Overview:
Atezolizumab is a monoclonal antibody targeting PD-L 1 (programmed death ligand 1) that is being developed for the treatment of hematologic malignancies and solid tumors. It has been approved by the FDA (U.S Food and Drug Administration) as second-line therapy for urothelial carcinoma and is awaiting approval for non-small cell lung cancer. In addition, it is also used to treat melanoma, small cell lung cancer, and hepatocellular carcinoma. The drug can be administered alone and combined with other drugs such as Bevacizumab, Cobimetinib, Vemurafenib, Paclitaxel, and Carboplatin for treating various malignancies.
How Does Atezolizumab Work?
Atezolizumab is a monoclonal antibody that gets attached to a protein called PD-L 1 (programmed death ligand 1) on cancer cells. It reduces the effects of this protein, increases the immune system’s ability to attack cancer cells, and retards disease progression.
Uses:
Atezolizumab is indicated for the following:
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First-line treatment for extensive-stage small cell lung cancer patients.
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Atezolizumab, combined with Bevacizumab, is indicated for treating patients with unresectable or metastatic hepatocellular carcinoma.
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Atezolizumab, combined with Cobimetinib and Vemurafenib, is indicated for treating patients with unresectable or metastatic melanoma.
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Treatment for locally advanced or metastatic urothelial cancer patients.
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Atezolizumab is a single agent for treating patients with metastatic non-small cell lung cancer.
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Atezolizumab, combined with Bevacizumab, Paclitaxel, and Carboplatin, is indicated for treating patients with metastatic non-squamous non-small cell lung cancer.
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Atezolizumab, combined with Paclitaxel protein-bound, and Carboplatin, is indicated for treating patients with metastatic non-squamous non-small cell lung cancer.
Dosage:
For small cell lung cancer, Atezolizumab 1200 mg intravenously on day 1. The drug is administered every second, third, and fourth week and continues until the disease progresses or has unacceptable toxicity.
For hepatocellular carcinoma, Atezolizumab 1200 mg intravenously with Bevacizumab 15 mg/kg intravenously on day 1. Repeat every three weeks until disease progression or unacceptable toxicity is experienced.
Warnings:
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Immune-Mediated Adverse Reactions - Immune-mediated adverse reactions can cause harm to the tissues or organ systems, such as immune-mediated pneumonitis, colitis, hepatitis, endocrine disorders, dermatologic reactions, nephritis, and solid organ transplant rejection. Hence, the organs' condition must be monitored closely during the administration of Atezolizumab. The drug is withheld or discontinued based on the severity of the adverse reactions.
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Infusion-Related Reactions - If patients show infusion-related reactions, the infusion of the drug is either interrupted, slowed down, or the drug is discontinued based on the severity of the reactions.
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Complications of Allogeneic HSCT (Hematopoietic Stem Cell Transplantation) - There are chances of serious fatal complications if the patient receives hematopoietic stem cell transplantation before and after administration of Atezolizumab.
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Embryo-Fetal Toxicity - Atezolizumab can cause harm to the fetus. Hence, women are advised to use contraceptives during the course of the treatment.
For Patients:-
What Do You Need to Know About Small Cell Lung Cancer?
Lung cancer is of two types. They are small cell lung cancer and non-small cell lung cancer. Small cell lung cancer is less common but can spread faster than the non-small cell type. If identified earlier, small cell lung cancer can be treated by radiation therapy, chemotherapy, and immunotherapy.
What Do You Need to Know About Hepatocellular Carcinoma?
Hepatocellular carcinoma is a primary liver cancer in individuals with chronic liver diseases like cirrhosis caused by hepatitis B or hepatitis C. The treatments for hepatocellular carcinoma may include liver transplant surgery, chemotherapy, radiation therapy, immunotherapy, and targeted drug therapy.
Learn More About Atezolizumab:-
Before Starting Atezolizumab: Before taking any medication (in this case, Atezolizumab), it is good to understand its risks and benefits. The drug can attack the normal organs and tissues of the body at times and can be life-threatening. The problems can take place during or after the treatment.
When and How Often to Take Atezolizumab?
Atezolizumab is administered intravenously for about 30 to 60 minutes every second, third, or fourth week. It can be administered only by the healthcare provider. The treatment may take around two years to complete. However, the healthcare professional will decide on the duration of the treatment.
How Effective Is Atezolizumab?
Atezolizumab is a part of immunotherapy drugs and has proven effective for many patients with cancers, extending their survival time and minimizing the worsening of the disease.
Things to Inform Your Doctor Before They Prescribe You Atezolizumab:
The following information has to be relayed to your physician before they prescribe Atezolizumab, including whether or not you:
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Have received an organ transplant.
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Have immune system problems like Crohn’s disease, lupus, or ulcerative colitis.
