Immunotherapy for Early-Stage Triple-Negative Breast Cancer: Understanding What Appear to Be Conflicting Results

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Results from two studies on using the immunotherapy medicines Tecentriq (chemical name: atezolizumab) or Keytruda (chemical name: pembrolizumab) along with chemotherapy to treat early-stage triple-negative breast cancer before surgery suggested that Keytruda offered benefits while Tecentriq did not.

The researchers who did the studies pointed out that the trials were very different, and the results were preliminary in one case, so they may offer different results when more data are available.

The studies were presented on Dec. 12, 2019, at the 2019 San Antonio Breast Cancer Symposium. Read the abstracts of:

About Tecentriq and Keytruda

Both Tecentriq and Keytruda are immunotherapies known as immune checkpoint inhibitors.

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.

Immune checkpoint inhibitors target 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.

PD-1 is a type of checkpoint protein found 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 cancer cells. An immune checkpoint inhibitor medicine that stops PD-1 from binding to PD-L1 allows T cells to attack the cancer cells.

Tecentriq is a PD-L1 inhibitor approved by the U.S. Food and Drug Administration to be used in combination with the chemotherapy medicine Abraxane (chemical name: albumin-bound or nab-paclitaxel) as a first treatment for unresectable locally advanced or metastatic triple-negative, PD-L1-positive breast cancer.

Keytruda blocks the PD-1 pathway. It is used to treat advanced-stage skin cancer, certain types of non-small cell lung cancer, advanced-stage head and neck squamous cell cancer, Hodgkin lymphoma, advanced-stage urothelial cancer, and advanced-stage cancers with microsatellite instability-high or mismatch repair deficient, a specific type of genetic marker.

About triple-negative breast cancer

Triple-negative breast cancer is:

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

So the growth of triple-negative disease isn’t driven by the hormones estrogen or progesterone or by the presence of too many HER2 receptors. This means that triple-negative breast cancer doesn’t respond to hormonal therapy (such as tamoxifen or an aromatase inhibitor), or therapies that target HER2 receptors, 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 10% to 20% of breast cancers — more than one out of every 10 — are triple-negative. Triple-negative breast cancer tends to be more aggressive than other types of breast cancer.

Triple-negative breast cancer usually is treated with a combination of surgery, radiation therapy, and chemotherapy. Researchers are constantly working to find new medicines to treat triple-negative breast cancer.

About the studies

KEYNOTE-522

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

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,” or pCR.

The KEYNOTE-522 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.

KEYNOTE-522 results presented at the European Society for Medical Oncology 2019 Congress in September showed that adding Keytruda to chemotherapy before surgery led to a better pathologic complete response in women diagnosed with early-stage triple-negative breast cancer, no matter if the cancer was PD-L1-positive or PD-L1-negative.

At the 2019 San Antonio Breast Cancer Symposium, Peter Schmid, M.D. of the Barts Cancer Institute at Queen Mary University of London presented updated KEYNOTE-522 results showing that adding Keytruda to chemotherapy before surgery led to better pathologic complete response rates in women diagnosed with early-stage triple-negative breast cancer that had spread to the lymph nodes, as well as better pathologic complete response rates in cancers that were stage III. Similar to the results presented in September, it didn’t matter if the cancers were PD-L1-positive or PD-L1-negative.

“Our results suggest that adding pembrolizumab to neoadjuvant chemotherapy is beneficial for patients with the most aggressive disease and the highest unmet need,” said Schmid. “I think the results have the potential to be practice-changing.”

Watch this video to hear Dr. Schmid discuss the results of the KEYNOTE-522 study:

NeoTRIPaPDL1

The NeoTRIPaPDL1 trial wants to see if adding Tecentriq to chemotherapy before surgery for early-stage, triple-negative breast cancer with a high risk of recurrence can improve the length of time the women lived without the cancer coming back.

The length of time a person lives without the cancer coming back is called event-free survival.

The NeoTRIPaPDL1 study included 280 women diagnosed with early-stage triple-negative breast cancer with a high risk of recurrence or locally advanced triple-negative breast cancer. Locally advanced breast cancer is breast cancer that has spread to tissue near the breast, but not to parts of the body away from the breast.

