Update: Pembrolizumab receives FDA approval for people with early-stage, triple-negative breast cancer
|Update at a glance||Clinical trials|
|Keynote-522 Study findings||Guidelines|
|Strengths and limitations||Questions for your doctor|
|What does this mean for me?||Resources|
UPDATE AT A GLANCE
What is this update about?
The FDA approved pembrolizumab (Keytruda) for treatment of early-stage triple-negative breast cancer (TNBC) that has a high risk for recurrence.
Why is this update important?
TNBC is an aggressive type of breast cancer with limited treatment options. In the U.S., TNBC is more common in younger women and in Black women. People with BRCA1 mutations are more likely to develop TNBC than any other type of breast cancer.
TNBC is difficult to treat, and it is almost always treated with chemotherapy and surgery. Although treatment is aggressive, TNBC has a high recurrence rate within the first five years after diagnosis. Even when TNBC is diagnosed early, it returns in 30 to 40 percent of patients. Thus, there is a great need for new treatment options for patients with TNBC.
Keytruda is a type of immunotherapy called a checkpoint inhibitor. Checkpoint inhibitors are drugs that prevent cancer cells from switching off immune cells. These drugs allow the immune system to find, unmask and destroy cancer cells. Checkpoint inhibitors are approved to treat several cancers, including skin, lung, blood, colon and endometrial cancers. They are also approved to be used with chemotherapy to treat TNBC that is metastatic, locally recurrent and unresectable (cannot be removed by surgery).
Keytruda is the first immunotherapy approved for the treatment of early-stage TNBC. It can now be used before surgery at the same time as chemotherapy. Following surgery, Keytruda is given alone.
The Keynote-522 study looked at the use of Keytruda with chemotherapy before surgery (neoadjuvant therapy) followed by Keytruda alone after surgery (adjuvant therapy). The study enrolled 1,174 patients with newly diagnosed, previously untreated, high-risk, early-stage TNBC. Patients were enrolled whether or not their tumor had the PD-L1 biomarker.
Patients were assigned to one of two groups:
- Keytruda plus chemotherapy
- Placebo (sugar pill) plus chemotherapy
The study looked at two outcomes:
- The absence of cancer, which is called a pathological complete response (pCR), at the time of surgery.
- 63% of patients who received Keytruda with chemotherapy had no cancer at the time of surgery compared to 56% of patients who received chemotherapy alone.
- The time after treatment that cancer does not come back or worsen, which is called event-free survival (EFS).
- The number of patients who experienced an EFS was 16% percent for patients who received Keytruda plus chemotherapy and 24% percent for patients who received chemotherapy alone.
Keytruda is given intravenously (IV) every three to six weeks depending on the dose. More than 20 percent of patients in this study reported side effects. Reported side effects included fatigue, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, difficult breathing, fever, hair loss, nerve pain, inflammation, headache, abdominal pain, joint and muscle pain, weight loss and insomnia.
The approval of Keytruda may potentially change standard treatment for early-stage TNBC.
- This is a large, randomized, double-blind placebo-controlled study.
- A key strength of this trial is that the patients who received Keytruda plus chemotherapy were compared to the patients who received a placebo plus chemotherapy.
- This allows for the direct comparison of the Keytruda—chemotherapy combination with chemotherapy alone.
- This study looked only at women with breast cancer. It is not known how well it will work for men with early-stage TNBC.
- Most participants were white (64%) or Asian (20%). It is not clear whether these results would be relevant for people of other races, e.g., Black or American Indian.
- This study has not yet reported on the inherited mutation status of participants. At the moment there is no reason to believe that Keytruda would work differently in patients with inherited mutations.
- If you are have been diagnosed with early-stage TNBC, you may be eligible for treatment with Keytruda.
- If you have been diagnosed with early-stage TNBC you may want to consider talking to a genetic counselor; TNBC is more common in people with an inherited mutation in BRCA1.
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- Schmid P, Cortes J, Dent R, et al: KEYNOTE-522: Phase 3 study of neoadjuvant pembrolizumab plus chemotherapy versus placebo plus chemotherapy, followed by adjuvant pembrolizumab versus placebo for early-stage triple-negative breast cancer. ESMO Virtual Plenary. Abstract VP7-2021. Presented July 15, 2021.
- Schmid P, Cortes J, Pusztai L, et al: Pembrolizumab for early triple-negative breast cancer. New England Journal of Medicine 2020; 382: 810-821.
FORCE receives funding from industry sponsors, including companies that manufacture cancer drugs, tests and devices. All XRAYS articles are written independently of any sponsor and are reviewed by members of our Scientific Advisory Board prior to publication to assure scientific integrity.