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Have undergone or are planning to undergo a stem cell transplant therapy.
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Have received radiation therapy to the chest area.
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Are pregnant or planning to become pregnant.
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Are breastfeeding or planning to breastfeed.
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Are taking over-the-counter medications, vitamins, and herbal supplements.
Starting Atezolizumab:-
How to Take Atezolizumab?
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Atezolizumab can be administered through an intravenous line for about 30 to 60 minutes by the healthcare professional.
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The drug is given every second, third, or fourth week.
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The number of treatments required will be decided by the healthcare professional.
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If there is a need for co-administration of the drug with another, it will also be decided by the healthcare professional.
Things to Do After You Start Taking Atezolizumab:
After taking Atezolizumab, schedule regular appointments with your doctor to get the drug administered without missing any doses and monitor any adverse effects that may develop due to the medication. The doctor may conduct physical and diagnostic tests to detect any abnormalities. If any adverse effects are evident, the doctor will decide whether the drug should be continued or not.
Look Out for Side Effects:
When used alone or in combination, the drug may cause specific side effects, which must be monitored and reported to the physician immediately.
The side effects, when administered alone, include
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Cough.
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Nausea.
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Decreased appetite.
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Feeling tired.
When administered with anticancer medicines, the side effects include
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Nausea.
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Decreased appetite.
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Diarrhea.
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Hair loss.
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Feeling tired.
When administered in hepatocellular carcinoma, the side effects include:
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Feeling tired.
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High blood pressure.
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Proteinuria.
When used with triple-negative breast cancer, the side effects include
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Cough.
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Headache.
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Nausea.
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Vomiting.
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Diarrhea.
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Constipation.
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Decreased appetite.
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Decreased white blood cells.
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Hair loss.
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Tingling or numbness in hands and feet.
When administered in melanoma, the side effects include
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Skin rash.
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Joint pain.
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Muscle pain.
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Bone pain.
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Liver injury.
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Fever.
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Swelling of hands and feet.
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Mouth swelling.
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Low thyroid hormone levels.
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Sunburn.
Dietary Alterations:
There is no data on dietary alterations during the administration of Atezolizumab.
What Should Be Done When You Miss a Dose?
If you missed an appointment for the administration of the drug, you must contact the healthcare provider immediately and reschedule your appointment.
What Should Be Done to Treat Atezolizumab Overdose?
There is no specific data on Atezolizumab overdose. Overdose on this drug is not usually possible as it is administered under the vigilance of the healthcare provider.
How to Store Atezolizumab?
Atezolizumab is available as a single dose vial that should be refrigerated at a temperature of two to eight degrees Celsius in its original packaging to protect it from light.
How to Handle Atezolizumab?
The drug should be stored at the recommended temperature but not frozen. In addition, the vial must not be shaken before use.
How to Dispose of Atezolizumab?
The patient cannot self-administer the drug, and is provided by the healthcare professional. Hence, the vials are disposed of by them only after sterilization through the autoclave.
Staying On Atezolizumab:-
Tips to Stay On Track: Scheduling regular appointments with the doctor is essential for staying on track with the treatment. If a dose is missed, the appointment must be rescheduled immediately.
For Doctors:-
Indication:
Atezolizumab is indicated for the following:
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First-line treatment for extensive-stage small cell lung cancer patients.
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Atezolizumab, combined with Bevacizumab, is indicated for treating patients with unresectable or metastatic hepatocellular carcinoma.
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Atezolizumab, combined with Cobimetinib and Vemurafenib, is indicated for treating patients with unresectable or metastatic melanoma.
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Treatment for locally advanced or metastatic urothelial cancer patients.
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Atezolizumab, as a single agent for treating patients with metastatic non-small cell lung cancer.
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Atezolizumab, combined with Bevacizumab, Paclitaxel, and Carboplatin, is indicated for treating patients with metastatic non-squamous non-small cell lung cancer.
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Atezolizumab, combined with Paclitaxel protein-bound, and Carboplatin, is indicated for treating patients with metastatic non-squamous non-small cell lung cancer.
Pharmacology:
Mechanism of Action:
Atezolizumab is a humanized immunoglobulin G antibody that binds to the PD-L 1 (programmed death ligand 1) and inhibits its attachment to the PD-1 and B 7.1 receptors. This releases the PD-L 1 mediated inhibition of immune response, including activation of an anti-tumor immune response without inducing antibody-dependent cellular cytotoxicity. The mechanism was noticed in mouse tumor models, demonstrating a decrease in tumor growth due to the blockade of PD-L 1 activity.
Pharmacodynamics:
Atezolizumab is found to have a long duration of action and is administered every three to four weeks.
Chemical Taxonomy:
Ingredients:
Active Ingredient:
The drug's active ingredient is Atezolizumab.
