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RxHarun

Atezolizumab – Uses, Dosage, Side Effects, Interactions

Dr. Harun Ar Rashid, MD - Arthritis, Bones, Joints Pain, Trauma, and Internal Medicine Specialist Dr. Harun Ar Rashid, MD - Arthritis, Bones, Joints Pain, Trauma, and Internal Medicine Specialist
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Drugs (A - Z)

Atezolizumab is a humanized IgG1 monoclonal anti-programmed death-ligand 1 (PD-L1) antibody is a monoclonal antibody used to treat advanced or metastatic urothelial carcinoma with disease progression during or up to 12 months after platinum-containing chemotherapy.

Atezolizumab is a humanized monoclonal antibody used to prevent the interaction of PD-L1 and PD-1, removing inhibition of immune responses seen in some cancers.[rx,rx] This medication is reserved for patients whose tumors express PD-L1, cannot receive platinum-based chemotherapy, or whose tumors do not respond to platinum-based chemotherapy.[rx] Atezolizumab was granted FDA approval on 18 October 2016.[rx]

Mechanism of action

Atezolizumab is a humanized IgG antibody that binds PD-L1, preventing its interaction with PD-1 and B7-1.[rx] Preventing the interaction of PD-L1 and PD-1 removes inhibition of immune responses such as the anti-tumor immune response but not antibody-dependent cellular cytotoxicity.[rx]

Atezolizumab is a humanized monoclonal antibody used to prevent the interaction of PD-L1 and PD-1, removing inhibition of immune responses seen in some cancers.[rx,rx] This drug has a long duration of action as it is usually given every 3-4 weeks.[rx] Atezolizumab should not be used in patients with immune-mediated pneumonitis, hepatitis, colitis, and some endocrinopathies.[rx]

Many immune and tumor-infiltrating cells express programmed death-ligand 1 (PD-L1), which negatively regulates the cytotoxic T-lymphocyte activation by binding to the programmed death-1 (PD-1) and B7.1 (CD80) receptors that cause suppression of T-cell migration, proliferation, and secretion of cytotoxic mediators leading to inhibited tumor cell killing.

Data from many clinical trials have shown that agents targeted at the PD-L1/PD-1 molecular pathway can induce antitumor activity early and across multiple neoplastic conditions. Atezolizumab is a humanized monoclonal anti-programmed death-ligand 1 (PD-L1) antibody that inhibits PD-L1–programmed death 1 (PD-1) PD-L1–B7-1 signaling, thereby resulting in tumor-specific cytotoxic T-cell immunity.

Indications

  • Atezolizumab is indicated to treat locally or advanced metastatic urothelial carcinoma in patients ineligible for cisplatin-containing chemotherapy with tumors expressing PD-L1, in patients ineligible for cisplatin-containing chemotherapy irrespective of PD-L1, have disease progression following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant chemotherapy.[rx]
  • Atezolizumab is also indicated first line for nonsmall cell lung cancer in combination with bevacizumab, paclitaxel, and carboplatin with no EGFR or ALK genomic abnormalities.[rx] It can be used in patients with disease progression during or after platinum-containing chemotherapy even if they have EGFR and ALK abnormalities.[rx]
  • Atezolizumab is indicated in combination with paclitaxel protein-bound to treat locally advanced or metastatic triple-negative breast cancer expressing PD-L1.[rx]
  • Finally, atezolizumab is indicated in combination with carboplatin and etoposide as first-line treatment for extensive stage small cell lung cancer.[rx]
  • Metastatic Hepatocellular Carcinoma
  • Metastatic Melanoma
  • Metastatic Non-Small Cell Lung Cancer
  • Metastatic Non-squamous Non-Small Cell Lung Cancer
  • Metastatic Ureter Urothelial Carcinoma
  • Non-Small Cell Lung Carcinoma (NSCLC)
  • Nonsmall Cell Lung Cancer, Stage II
  • Small Cell Lung Cancer (SCLC)
  • Stage IIIA Non-Small Cell Lung Cancer
  • Triple Negative Breast Cancer
  • Unresectable Hepatocellular Carcinoma (HCC)
  • Unresectable Melanoma
  • Locally advanced Urothelial Carcinoma

Use in Cancer

Atezolizumab is approved to treat:

