checkpoint protein on T cells. PD-L1 is another checkpoint protein found on many healthy cells in the body. When PD-1 binds to PD-L1, it stops T cells from killing a cell. Some cancer cells have a lot of PD-L1 on their surface, which stops T cells from killing these cells. Keytruda stops PD-1 from binding to PD-L1 and allows T cells to attack the cancer cells.

Keytruda is approved to treat a number of cancers, including advanced-stage skin cancer, certain types of non-small cell lung cancer, and Hodgkin lymphoma.

Keytruda is given as an injection in a doctor's office. For most of the cancers it is approved to treat, Keytruda is given every 3 weeks.

About the KEYNOTE-522 study

The KEYNOTE-522 study wanted to see if adding Keytruda to chemotherapy before surgery for early-stage, triple-negative breast cancer would improve pathologic complete response, as well as lengthen the amount of time women lived before having a recurrence.

The study included 1,174 women diagnosed with early-stage, triple-negative breast cancer. The women were randomly assigned in a 2:1 ratio to one of two treatments before surgery:

  • one group was treated with chemotherapy and Keytruda (784 women)
  • the other group was treated with chemotherapy and a placebo injection that looked just like Keytruda (390 women)

The chemotherapy regimen for both groups was:

  • four cycles of Taxol (chemical name: paclitaxel) plus carboplatin
  • followed by four cycles of Adriamycin (chemical name: doxorubicin) or Ellence (chemical name epirubicin) plus Cytoxan (chemical name: cyclophosphamide)

The Keytruda dose was 200 milligrams (mg) injected every 3 weeks.

After the women had breast cancer surgery, they were treated with nine cycles of either Keytruda or the placebo. If a woman had a breast cancer recurrence or developed unacceptable side effects, this post-surgery treatment was stopped.

Half the women were followed for longer than 15.5 months and half were followed for a shorter time.

Results from 602 women were included in this analysis.

Overall pathologic complete response was:

  • 64.8% for women treated with Keytruda and chemotherapy
  • 51.2% for women treated with chemotherapy alone

This difference was statistically significant, which means that it was likely due to the addition of Keytruda and not just because of chance.

The researchers also compared pathologic complete response rates between women diagnosed with breast cancer that was PD-L1-positive and breast cancer that was PD-L1-negative.

Pathologic complete response for PD-L1-positive cancers was:

  • 68.9% for women treated with Keytruda and chemotherapy
  • 54.9% for women treated with chemotherapy alone

Pathologic complete response for PD-L1-negative cancers was:

  • 45.3% for women treated with Keytruda and chemotherapy
  • 30.3% for women treated with chemotherapy alone

The researchers said that Keytruda also seemed to reduce the risk of recurrence.

"These are preliminary data, but they provide a strong sign that the addition of immune therapy to neoadjuvant chemotherapy prevents breast cancer recurrence," said Dr. Schmid. "If we prevent recurrence, we cure more patients, but we need longer-term data for confirmation."

What about side effects?

About three-quarters of the women in each treatment group experienced moderate to severe side effects:

  • 78.0% of women treated with Keytruda and chemotherapy had grade 3 or higher side effects
  • 73.0% of women treated with chemotherapy alone had grade 3 or higher side effects

In his presentation, Schmid said that many of the side effects were linked to the intensive chemotherapy regimen.

Side effects that could be linked to immunotherapy happened in 42% of the women treated with Keytruda and 21% of the women treated with the placebo.

"[Keytruda] added some side effects to chemotherapy but there were no new safety signals," Schmid said.

"Triple negative breast cancer accounts for 15% of breast cancers. It represents an unmet medical need, since the only approved medical therapy at early stages of the disease is chemotherapy," commented Fabrice Andre, M.D., Ph.D., of the Institut Gustave Roussy, Villejuif, France, who was not involved in the study. "This study could have a major impact on treatment for these patients."

What this means for you

While the results of the KEYNOTE-522 study are very exciting and promising, it’s important to know that the follow-up for the study was only about a year. Longer follow-up time will offer more information on how long the cancers respond to Keytruda and provide more mature data on how long women live without a recurrence. It also will be important to know if Keytruda improves overall survival, which is how long a person lives, whether or not the cancer comes back.

If you've been diagnosed with early-stage, triple-negative breast cancer and are deciding on treatments, you may want to talk to your doctor about this study. You also may want to ask if it’s possible to do PD-L1 testing on the cancer to see if you might benefit the most from a medicine like Keytruda. You also may want to ask about other trials looking at Keytruda and whether any of them might be a good fit for your unique situation.

For more information on immunotherapy medicines, how they work, and their possible side effects, visit the Immunotherapy pages.

To talk with others about this study and immunotherapy, join the Discussion Board forum Immunotherapy - Before, During, and After.

Editor’s Note: On Nov. 13, 2020, the U.S. Food and Drug Administration (FDA) approved Keytruda in combination with chemotherapy to treat unresectable locally advanced or metastatic triple-negative, PD-L1-positive breast cancer. On July 26, 2021, the FDA approved Keytruda in combination with chemotherapy before surgery, followed by Keytruda alone after surgery to treat early-stage triple-negative breast cancer with a high risk of recurrence (the cancer coming back).

Written by: Jamie DePolo, senior editor

Reviewed by: Brian Wojciechowski, M.D., medical adviser

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