Atezolizumab

Atezolizumab is designed to reverse the action of a protein called programmed death ligand 1 (or PD-L1) which often prevents the immune system from fighting cancer.

Overview

Atezolizumab is used in the treatment of advanced urothelial carcinoma and non-small cell lung cancer. It is prescribed when a patient's cancer has not improved as a result of platinum-based chemotherapy. The main activity of atezolizumab is to bind to a protein called programmed death ligand 1 (or PD-L1), which can deactivate the immune's system's T-cells and prevent them from fighting the cancerous cells. Atezolizumab's binding to PD-L1 prevents this protein from deactivating these and other cells and enables the immune system to aid in fighting cancerous cells.

Trials for Atezolizumab have been very encouraging, with significant improvement in overall survival rates among patients with high PD-L1 expression. The success of Atezolizumab in these patients also resulted in better response to chemotherapy according to one study. It is important to note that Atezolizumab is recommended only for patients with high PD-L1 expression, and may not be as effective in those with lower levels of PD-L1.

Conditions Treated

  • Cancer

Drug Type

  • Immunotherapy

Side Effects

Medications often produce adverse effects. These usually create no more than minor discomfort and subside as a patient's body becomes accustomed to the medication. Sometimes side effects can become serious, and should be reported to the patient's caregiver if this happens. Side effects of Atezolizumab can include:

  • Fatigue
  • Decreased Appetite
  • Nausea
  • Vomiting
  • Constipation
  • Diarrhea
  • Abdominal Pain
  • Urinary Tract Infection
  • Fever
  • Swelling of The extremities
  • Back or Neck Pain
  • Joint Pain
  • Anemia
  • Dehydration
  • Itching
  • Rash
  • Intestinal Obstruction
  • Urinary Obstruction
  • Blood in the Urine
  • Shortness of Breath
  • Cough
  • Acute Kidney Injury
  • Venous Thromboembolism
  • Severe Infection (Sepsis)
  • Pneumonia

In addition to these commonly reported side effects, Atezolizumab can also cause several conditions affecting the patient's immune system, a risk of immunotherapy. These include:

  • Immune-Related Pneumonitis
  • Immune-Related Hepatitis
  • Immune-Related Colitis
  • Immune-Related Endocrinopathies
  • Other Immune-Related Adverse Reactions

As an intravenous drug, infection and infusion-related reactions are also a risk.

Dosage

Atezolizumab is administered intravenously at a dose of 1200mg over 60 minutes. If the first dose is tolerated, any subsequent doses may be administered in 30 minutes. The infusions take place every three weeks until the disease has either responded to treatment or unacceptable toxicity occurs. Occasionally, side effects may prompt the patient's caregiver to interrupt treatment until the effects subside, and resume at the doctor's discretion. More severe reactions may prompt permanent discontinuation. Causes of interruption include:

5 AST or ALT or >3 x ULN total bilirubin

Diarrhea or Colitis (Grade 1 or 2)

Adrenal Insufficiency, hyperglycemia, hyperthyroidism, hypothyroidism or symptomatic hypophysitis (grade 3 or 4).

ocular inflammatory toxicity (Grade 2)

pancreatitis (Grade 1 or 2) increases in amylase or lipase levels (Grade 3 or 4); such as >2 x ULN

Infection (Grade 3 or 4)

Infusion-Related Reactions (Grade 2 or 3)

Rash (Grade 3)

If adverse reactions recover to grades 0 or 1, the caregiver may resume administration of Atezolizumab

The following reactions will prompt permanent discontinuation

Pneumonitis (Grade 3 or 4)

5 x ULN AST or ALT or >3 ULN total bilirubin

Diarrhea or Colitis (Grade 3 or 4)

Hypophysitis (Grade 4)

Myasthenic syndrome/Myasthenia Gravis, Gullian-Barre, or meningoencephalitis

Ocular inflammatory toxicity (Grade 3)

Pancreatitis (Grade 4) or any grade of Pancreatitis if it is recurrent

Infusion-related reactions

Rash (Grade 4)

Additionally, Atezolizumab may be approved under accelerated approval based on the response rate of the tumor and its durability of response.

Continued approval for this indication may be contingent upon the use of confirmatory trials to provide verification and description of patient benefits.

Drug Interaction

As an immunotherapy, Atezolizumab can have an effect on the body's response to vaccines. These drugs constitute a large portion of the list of meds with which Atezolizumab is known to interact. Atezolizumab is known to have interactions with the following medications.