  • Hepatocellular carcinoma (a type of liver cancer) that is metastatic or cannot be removed by surgery. Atezolizumab is used with bevacizumab in patients who have not received systemic therapy.
  • Melanoma has a certain mutation in the BRAF gene. Atezolizumab is used with cobimetinib fumarate and vemurafenib in adults whose cancer is metastatic or cannot be removed by surgery.
  • Non-small cell lung cancer. Atezolizumab is used:
    • As adjuvant therapy after surgery and platinum chemotherapy in adults with stage IIA, stage IIB, or stage IIIA cancer that has the PD-L1 protein.
    • Is the first treatment in adults with metastatic cancer that has the PD-L1 protein and does not have a mutation in the EGFR gene or the ALK gene.
    • With bevacizumab, paclitaxel, and carboplatin or paclitaxel albumin-stabilized nanoparticle formulation and carboplatin as the first treatment in adults with non-squamous metastatic cancer that does not have a mutation in the EGFR gene or ALK gene.
    • In adults with metastatic cancer that got worse during or after treatment with platinum chemotherapy. For patients whose cancer has a mutation in the EGFR gene or ALK gene, atezolizumab is used if their cancer has gotten worse after treatment with FDA-approved therapy for these mutations.
  • Small cell lung cancer. Atezolizumab is used with carboplatin and etoposide as the first treatment in adults with extensive-stage cancer.
  • Urothelial cancer (a type of cancer in the bladder or urinary tract) that is metastatic or cannot be removed by surgery. Atezolizumab is used in:
    • Adults whose cancer has the PD-L1 protein cannot be treated with cisplatin.
    • Adults whose cancer cannot be treated with platinum chemotherapy.

This use is approved under FDA’s Accelerated Approval Program. As a condition of approval, a confirmatory trial(s) must show that atezolizumab provides a clinical benefit in these patients.

Atezolizumab is also being studied in the treatment of other types of cancer.

or

Atezolizumab is a humanized IgG1 monoclonal anti-programmed death-ligand 1 (PD-L1) antibody that has been approved by the U.S Food Drug Administration (FDA) for various neoplastic conditions either as a single agent or in combination with other chemotherapeutic agents. Atezolizumab is FDA approved for the following neoplastic conditions:

Locally Advanced or Metastatic Urothelial Carcinoma
  • Atezolizumab, as a single agent, is indicated in patients with locally advanced or metastatic urothelial carcinoma.

    • Who are ineligible for cisplatin-containing chemotherapy with a level of tumor PD-L1 expression, or
    • Are ineligible for any platinum-containing chemotherapy irrespective of their PD-L1expression status, or
    • Have the progression of their disease during or following any platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy
  • Extensive-stage Small Cell Lung Cancer

    • Atezolizumab, in combination with carboplatin and etoposide, is indicated as the first-line treatment of adult patients with extensive-stage small-cell lung cancer.
  • Metastatic Non-small-cell Lung Cancer (NSCLC)

    • Atezolizumab, as a single agent, is indicated in patients with metastatic NSCLC with high PD-L1 expression, regardless of histologic type.
    • Atezolizumab, in combination with bevacizumab plus chemotherapy (paclitaxel and carboplatin), is indicated for the first-line treatment of adult patients with metastatic non-squamous NSCLC regardless of PD-L1 expression and (epidermal growth factor receptor)EGFR or anaplastic lymphoma kinase (ALK) genomic tumor alterations.
    • Atezolizumab in combination with nanoparticle albumin-bound paclitaxel and carboplatin is indicated for the first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations.
    • Atezolizumab as a single agent is indicated for treating adult patients with metastatic NSCLC who have disease progression during or despite receiving platinum-containing chemotherapy.
  • Metastatic Triple-negative Breast Cancer

    • Atezolizumab, in combination with nanoparticle albumin-bound paclitaxel, is indicated for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer whose tumors express PD-L1.
Unresectable or Metastatic Hepatocellular Carcinoma
  • Atezolizumab, in combination with bevacizumab, is indicated to treat patients with unresectable or metastatic hepatocellular carcinoma (HCC) who have not previously received treatment with chemotherapy.
Unresectable or Metastatic Melanoma
  • Atezolizumab, in combination with vemurafenib and cobimetinib, is indicated to treat patients with BRAF mutation-positive unresectable or metastatic melanoma.