This article is relevant for:
People with early-stage, triple-negative breast cancer who have a high risk for recurrence
This article is also relevant for:
People with breast cancer
People newly diagnosed with cancer
People with triple negative breast cancer
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The National Comprehensive Cancer Network (NCCN) has guidelines for treatment of early-stage TNBC, which includes the following.
- Genetic testing:
- All people diagnosed with TNBC at any age meet guidelines for genetic counseling and testing.
- Treatment for TNBC
- For small tumors (≤ 0.5 cm) with no positive lymph nodes, adjuvant chemotherapy is not generally recommended.
- For small tumors (< 0.5 cm) with 1 positive lymph node or tumors between 0.6 and 1.0 cm, consider adjuvant chemotherapy.
- For tumors that are > 1.0 cm, adjuvant chemotherapy is recommended.
- For stage 2 or stage 3 TNBC in people who are at high risk for recurrence, the panel recommends neoadjuvant pembrolizumab in combination with chemotherapy followed by adjuvant pembrolizumab.
- For people with an inherited BRCA1 or BRCA2 mutation who are at high risk for recurrence, consider adjuvant olaparib for one year after chemotherapy is completed.
- Is Keytruda a treatment option for my type of breast cancer?
- If Keytruda is not an option for me now, might it be an option in the future?
- What side effects might I experience with this treatment?
- If I have serious side effects, will I need to stop treatment?
- Are any other drugs available to treat my cancer?
- Should my tumor be genetically tested to see if there are other treatments my cancer may respond to?
The following are studies enrolling people with early-stage, TNBC.
- NCT03498716: A Study Comparing Atezolizumab (Anti PD-L1 Antibody) In Combination With Adjuvant Anthracycline/Taxane-Based Chemotherapy Versus Chemotherapy Alone In Patients With Operable Triple-Negative Breast Cancer. This study will evaluate the efficacy, safety, and pharmacokinetics of adjuvant atezolizumab (an immunotherapy) in combination with chemotherapy in patients with Stage II-III TNBC (Triple Negative Breast Cancer).
- NCT04584255: Treating Early-Stage BRCA, or PALB2-Associated Breast Cancer with a PARP Inhibitor (Niraparib) and Immunotherapy (Dostarlimab). This research study involves pre-operative therapy that is specifically targeted for breast cancer in individuals with BRCA mutations.
- NCT04674306: Adjuvant Therapy With an Alpha-lactalbumin Vaccine in Triple-Negative Breast Cancer. The purpose of this study is to determine the safety as well as the most effective dose of the alpha-lactalbumin vaccine (aLA breast cancer vaccine) to treat patients with non-metastatic triple negative breast cancer.
- NCT03872388: Atorvastatin in Treating Patients With Stage IIb-III Triple Negative Breast Cancer Who Did Not Achieve a Pathologic Complete Response After Receiving Neoadjuvant Chemotherapy. This phase II trial studies how well atorvastatin works in treating patients with stages IIb-III triple negative breast cancer who did not achieve a pathologic complete response to neoadjuvant chemotherapy. Atorvastatin is used for the treatment of high cholesterol and may reduce the risk of triple negative breast cancer from coming back.
- NCT03562637: Study of Adagloxad Simolenin (OBI-822)/OBI-821 in the Adjuvant Treatment of Patients With Globo H Positive TNBC. The GLORIA study is a Phase III, randomized trial looking at the use of the drug adagloxad simolenin (OBI-822) in combination with the drug OBI-821 in the adjuvant treatment of patients with high-risk early-stage TNBC.
A number of other clinical trials for patients with early-stage TNBC can be found here.
Who covered this study?
FDA approves Keytruda for high-risk, early-stage triple-negative breast cancer This article rates 3.0 out of 5 stars
FDA Approves Neoadjuvant Pembrolizumab Combination for Early TNBC Indication This article rates 3.0 out of 5 stars
Clinical Oncology News
Keytruda Approved to Treat High-Risk, Early-Stage TNBC This article rates 3.0 out of 5 stars
IN-DEPTH REVIEW OF RESEARCH
Immunotherapies are cancer treatments that use the immune system to attack and remove cancer cells. Immunotherapies may be given in combination with another cancer treatment or used alone. Some immunotherapies are also targeted therapies because they use antibodies to target abnormal proteins or receptors that are found in high quantities in cancer cells or the surrounding tissue.
Several types of cancer immunotherapies are used to treat cancer, including immune checkpoint inhibitors, monoclonal antibodies, non-specific immunotherapies and cancer vaccines.
