Update: Pembrolizumab receives FDA approval for people with early-stage, triple-negative breast cancer

IN-DEPTH REVIEW OF RESEARCH

Study background

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

Study design

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.

Study findings

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

Strengths

• 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.

Limitations

• 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. 

Context

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.

Conclusions

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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posted 9/2/21