Contraindications

The following conditions are contraindicated with this drug. Check with your physician if you have any of the following:

  • a bad infection
  • overactive thyroid gland
  • a condition with low thyroid hormone levels
  • type 1 diabetes mellitus
  • decreased function of the adrenal gland
  • Guillain-Barre syndrome
  • myasthenia gravis, a skeletal muscle disorder
  • inflammation of the middle tissue heart muscle
  • a type of inflammation of the lung called interstitial pneumonitis
  • inflammation of the large intestine
  • acute inflammation of the liver
  • kidney inflammation
  • muscle inflammation
  • pregnancy
  • a patient who is producing milk and breastfeeding
  • pancreatitis
  • inflammation of the pituitary gland

Dosage

Strengths: 1200 mg/20 mL; 840 mg/14 mL

Urothelial Carcinoma

MONOTHERAPY:

  • 840 mg IV every 2 weeks OR 1200 mg IV every 3 weeks OR 1680 mg IV every 4 weeks until disease progression or unacceptable toxicity
  • Administer the first infusion over 60 minutes; if well tolerated, administer subsequent infusions over 30 minutes

Non-Small Cell Lung Cancer

MONOTHERAPY:

  • 840 mg IV every 2 weeks OR 1200 mg IV every 3 weeks OR 1680 mg IV every 4 weeks until disease progression or unacceptable toxicity

NOTE: Administer the first infusion over 60 minutes; if well tolerated, administer subsequent infusions over 30 minutes

IN COMBINATION WITH PLATINUM-BASED CHEMOTHERAPY:

  • 1200 mg IV every 3 weeks until disease progression or unacceptable toxicity; administer atezolizumab prior to chemotherapy and bevacizumab when given on the same day; following completion of 4 to 6 cycles of chemotherapy, and if bevacizumab is discontinued, the recommended dosage of atezolizumab
  • 840 mg IV every 2 weeks OR 1200 mg IV every 3 weeks OR 1680 mg IV every 4 weeks until disease progression or unacceptable toxicity

NOTE: Administer the first infusion over 60 minutes; if well tolerated, administer subsequent infusions over 30 minutes

Non-small cell lung cancer (NSCLC):

  • As a single agent for first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression (PD-L1 stained 50% or greater of tumor cells or PD-L1 stained tumor-infiltrating immune cells covering 10% or greater of the tumor area.
  • In combination with bevacizumab, paclitaxel, and carboplatin, for first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations.
  • In combination with paclitaxel protein-bound and carboplatin, for first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations.
  • As a single-agent, for the treatment of adult patients with metastatic NSCLC who have disease progression during or following platinum-containing chemotherapy (patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for NSCLC harboring these aberrations prior to receiving this drug).

Breast Cancer

  • 840 mg IV on Days 1 and 15 followed by paclitaxel protein-bound 100 mg/m2 IV on Days 1, 8, and 15 for each 28-day cycle until disease progression or unacceptable toxicity

NOTE: Administer the first infusion over 60 minutes; if well tolerated, administer subsequent infusions over 30 minutes

Small Cell Lung Cancer

  • 1200 mg IV every 3 weeks in combination with carboplatin and etoposide until disease progression or unacceptable toxicity; following completion of 4 cycles of carboplatin and etoposide, the recommended dosage of atezolizumab is:
  • 840 mg IV every 2 weeks OR 1200 mg IV every 3 weeks OR 1680 mg IV every 4 weeks until disease progression or unacceptable toxicity

NOTE: Administer the first infusion over 60 minutes; if well tolerated, administer subsequent infusions over 30 minutes

Hepatocellular Carcinoma

  • 1200 mg IV over 60 minutes, followed by 15 mg/kg of bevacizumab on the same day, every 3 weeks until disease progression or unacceptable toxicity; if bevacizumab is discontinued for toxicity, the recommended dosage of atezolizumab is:
  • 840 mg IV over 60 minutes every 2 weeks OR 1200 mg IV over 60 minutes every 3 weeks OR 1680 mg IV over 60 minutes every 4 weeks
  • Duration of therapy: Until disease progression or unacceptable toxicity.