Inactive Ingredients:
The inactive ingredients are glacial acetic acid, L-histidine, polysorbate 20, and sucrose.
Absorption:
When the pharmacokinetic analysis was performed in patients with urothelial carcinoma, the AUC (area under the curve which reflects the actual exposure of the body to the drug after administration) was 2.19 to 2.73 micrograms/mL, and the Cmax (highest concentration of drug in the body after the dose) was 0.27 to 0.35 micrograms/mL.
Distribution:
The volume of distribution of the drug is 6.91 L. The monoclonal antibodies do not bind to plasma proteins that are not designed to target, but bind to the PD-L 1 (programmed death ligand 1) and demonstrate a decrease in tumor growth.
Metabolism:
Monoclonal antibodies break down into smaller polypeptides and amino acids.
Elimination:
Atezolizumab is not renally excreted. It stays in the body for around five months when it gets broken down.
Toxicity:
No data have been found about the carcinogenic or genotoxic potential of Atezolizumab. The male and female reproductive organs of monkeys were assessed by administering Atezolizumab. The studies revealed that Atezolizumab causes irregular menstrual cycles and a lack of newly formed corpus lutea in the ovaries of the female monkeys. There were no significant effects noticed on the male monkeys.
Warning and Precaution:
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Immune-Mediated Adverse Reactions: Immune-mediated adverse reactions can cause harm to the tissues or organ systems, such as immune-mediated pneumonitis, colitis, hepatitis, endocrine disorders, dermatologic reactions, nephritis, and solid organ transplant rejection. The other immune-mediated adverse reactions include pericarditis, myocarditis, vasculitis, uveitis, iritis, encephalitis, meningitis, myelitis, nerve paresis, pancreatitis, myositis, hypoparathyroidism, hemolytic anemia, aplastic anemia, sarcoidosis, immune thrombocytopenic purpura, and lymphadenitis. Hence, the organs' condition must be monitored closely during the administration of Atezolizumab. The drug is withheld or discontinued based on the severity of the adverse reactions.
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Infusion-Related Reactions: If the patients show infusion-related reactions, the infusion of the drug is interrupted, slowed down, or discontinued based on the severity of the reactions.
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Complications of Allogenic HSCT (Hematopoietic Stem Cell Transplantation): There are chances of serious fatal complications if the patient receives hematopoietic stem cell transplantation before and after administration of Atezolizumab. Transplant-related complications include hyperacute, acute, or chronic graft-versus-host disease and hepatic veno-occlusive disease. Hence these patients must be monitored regularly, and the drug administration must be interrupted promptly.
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Embryo-Fetal Toxicity: Atezolizumab is found to cause harm to the fetus based on its mechanism of action. But there is no available data on the administration of the drug to pregnant women. Animal studies have shown that the drug's mechanism of action can cause immune-related rejection of the developing fetus. Hence, the pregnancy status of the women should be monitored before administering the drug. In addition, women are advised to use contraceptives during the course of the drug.
Dosage and Forms:
Atezolizumab is available as a single dose vial in dosage forms such as 840 mg/14 mL (60 mg/mL) and 1200 mg/20 mL (60 mg/mL).
Administration of the Drug:
Atezolizumab is administered through an intravenous line for 60 minutes during the first visit. If the first infusion is tolerated, the subsequent infusions every second, third, or fourth week can be administered over 30 minutes. The other drugs must not be administered through the same intravenous line. Do not administer as an intravenous bolus.
Contraindications:
The administration of Atezolizumab is contraindicated in the following conditions.
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Infection.
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Low thyroid hormone levels.
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Overactive thyroid gland.
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Type 1 diabetes mellitus.
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Interstitial pneumonitis.
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Inflammation of the large intestine.
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Decreased function of the adrenal glands.
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Acute inflammation of the liver.
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Muscle inflammation.
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Kidney inflammation.
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Pancreatitis.
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Inflammation of the pituitary gland.
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Pregnancy.
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Breastfeeding.
Clinical Studies for Atezolizumab:
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The safety of Atezolizumab was evaluated in a multicenter, open-label trial in locally advanced or metastatic urothelial carcinoma patients who did not receive cisplatin-containing chemotherapy. One hundred nineteen patients were included in the study who received Atezolizumab 1200 mg intravenously every three weeks until either unacceptable toxicity or disease progression was noticed. The drug was administered for a duration of 15 weeks. The administration of Atezolizumab led to adverse events, such as myocardial infarction, cardiac arrest, respiratory failure, or sepsis, which eventually led to death: Serious adverse reactions such as diarrhea, intestinal obstruction, sepsis, acute kidney injury, and renal failure occurred in 37 % of the patients. The drug was discontinued due to adverse reactions such as diarrhea, fatigue, hypersensitivity, and dyspnea. Adverse reactions leading to interruption were fatigue, diarrhea, urinary tract infection, intestinal obstruction, infusion-related reaction, peripheral edema, respiratory tract infection, creatinine increase, decreased appetite, hyponatremia, back pain, cough, abdominal pain, pruritus, pyrexia, and venous thromboembolism.