The women were randomly assigned to receive one of two treatments before surgery:

  • one group was treated with chemotherapy and Tecentriq (138 women)
  • one group was treated with chemotherapy and a placebo infusion that looked just liked Tecentriq (142 women)

The chemotherapy regimen for both groups was:

  • eight cycles of carboplatin plus Abraxane

The Tecentriq dose was 1,200 mg infused every 3 weeks for eight cycles.

After the women had breast cancer surgery, they were treated with four cycles of Adriamycin or Ellence plus Cytoxan.

Also at the 2019 San Antonio Breast Cancer Symposium, Luca Gianni, M.D., president of Fondazione Michelangelo in Milan, presented NeoTRIPaPDL1 study results, showing that adding Tecentriq to chemotherapy before surgery led to slightly higher pathologic complete response rates in women diagnosed with early-stage triple-negative breast cancer, but the increase wasn’t statistically significant, which means that it could have happened by chance rather than because of the addition of Tecentriq.

When the researchers looked at pathologic complete response rates in cancers that were PD-L1-positive compared to cancers that were PD-L1-negative, they found that PD-L1-positive cancers were more likely to have a better pathologic complete response.

Gianni was quick to point out that pathologic complete response was not the primary goal of the study. Event-free survival was.

“Our observations may indicate that there is no therapeutic benefit to adding atezolizumab to neoadjuvant chemotherapy compared to chemotherapy alone, or it may simply mean that any beneficial effects of the combination will be seen in the long term,” said Gianni. “Pathologic complete response does not provide information about the quality of response, which is why we did not use it as the primary endpoint for this study. Further analyses may reveal differences in the quality of response between the treatment groups.”

Listen to a Breastcancer.org podcast with Luca Gianni about the NeoTRIPaPDL1 study.

Understanding the results

Initially, it may seem that the two studies have conflicting results. So it’s important to look at the differences in the studies to understand the differences in results.

  • The KEYNOTE-522 study is looking at pathologic complete response. This can be measured immediately after surgery. The NeoTRIPaPDL1 study is looking at event-free survival. The women in the study must be followed for several years to see if the cancer comes back. While these early NeoTRIPaPDL1 study results found Tecentriq made no difference in pathologic complete response, that doesn’t mean that Tecentriq won’t affect the length of event-free survival.
  • The KEYNOTE-522 study combined Keytruda with a chemotherapy regimen that included Adriamycin or Ellence before surgery. Both Adriamycin and Ellence are anthracyclines. The NeoTRIPaPDL1 study combined Tecentriq with a chemotherapy regimen that did not include an anthracycline before surgery. It has been suggested that anthracycline chemotherapy may enhance the effects of immunotherapy medicines, which may have affected the outcomes of the studies.
  • While Tecentriq and Keytruda are both immunotherapy medicines, Tecentriq is a PD-L1 inhibitor and Keytruda blocks the PD-L1 pathway. So the two medicines act in slightly different ways in the body. This may have affected the outcomes of the studies.

Side effects

In the KEYNOTE-522 study, 78% of the women treated with Keytruda and chemotherapy had grade 3 or higher side effects compared to 73% of the women treated with chemotherapy alone. 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.

In the NeoTRIPaPDL1 study, side effects that could be linked to immunotherapy happened in 21.8% of women treated with Tecentriq and 7.1% of women treated with the placebo.

Gianni said, overall, the rates of specific side effects were similar in both treatment groups, except for a higher rate of liver function problems in the women treated with Tecentriq.

The most common side effects in the NeoTRIPaPDL1 study were:

  • low white blood cell counts
  • nausea
  • fatigue
  • anemia
  • peripheral neuropathy
  • vomiting

What this means for you

While the results of the KEYNOTE-522 study seem promising and the results of the NeoTRIPaPDL1 study seem disappointing, it’s important to know that the follow-up time for these studies so far is very short — only about a year. Longer follow-up time will offer more information on how long cancers respond to Keytruda, as well as event-free survival rates in the Tecentriq study. It also will be important to know if either medicine 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 these studies. 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 or Tecentriq. You also may want to ask about other trials looking at these medicines 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 Breastcancer.org Immunotherapy pages.

To talk with others about these studies and immunotherapy, join the Breastcancer.org Discussion Board forum Immunotherapy - Before, During, and After.

Written by: Jamie DePolo, senior editor


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