NOTE: Administer the first infusion over 60 minutes; if well tolerated, administer subsequent infusions over 30 minutes

Melanoma – Metastatic

  • Prior to initiating atezolizumab, patients should receive a 28-day treatment cycle of cobimetinib 60 mg orally once a day (21 days on and 7 days off) and vemurafenib 960 mg orally 2 times a day on Days 1 through 21, and vemurafenib 720 mg orally 2 times a day on Days 22 through 28.
  • Atezolizumab dose: 840 mg IV over 60 minutes every 2 weeks until disease progression or unacceptable toxicity, when administered with cobimetinib 60 mg orally once a day (21 days on and 7 days off) and vemurafenib 720 mg orally 2 times a day
    NOTE: Administer the first infusion over 60 minutes; if well tolerated, administer subsequent infusions over 30 minutes

Renal Dose Adjustments

  • Mild to moderate renal impairment: No adjustment recommended.
  • Severe renal impairment: Data not available

THERAPY MODIFICATIONS FOR ADVERSE REACTIONS:
NEPHRITIS WITH RENAL DYSFUNCTION:

  • Grades 2 or 3 increased blood creatinine: Withhold therapy; resume with complete or partial resolution (Grade 0 to 1) after corticosteroid taper; permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating steroids.
  • Grade 4 increased blood creatinine: Permanently discontinue therapy.

Liver Dose Adjustments

  • Mild hepatic impairment: No adjustment recommended.
  • Moderate to severe hepatic impairment: Data not available

THERAPY MODIFICATIONS FOR ADVERSE REACTIONS:
HEPATITIS WITH NO TUMOR INVOLVEMENT OF THE LIVER:

  • ALT or AST greater than 3 and up to 8 times upper limit of normal [ULN] or total blood bilirubin greater than 1.5 and up to 3 x ULN: Withhold therapy until Grade 1 or resolved and corticosteroid dose is less than or equal to prednisone 10 mg per day (or equivalent).
  • ALT or AST greater than 8 x ULN or blood bilirubin greater than 3 x ULN: Permanently discontinue therapy.

HEPATITIS WITH TUMOR INVOLVEMENT OF THE LIVER (if AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue therapy based on recommendations for hepatitis with no liver involvement):

  • Baseline AST or ALT is more than 1 and up to 3 times upper limit of normal (ULN) and increases to more than 5 and up to 10 x ULN or baseline AST or ALT is more than 3 and up to 5 x ULN and increases to more than 8 and up to 10 x ULN: Withhold therapy; resume with complete or partial resolution (Grade 0 to 1) after corticosteroid taper; permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating steroids.
  • If AST or ALT increases to more than 10 x ULN or total bilirubin increases to more than 3 x ULN: Permanently discontinue therapy.

Dose Adjustments

Dose Modifications:

  • No dose reductions of this drug are recommended. In general, withhold therapy for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue therapy for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids.

THERAPY MODIFICATIONS FOR ADVERSE REACTIONS:
PNEUMONITIS:

  • Grade 2: Withhold therapy; resume with complete or partial resolution (Grade 0 to 1) after corticosteroid taper; permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating steroids. when the event improves to Grade 1 or resolved, and corticosteroids have been reduced to 10 mg or less oral prednisone or equivalent per day.
  • Grade 3 or 4: Permanently discontinue therapy.

COLITIS:

  • Grade 2 or 3: Withhold therapy; resume with complete or partial resolution (Grade 0 to 1) after corticosteroid taper; permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating steroids.
  • Grade 4: Permanently discontinue therapy.

ENDOCRINOPATHIES:

  • Grade 3 or 4: Withhold dose until stable or permanently discontinue depending on severity.:

EXFOLIATIVE DERMATOLOGIC CONDITIONS:

  • Suspected Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or Drug Rash with Eosinophilia and Systemic Symptoms (DRESS): Withhold therapy; resume with complete or partial resolution (Grade 0 to 1) after corticosteroid taper; permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating steroids. when the event improves to Grade 1 or resolved, and corticosteroids have been reduced to 10 mg or less oral prednisone or equivalent per day.
  • Confirmed SJS, TEN, or DRESS: Permanently discontinue therapy.

MYOCARDITIS:

  • Grades 2, 3, or 4: Permanently discontinue therapy.

NEUROLOGICAL TOXICITIES:

  • Grade 2: Withhold therapy; resume with complete or partial resolution (Grade 0 to 1) after corticosteroid taper; permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating steroids. when the event improves to Grade 1 or resolved, and corticosteroids have been reduced to 10 mg or less oral prednisone or equivalent per day.
  • Grades 3 or 4: Permanently discontinue therapy.

INFUSION-RELATED REACTIONS:

  • Grade 1 or 2: Interrupt or slow the rate of infusion.
  • Grade 3 or 4: Permanently discontinue therapy.