  • Major Interactions
  • Adalimumab
  • BCG
  • Certolizumab
  • Etanercept
  • Fingolimod
  • Golimumab
  • Infliximab
  • Influenza Virus Vaccine
  • Leflunomide
  • Measles Virus Vaccine
  • Mumps Virus Vaccine
  • Natlizumab
  • Rotavirus Vaccine
  • Rubella Virus Vaccine
  • Smallpox Vaccine
  • Talimogene Laherparepvec
  • Teriflumonide
  • Tofactinib
  • Typhoid Vaccine (Live)
  • Varicella Virus Vacine
  • Yellow Fever Vaccine
  • Zoster Vaccine (Live)
  • Moderate Intteractions
  • Adenovirus Vaccine
  • Aleacept
  • Alemtuzumab
  • Anakinra
  • Antrax Vaccine Adsorbed
  • Azathioprine
  • Canakinumab
  • Candida Albacans Extract
  • Cholera Vaccine
  • Cholera Vaccine Live
  • Cladribine
  • Coccidioidin Skin Test
  • Denosumab
  • Diphtheria and Tetanus Toxoids (Perussis, Acellular)
  • Efalizumab
  • Haemophilus b conjugate (hboc) vaccine
  • Hepatitis a adult vaccine
  • Hepatitis a adult vaccine / hepatitis b adult vaccine
  • Hepatitis a pediatric vaccine
  • Hepatitis b pediatric vaccine
  • Histoplasmin
  • Human papillomavirus vaccine
  • Idelalisib
  • Influenza virus vaccine
  • Japanese enceph vacc sa14-14-2, inactivated
  • Japanese encephalitis virus vaccine nakayama
  • Lyme disease vaccine
  • Meningococcal conjugate vaccine
  • Meningococcal group B vaccine
  • Meningococcal polysaccharide vaccine
  • Mixed respiratory vaccine
  • Mumps skin test antigen
  • Ocrelizumab
  • Omacetaxine
  • Plague vaccine
  • Pneumococcal vaccine
  • Poliovirus vaccine
  • Rabies vaccine
  • Rilonacept
  • Roflumilast
  • Sipuleucel-T
  • Skin test antigens, multiple
  • Staphage lysate (spl)
  • Tetanus toxoid
  • Trichophyton skin test
  • Tuberculin purified protein derivative
  • Typhoid vaccine, inactivated
  • Ustekinumab

Warnings

Immune-Related Pneumonitis

Atezolizumab carries a risk of immune-mediated pneumonitis or interstitial lung disease, defined as requiring treatment with corticosteroids and with no clear alternate etiology. Patients should be monitored for signs and symptoms of pneumonitis using radiographic imaging. Steroids should be administered at a dose of 1 to 2 mg per day, followed by corticosteroid taper. Atezolizumab should be withheld until the grade 2 or greater pneumonitis is resolved. If Grade 3 or 4 Pneumonitis occurs, Atezolizumab must be permanently discontinued.

Immune-Related Hepatitis

Another risk of Atezolizumab is immune-related hepatitis, defined as requiring the use of corticosteroids and with no clear etiology. Liver test abnormalities have seen occurrence in patients receiving Atezolizumab treatment. Patients must be monitored for signs and symptoms of hepatitis during treatment with Atezolizumab. Corticosteroids must be administered at a dose of 1-2 mg/kg per day prednisone equivalents for Grade 2 or greater transaminase elevations, with or without concomitant elevation in total bilirubin. Administration of corticosteroids must be followed by a corticosteroid taper. Atezolizumab must be withheld for patients with grade 2 hepatitis, and permanently discontinued in patients with Grade 3 or 4 or greater immune-mediated hepatitis.

Immune-Related Colitis

Atezolizumab can cause immune-related colitis or diarrhea, defined as requiring the use of corticosteroids and with no clear alternate etiology. Patients should be monitored for signs and symptoms of diarrhea or colitis. Atezolizumab should be withheld for colitis of grade 2. If symptoms last for more than five days or recur, prednisone should be administered at a dose of 1-2 mg/kg or equivalent. Treatment should also be withheld for Grade 3 colitis. IV methylprednisolone should be administered at a dose of 1-2 mg/kg per day or equivalent. Once the patient has improved, treatment should be converted to oral steroids. If grade 2 and grade 3 colitis improve to grade 0 or 1, the caregiver should taper the steroid dosage of the course of less than one month. If the colitis and diarrhea improve to grade 0 or 1 within twelve weeks, and there has been a reduction in corticosteroids to a dosage of less than 10mg oral prednisone per day, then treatment with atezolizumab can resume. If diarrhea or colitis occurs at grades 3 or 4, permanent discontinuation of Atezolizumab is in order.

Immune-related endocrinopathies

The occurrence of immune-related thyroid disorders, including adrenal insufficiency and diabetes mellitus type 1, including diabetic ketoacidosis has happened with patients receiving Atezolzumab treatment. Patients should be monitored for clinical signs and symptoms of endocrinopathies.

Hypophysitis should be treated by the administration of corticosteroids and hormone replacement as clinically indicated. Atezolizumab should be withheld in cases of grade 2 or 3 hypophysitis and permanently discontinued in cases of grade 4 hypophysitis.

