Adding the immunotherapy medicine Keytruda (chemical name: pembrolizumab) to chemotherapy improved overall survival more than chemotherapy alone in people diagnosed with metastatic triple-negative, strongly PD-L1-positive breast cancer, according to the KEYNOTE-355 study’s final results.
The research was presented on Sept. 19, 2021, at the European Society for Medical Oncology (ESMO) Congress 2021. Read the abstract of “KEYNOTE-355: Final results from a randomized, double-blind phase III study of first-line pembrolizumab + chemotherapy vs placebo + chemotherapy for metastatic TNBC.”
Hope Rugo, M.D., professor of medicine in the Division of Hematology and Oncology at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, presented the research. Dr. Rugo is also a member of the Breastcancer.org Professional Advisory Board. She recently joined the Breastcancer.org Podcast to discuss the KEYNOTE-355 study.
Metastatic breast cancer is cancer that has spread to parts of the body away from the breast, such as the bones, liver, or brain.
About triple-negative breast cancer
Triple-negative breast cancer is:
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 medicines that target the HER2 protein.
Keytruda is a type of immunotherapy medicine known as an immune checkpoint inhibitor. To start an immune 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) and “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 the 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 shields 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 cells identify the cell. If the surface proteins signal that the cell is normal and healthy, the T cells leave it alone. If the surface proteins suggest the cell is cancerous or unhealthy in another way, the T cells start to attack 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 surfaces, which stops T cells from killing these cells. These types of cancers are considered PD-L1-positive. Keytruda stops PD-1 from binding to PD-L1 and allows T cells to attack the cancer cells.
In 2020, the U.S. Food and Drug Administration (FDA) approved the combination of Keytruda and chemotherapy to treat unresectable locally advanced or metastatic triple-negative, PD-L1-positive 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. Unresectable means the cancer can’t be removed with surgery.
The FDA based its approval on earlier results from the KEYNOTE-355 trial, which showed that a combination of Keytruda and chemotherapy offered better progression-free survival than chemotherapy alone as the first treatment for PD-L1-positive, metastatic or unresectable locally advanced triple-negative breast cancer.
Progression-free survival is how long people live without the cancer growing.
These latest results from the KEYNOTE-355 study presented overall survival data.
“In a disease like this, overall survival is a critical endpoint,” Dr. Rugo told Breastcancer.org. “We always call it the gold standard. It is really important for us to see overall survival, if we can.”
About the KEYNOTE-355 study
The KEYNOTE-355 study included 847 people diagnosed with either:
- metastatic triple-negative breast cancer that had not been treated with chemotherapy yet
- triple-negative breast cancer that had come back in the breast area and could not be removed with surgery; these people had been considered disease-free for at least 6 months after treatment for the initial breast cancer
The researchers looked at whether the cancers had the PD-L1 protein on the surfaces of their cells, as well as how much PD-L1 was on the cells’ surface. Cancers that scored 10 or higher on the PD-L1 test were considered to have high levels of PD-L1. Cancers that scored 1 or higher were considered PD-L1-positive.
The people were randomly assigned to two treatment regimens:
- 566 people received Keytruda every 3 weeks plus the researchers’ choice of one of three chemotherapy regimens: Abraxane (chemical name: albumin-bound or nab-paclitaxel), Taxol (chemical name: paclitaxel), or Gemzar (chemical name: gemcitabine)/carboplatin
- 281 people received a placebo (an injection that was just like Keytruda, but contained no medicine) plus the researchers’ choice of Abraxane, Taxol, or Gemzar/carboplatin
The researchers followed half the people for about 44 months and followed half for shorter periods of time.
The results showed that adding Keytruda to chemotherapy improved overall survival by almost 7 months and reduced the risk of dying from breast cancer by 27% in people with cancers that scored 10 or higher on the PD-L1 test.
About 75% of the cancers scored 1 or higher on the PD-L1 test, and about 39% of the cancers had a score of 10 or higher on the test.
Overall survival was:
- 23 months for people with cancers scoring 10 or higher on the PD-L1 test who received Keytruda and chemotherapy
- 16.1 months for people with cancers scoring 10 or higher on the PD-L1 test who received chemotherapy alone
- 17.6 months for people with cancers scoring 1 or higher on the PD-L1 test who received Keytruda and chemotherapy
- 16.0 months for people with cancers scoring 1 or higher on the PD-L1 test who received chemotherapy alone
- 17.2 months for all the people in the study who received Keytruda and chemotherapy
- 15.5 months for all the people in the study who received chemotherapy alone
The difference in overall survival between people with cancers scoring 10 or higher on the PD-L1 test who received Keytruda and chemotherapy and people who received chemotherapy alone was statistically significant, which means that it was likely because of the difference in treatment and not just due to chance.
“These results support pembrolizumab/chemotherapy as a new standard-of-care treatment regimen for patients with locally recurrent unresectable or metastatic [triple-negative breast cancer] whose tumors express PD-L1 with a [PD-L1 test score of 10 or higher],” Dr. Rugo said during her presentation.
Rates of side effects were similar between the two treatment groups. Of all the people who had at least one treatment-related side effect:
- 96.3% of the people received Keytruda and chemotherapy
- 95.0% of the people received chemotherapy alone
Rates of serious side effects — grade 3 to 5 — were:
- 68.1% in people who received Keytruda and chemotherapy
- 66.9% in people who received chemotherapy alone
Two people who received Keytruda and chemotherapy died from a treatment-related side effect. No people who received chemotherapy alone died from a treatment-related side effect.
The most common side effects were:
- anemia (low red blood cell counts)
- low white blood cell counts
- hair loss
Overall, because of side effects:
- 18.3% of people receiving Keytruda and chemotherapy stopped treatment
- 11.0% of people receiving chemotherapy alone stopped treatment
Because Keytruda is an immunotherapy medicine, the researchers looked specifically at side effects that affected the immune system. Of all the people who had an immune-related side effect:
- 26.5% of people received Keytruda and chemotherapy
- 6.4% of people received chemotherapy alone
About 5% of people who received Keytruda and chemotherapy had a grade 3 to 5 immune-related side effect, but no one died from an immune-related side effect.
“Safety was consistent with the known profiles of each regimen,” Dr. Rugo said. “There were no new safety concerns.”
What this means for you
If you’ve been diagnosed with metastatic triple-negative, strongly PD-L1 positive breast cancer, these latest results from the KEYNOTE-355 study are very reassuring.
After 44 months of follow-up time, Keytruda continues to offer benefits, including significantly improving overall survival.
Learn more about Keytruda.
To talk with others about this study and immunotherapy, join the Breastcancer.org Discussion Board forum Immunotherapy - Before, During, and After.
Written by: Jamie DePolo, senior editor
Reviewed by: Brian Wojciechowski, MD, medical adviser
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