Keytruda (pembrolizumab) is an immune checkpoint inhibitor. Immune checkpoint inhibitors are drugs that prevent cancer cells from switching off immune cells. This allows the immune system to find and destroy cancer cells.
PD-L1 is a protein found on some normal cells and some cancer cells. PD-1 is a different protein on immune cells. When it binds to PD-L1, it normally helps to keep immune cells from attacking other cells in the body. The binding of these two proteins tells immune cells to leave other cells alone. Some cancer cells have large amounts of PD-L1, which helps them hide from an immune attack.
Drugs that target either PD-1 or PD-L1 can block this binding and boost the immune response against cancer cells. These drugs work by revealing cancer cells to the body’s own immune response. Ideally, immune cells then recognize cancer cells as foreign and can then destroy them.
Checkpoint inhibitors have shown a great deal of promise in treating certain cancers. One of these is Keytruda, which works by targeting PD-L1.
Researchers of this study wanted to know
Researchers wanted to know if Keytruda when taken as neoadjuvant therapy (before surgery) and continued alone after surgery (adjuvant therapy) increased pathological complete response and event-free survival in patients with early-stage triple-negative breast cancer (TNBC) that is at high risk for recurrence.
Populations looked at in this study
The Keynote-522 trial included 1,174 patients with newly diagnosed, untreated, high-risk early-stage TNBC. Patients with active autoimmune disease or a medical condition that required immune suppression were not eligible to participate. Patients were enrolled in the study whether or not their tumor expressed PD-L1.
The study participants were:
- median age 49 (ranging from 22 to 80)
- 99% female
- 64% white
- 20% Asian
- 4.5% Black
- 1.8% American Indian or Alaska Native
- 56% were premenopausal
- 44% were postmenopausal
Participants were randomized (2:1) to one of two treatment arms:
- Arm 1 consisted of 784 patients who received Keytruda (200mg) every three weeks plus chemotherapy (carboplatin and paclitaxel) for four cycles. This was followed by four additional cycles of Keytruda every three weeks plus chemotherapy (doxorubicin or epirubicin plus cyclophosphamide). After surgery, patients received nine cycles of Keytruda every three weeks.
- Arm 2 consisted of 390 patients who received a placebo every three weeks for four cycles. Patients also received chemotherapy (carboplatin and paclitaxel). This was followed by four additional cycles of placebo plus chemotherapy (doxorubicin or epirubicin plus cyclophosphamide). Following surgery, patients received nine cycles of placebo every three weeks.
Researchers observed two primary endpoints. Pathological complete response (pCR), which was defined as the absence of invasive cancer in the breast and lymph nodes at the time of surgery. Event-free survival (EFS), which was defined as the period when participants were assigned to a treatment group to the first disease progression, local or distant recurrence, another primary breast cancer or death due to any cause.
Of the 784 patients treated with Keytruda:
- 494 (63%) had a pCR.
- 123 (16%) an EFS.
Of the 390 patients treated with placebo:
- 217 (56%) had a pCR.
- 93 (24%) had an EFS.
In this study, fatal adverse reactions occurred in under one percent of patients receiving Keytruda (the average time on Keytruda was 13 months). Serious adverse side effects occurred in 44 percent of patients. Keytruda was discontinued in 20 percent of patients due to adverse reactions.
Strengths and Limitations
- This is a large, randomized, double-blind placebo-controlled study.
- A key strength of this trial is the control group of patients who received chemotherapy but not Keytruda. This allows for the direct comparison of the Keytruda–chemotherapy combination with chemotherapy alone.
- This study looked only at women with breast cancer. It is not known how well the addition of Keytruda may benefit men with early-stage TNBC.
- Most (64%) participants were white. It is not clear whether these results would be relevant for people of other races.
Unlike traditional cancer treatments such as radiation therapy and chemotherapy, immunotherapy is a novel treatment that helps the immune system attack cancer cells. In studies of different types of cancer, immunotherapy has been found to have advantages over traditional therapy and for certain cancers can prolong progression-free survival (PFS) and overall survival (OS). However, because it revs up the immune system, immunotherapy may also cause severe adverse reactions. Researchers are continuing to work on identifying the best targets for different immunotherapies, improving treatment regimens and reducing toxic side effects.
The cost of immunotherapy can be substantial. Merck, the company that manufactures Keytruda, provides multiple programs that help appropriate patients access this immunotherapy. For more information visit www.merckaccessprogram-keytruda.com.
FDA approval of Keytruda to treat early-stage TNBC that has a high risk for recurrence has led to a change in guidelines for how early-stage TNBC is treated. The inclusion of immunotherapy is a significant addition to treatment options for patients with TNBC.
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