Side Effects

The Most Common

  • back, neck, or joint pain
  • pale skin
  • swelling of arms
  • loss of appetite
  • nausea
  • vomiting
  • constipation
  • hair loss
  • diarrhea, stomach pain, blood or mucus in the stool, or black tarry, sticky, stools
  • ongoing pain that begins in the upper left or middle of the stomach but may spread to the back, fever, nausea, vomiting
  • fever, sore throat, cough, chills, flu-like symptoms, frequent, urgent, difficult, or painful urination, or other signs of infection
  • decreased urination, blood in urine, swelling in your ankles or feet, or loss of appetite
  • new or worsening cough which may be bloody, shortness of breath, or chest pain
  • yellowing of the skin or eyes, extreme tiredness, bleeding or bruising easily, nausea or vomiting, pain in the upper right part of the stomach, dark (tea-colored) urine, decreased appetite

More Common

  • headaches that won’t go away or unusual headaches; extreme tiredness; rapid heartbeat; constipation; increased sweating; feeling cold; deepening of voice; hair loss; feeling more hungry or thirsty than usual; dizziness or fainting; increased urination; weight loss or gain; vision changes; changes in mood or behavior such as decreased sex drive or feeling irritable, confused, or forgetful
  • rash or itching, blistering or peeling skin
  • sores in mouth, nose, throat, or genital area
  • persistent muscle pain, cramping, or weakness; neck stiffness
  • numbness or tingling in the arms or legs
  • blurry or double vision, sensitivity to light, or other vision problems, eye pain or redness
  • feeling more hungry or thirsty than usual, increased urination, extreme tiredness, weakness, breath that smells fruity
  • chest pain, shortness of breath, fast or irregular heartbeat, swelling of ankles
  • tightness in the chest,
  • tingling of the hands, arms, legs, or feet,
  • frequent urge to urinate,
  • weakness,
  • tiredness,
  • headache,
  • loss of appetite,
  • sores or white spots in the mouth,
  • unusual bleeding or bruising,

Rare

  • difficulty breathing,
  • swelling of the face, lips, tongue, or throat,
  • nausea,
  • nosebleed,
  • blurred vision,
  • rapid weight gain,
  • constipation,
  • cough,
  • diarrhea,
  • burning or painful urination,
  • dizziness,
  • earache,
  • fever,
  • slow or fast heartbeat,
  • sore throat,
  • stuffy or runny nose,
  • vomiting,
  • anxiety,
  • confusion,
  • depression,
  • difficulty chewing, swallowing, or talking,
  • dry skin and hair,
  • irritability,
  • clay-colored stools,
  • muscle cramp and stiffness,
  • rapid or shallow breathing,
  • seizures,
  • trouble sleeping,
  • yellowing of eyes and skin (jaundice),
  • blistering, peeling, or loosening of the skin,
  • Red skin lesions with a purple center,
  • fruit-like breath odor, and
  • sweating

Drug Interaction

Pregnancy and Lactation

FDA pregnancy category: Not assigned

Pregnancy

Based on its mechanism of action, can cause fetal harm when administered during pregnancy. No available data on use in pregnant women. Advise females of reproductive potential to use effective contraception during treatment and for at least 5 months following the last dose. Based on animal studies, atezolizumab may impair fertility in females of reproductive potential while receiving treatment

Lactation

Unknown if distributed in human breast milk. As human IgG is excreted in human milk, the potential for absorption and harm to the infant is unknown. Advise a lactating woman not to breastfeed during treatment and for at least 5 months after the last dose

How should this medicine be used?

Atezolizumab injection comes as a solution (liquid) to be injected into a vein over 30 to 60 minutes by a doctor or nurse in a hospital or medical facility. It is usually injected once every 2, 3, or 4 weeks depending on your dose. The length of your treatment will be decided by your doctor and depends on the type of cancer being treated, how well your body responds to the medication and the side effects that you experience.

Atezolizumab injection may cause serious reactions during the infusion of the medication. A doctor or nurse will monitor you carefully while you are receiving the medication. If you experience any of the following symptoms, tell your doctor immediately: flushing, fever, chills, shaking, dizziness, feeling faint, shortness of breath, wheezing, difficulty breathing, itching, rash, back or neck pain, or swelling of the face or lips.