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The safety of Atezolizumab was evaluated in a multicenter, open-label, randomized trial for the adjuvant treatment of patients with NSCLC (non-small cell lung cancer)who had complete tumor resection and received up to four cycles of Cisplatin-based adjuvant chemotherapy. Patients received Atezolizumab 1200 mg every three weeks for one year unless disease progression or unacceptable toxicity occurred. The drug led to fatal adverse reactions, such as multiple organ dysfunction syndromes, pneumothorax, interstitial lung disease, cerebrovascular accident, arrhythmia, acute cardiac failure, myocarditis, acute myeloid leukemia, and death. The most common adverse reactions leading to Atezolizumab discontinuation were pneumonitis, hypothyroidism, increased aspartate aminotransferase, arthralgia, and increased alanine aminotransferase. The drug was interrupted in 29 % of patients due to adverse reactions such as rash, hyperthyroidism, hypothyroidism, pyrexia, upper respiratory tract infection, headache, peripheral neuropathy, and pneumonia.
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The safety of Atezolizumab with Carboplatin and Etoposide was evaluated in a randomized, multicenter, double-blind, placebo-controlled trial in which 198 patients with small cell lung cancer received Atezolizumab 1200 mg and Carboplatin 5 mg/mL/min on day 1 and Etoposide 100 mg/square meters intravenously on days 1, 2 and 3, followed by Atezolizumab 1200 mg every three weeks until the disease progresses or unacceptable toxicity is noticed. The drug led to fatal adverse reactions, such as pneumonia, respiratory failure, neutropenia, and death in 2 % of the patients. Infusion-related reactions in 2 % of patients were the most frequent adverse reactions requiring permanent discontinuation. The drug administration was interrupted in 59 % of the patients due to adverse reactions such as neutropenia, anemia, leukopenia, thrombocytopenia, fatigue, infusion-related reaction, pneumonia, febrile neutropenia, and nausea.
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The safety of Atezolizumab combined with Bevacizumab was evaluated in a randomized, open-label trial in locally advanced or metastatic or unresectable hepatocellular carcinoma patients who have not received systemic treatment. Patients received 1200 mg of Atezolizumab intravenously followed by 15 mg/kg Bevacizumab every three weeks or 400 mg of Sorafenib given orally twice daily until the disease progresses or unacceptable toxicity is noticed. The drug was administered for a duration of 7.4 months, and Bevacizumab was 6.9 months. The most common adverse reactions leading to Atezolizumab discontinuation were hemorrhages, including gastrointestinal, subarachnoid, and pulmonary hemorrhages, infusion-related reactions, and autoimmune hepatitis. The drug was interrupted in 41 % of patients in the Atezolizumab and Bevacizumab as there were liver function laboratory abnormalities, including increased transaminases, bilirubin, or alkaline phosphatase infections, gastrointestinal hemorrhages, thrombocytopenia, hyperthyroidism, and pyrexia.
Drug Interactions:
There is an increased risk or severity of adverse reactions when Atezolizumab is administered in combination with Abciximab, Antilymphocyte immunoglobulin, Bevacizumab, and Cetuximab. In addition, thrombogenic activities can occur when Atezolizumab is combined with Denosumab and Dienestrol.
Other Specifications:-
Atezolizumab in Pregnant and Lactating Women:
Animal studies have reported that Atezolizumab causes fetal death. There is no specific data regarding administering Atezolizumab to a pregnant woman. However, the drug is contraindicated due to its mechanism of action that can harm the fetus.
Atezolizumab in Lactating Women:
There is no evidence for the presence of the drug in breast milk. However, breastfeeding women are advised not to breastfeed until five months after the last dose to avoid developing adverse reactions in breastfed infants.
Atezolizumab in Pediatric Patients:
The use of Atezolizumab in pediatric patients has not been established yet. However, certain studies suggest no new safety signals have been set for children.
Atezolizumab in Geriatric Patients:
No significant differences were noticed between the geriatric and pediatric patients on the safety and effectiveness of the drug for small cell lung cancer.
Atezolizumab in Renal Impairment Patients:
No dose alterations are recommended in patients with mild to moderate renal impairment, and there is no data on recommended doses for patients with end-stage renal disease.
Atezolizumab in Hepatic Impairment Patients:
Atezolizumab is not recommended for patients with moderate to severe hepatic impairment, and no dose adjustments are required for patients with mild hepatic impairment.
