Atezolizumab, known by its brand name Tecentriq, is an immunotherapy drug that works with a person’s immune system to fight cancer. It belongs to a class of drugs known as immune checkpoint inhibitors. This treatment enhances the body’s natural defenses to target and destroy cancerous cells and has been used for several types of cancer.
Mechanism of Action
The immune system has checkpoints, which are molecules on immune cells that regulate an immune response. Cancer cells can exploit these checkpoints to avoid being attacked. One such checkpoint involves the interaction between programmed death-ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1).
Many cancer cells have high amounts of the PD-L1 protein on their surface. When PD-L1 binds to the PD-1 receptor on a T-cell, an immune cell that fights disease, it signals the T-cell not to attack. This interaction acts as a “brake” on the immune response, allowing the tumor to hide from the body’s defenses.
Atezolizumab is a monoclonal antibody that targets and attaches to the PD-L1 protein. By binding to PD-L1, the drug blocks it from interacting with the PD-1 receptor on T-cells. This action releases the “brake” on the immune system, allowing T-cells to recognize and attack cancer cells and restoring the immune system’s ability to destroy the tumor.
Use in Triple-Negative Breast Cancer
Atezolizumab was investigated for triple-negative breast cancer (TNBC), a subtype defined by the absence of estrogen, progesterone, and HER2 receptors. The lack of these receptors means common targeted therapies are ineffective, making TNBC challenging to treat. Its use was specified for patients whose TNBC tumors also tested positive for the PD-L1 protein.
The presence of PD-L1 on tumor-infiltrating immune cells served as a biomarker to identify individuals who might benefit, as it suggested the cancer was using this pathway to suppress the immune system. To determine if a patient was a candidate, biomarker testing was performed on a sample of the tumor tissue.
The test, an immunohistochemical (IHC) assay, measured the percentage of the tumor area covered by PD-L1-staining immune cells. A result showing that 1% or more of these cells expressed PD-L1 was required for a patient to be considered for treatment.
Treatment Administration
Atezolizumab is administered through an intravenous (IV) infusion. The initial infusion is given over 60 minutes, and if well-tolerated, subsequent infusions may be administered over 30 minutes. For triple-negative breast cancer, atezolizumab was used in combination with a chemotherapy drug called nab-paclitaxel (Abraxane).
The schedule was designed to pair the immune-stimulating effects of atezolizumab with the cancer-cell-killing action of chemotherapy. A standard treatment cycle lasted 28 days, where atezolizumab was given on days 1 and 15, and nab-paclitaxel was given on days 1, 8, and 15. This regimen continued until the disease progressed or the patient experienced unacceptable toxicity.
Managing Side Effects
The side effects of atezolizumab are distinct from traditional chemotherapy because they stem from its immune-activating mechanism. By activating the immune system, the treatment can cause the body to attack healthy cells, leading to immune-related adverse events. These events can range from mild to severe and affect various parts of the body.
Common side effects include fatigue, nausea, decreased appetite, and skin rash. Patients should communicate any new or worsening symptoms to their medical team promptly.
Less frequently, significant inflammation in organs can occur, such as pneumonitis (lungs), colitis (colon), and hepatitis (liver). Symptoms like diarrhea, severe abdominal pain, or shortness of breath should be reported immediately, as they may signal a serious reaction that requires medical intervention, such as using corticosteroids to suppress the immune response.
Efficacy and Regulatory Status
The evaluation of atezolizumab for TNBC came from the IMpassion130 clinical trial. For patients with metastatic, PD-L1 positive TNBC, the combination of atezolizumab and nab-paclitaxel extended progression-free survival compared to nab-paclitaxel alone. Based on these results, the U.S. Food and Drug Administration (FDA) granted an accelerated approval for this indication in March 2019.
Accelerated approvals are conditional and require subsequent trials to confirm a drug’s benefit. The confirmatory trial, IMpassion131, failed to show a statistically significant improvement in progression-free survival for patients receiving atezolizumab plus a different paclitaxel formulation.
As a result, the manufacturer voluntarily withdrew the breast cancer indication for atezolizumab in the United States in August 2021. This withdrawal means the drug is no longer approved for treating TNBC in the U.S., though it remains approved for other cancers. The drug’s regulatory status for breast cancer may differ in other countries, as its approval in Europe was not affected by the U.S. decision.