Thyroid function should be monitored prior to and periodically during treatment with atezolizumab. If patients have abnormal thyroid tests but are asymptomatic, they can receive atezolizumab. In cases of symptomatic hypothyroidism, atezolizumab should be withheld and an anti-thyroid drug should be used if needed. Isolated hypothyroidism should be managed with replacement therapy, corticosteroids should not be used. In cases of symptomatic hyperthyroidism, atezolizumab should be withheld and an anti-thyroid drug should be initiated as needed. When symptoms of hypothyroidism and hyperthyroidism are controlled and there is an improvement in thyroid function, atezolizumab treatment may resume.

Adrenal insufficiency will prompt physicians to withhold atezolizumab and administer IV methylprednisolone at 1-2 mg/kg per day. Once symptoms improve, the IV methylprednisolone will be replaced with 1-2 mg/kg per day of oral prednisone or equivalent. Once symptoms improve to grade 1 or better, a steroid taper should start, taking place over the course of less than one month.

Atezolizumab treatment has also been known to cause new onset diabetes with ketoacidosis. For treatment of type 1 diabetes mellitus, insulin is used. Atezolizumab treatment should be withheld for hyperglycemia of Grade 3 or worse. When insulin replacement therapy results in metabolic control, atezolizumab can be resumed.

Atezolizumab may cause a number of other immune-related adverse reactions including meningoencephalitis, myasthenic syndrome/myasthenia gravis, Guillain -Barre, ocular inflammatory toxicity, and pancreatitis. Increases in serum amylase have also been reported.

Patients should be monitored for signs of meningitis or encephalitis. If either of these conditions occurs, atezolizumab should be permanently discontinued.

Patients should be monitored for any sign of motor and sensory neuropathy. If this occurs, atezeolizumab should be permanently discontinued.

If acute pancreatitis (grade 2 or 3), or serum amylase or lipase levels of greater than grade 3 occurs,atezolizumab should be withheld. Pancreatitis should be treated with 1-2 mg/kg of IV methylprednisolone or equivalent per day. Once symptoms improve, IV will be replaced by 1-2 mg/kg or oral prednisone or equivalent per day. When serum amylase and lipase levels improve to lower than grade one within 12 weeks, resolution of pancreatitis symptoms occurs, and corticosteroids have been reduced to less than 10 mg of oral prednisone or equivalent per day, then treatment with atezolizumab treatment can resume. If pancreatitis occurs at grade 4 or is recurrent, permanently discontinue atezolizumab.

Atezolizumab carries the risk for severe infections, including sepsis, herpes encephalitis, and mycobacterial infection resulting in retroperitoneal hemorrhage. Patients must be monitored for signs and symptoms of infection and treated with antibiotics for both suspected and confirmed bacterial infections. If infection occurs at grade 3 or worse, withhold atezolizumab.

Atezolizumab carries a very high risk of fetal harm. Its inhibition of the PD-L1/PD-1 pathway can increase the risk of the immune system rejecting the developing fetus, causing fetal death. Pregnant women being treated with atezolizumab should be advised of the risk the drug poses to a fetus, and women capable of pregnancy should be encouraged to use contraception both during the treatment and for five months after the last dose.

Additionally, women are discouraged from breastfeeding both during atezolizumab treatment and for five months after the last dose, due to the potential for secretion which can result in an adverse reaction for the child.

Storage

Intact vials of Atezolizumab should be stored at 2-8 degrees Celsius, or 36-46 degrees Fahrenheit. They should not be shaken or frozen. It is recommended that solutions diluted for infusion be used immediately following preparation. If not used immediately, it may be stored for no more than six hours (including time of administration) at room temperature or 24 hours refrigerated at 2-8 degrees or 36-46 degrees Fahrenheit. It should never be frozen.

Summary

Atezolizumab is an immunotherapy that has proven success in aiding the immune system with fighting cancerous

tumors caused by Urothelial Carcinoma and non-small cell lung cancer. Trials of atezolizumab have yielded largely positive success rates in these patients. It is important to note, however, that the drug is specifically intended for patients with high expressions of the protein programmed death-ligand 1 (PD-L1) and may not have the same effect on patients without the same levels of PDL1 expression.

Natrually, immunotherapies carry a high risk of infection and adverse reactions. Interactions between atezolizumab and various vaccinations can have serious effects. The risk of conditions such as pancreatitis, colitis, meningitis, and encephalitis is also present. Also, in pregnant women, atezolizumab can cause great harm to the fetus including death, so the drug is not recommended for gestating women. Women are discouraged from becoming pregnant both during atezolizumab treatment and up to five months after their final dose. Breastfeeding is also not recommended. Endocrinopathies such as diabetes and adrenal insufficiency are also a possibility.

Atezolizumab can be an effective treatment, as long as all precautions are taken before, during, and after treatment to ensure safety and maximum effectiveness.

Resources
Last Reviewed:
December 23, 2017
Last Updated:
December 22, 2017