Your doctor may need to slow down your infusion, delay or stop your treatment, or treat you with other medications if you experience certain side effects. Be sure to tell your doctor how you are feeling during your treatment with atezolizumab injection.

Your doctor or pharmacist will give you the manufacturer’s patient information sheet (Medication Guide) when you begin treatment with atezolizumab injection and each time you receive the medication. Read the information carefully and ask your doctor or pharmacist if you have any questions. You can also visit the Food and Drug Administration (FDA) website (http://www.fda.gov/Drugs/DrugSafety/ucm085729.htm) or the manufacturer’s website to obtain the Medication Guide.

What special precautions should I follow?

Before receiving atezolizumab injection,

  • tell your doctor and pharmacist if you are allergic to atezolizumab, any other medications, or any of the ingredients in atezolizumab injection. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
  • tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor if you have or have ever had an organ or bone marrow transplant or radiation therapy to your chest area; lung or breathing problems; any condition that affects your nervous system such as myasthenia gravis (a disorder of the nervous system that causes muscle weakness) or Guillain-Barré syndrome (weakness, tingling, and possible paralysis due to sudden nerve damage); an autoimmune disease (a condition in which the immune system attacks a healthy part of the body) such as Crohn’s disease (a condition in which the immune system attacks the lining of the digestive tract causing pain, diarrhea, weight loss, and fever), ulcerative colitis (a condition that causes swelling and sores in the lining of the colon [large intestine] and rectum) or lupus (condition in which the immune system attacks many tissues and organs including the skin, joints, blood, and kidneys); diabetes; thyroid problems; or kidney or liver disease. Also, tell your doctor if you have or have ever had cytomegalovirus (CMV; a viral infection that may cause symptoms in patients with weak immune systems).
  • tell your doctor if you are pregnant, or plan to become pregnant. You will have to take a pregnancy test before starting treatment. You should not become pregnant while you are receiving atezolizumab injection and for 5 months after your last dose. Talk to your doctor about birth control methods that you can use during your treatment. If you become pregnant while receiving atezolizumab injection, call your doctor immediately. Atezolizumab may harm the fetus.
  • tell your doctor if you are breastfeeding. Your doctor will probably tell you not to breastfeed during your treatment and for 5 months after your last dose.

Adverse Consciousness

As with other approved PD-1/PD-L1-targeted therapies, the use of atezolizumab can be associated with immune-mediated adverse events (imAEs), which can be severe or fatal and involve any organ system manifesting as described below.

Infusion-related Reactions

  • Anaphylaxis and hypersensitivity

Immune-mediated Colitis

  • Immune-mediated colitis is characterized by signs and symptoms of diarrhea or increased ostomy output, colitis, and or perforation. All other etiologies of diarrhea and colitis should be excluded, including endoscopic evaluation. Based on the clinical and endoscopic severity, immune-mediated colitis is classified into four different grades:

    • Grade 1: < 4 stools per day or mild increase in ostomy output compared to baseline
    • Grade 2:  4 to 6 stools per day or moderate increase in ostomy output compared to baseline (compared with baseline) and/or colitis symptoms
    • Grade 3: ≥7 stools per day or severe increase in ostomy output compared to baseline with colitis
    • Grade 4: Severe colitis resulting in bowel perforation requiring urgent surgical intervention

Immune-mediated Cutaneous Adverse Effects

  • Immune-mediated cutaneous adverse reactions are common and manifest as itching, maculopapular rash, lichenoid reactions, vitiligo, and pruritus.
  • Based on the clinical severity and percentage of involvement of the body surface area, they are classified into four grades:

    • Grade 1: asymptomatic with macules/papules involving <10% of the body surface area
    • Grade 2: macules/papules involving 10% to 30% of the body surface area with or without symptoms
    • Grade 3: macules/papules involving >30% of the body surface area with or without symptoms
    • Grade 4: Severe cutaneous reactions such as Stevens-Johnson syndrome, TEN, and bullous dermatitis covering >30% of BSA and requiring intensive care unit (ICU) admission.

Immune-mediated Endocrinopathies

  • Immune-mediated endocrinopathies can present with signs and symptoms of adrenal insufficiency, thyroiditis, hypothyroidism, hyperthyroidism, hypophysitis, and diabetes, either alone related to one endocrine organ or in combination.

Immune-mediated Hepatitis

  • Immune-Mediated Hepatitis typically manifests with elevation in liver function tests.
  • Based on the severity of liver test abnormalities and hepatic dysfunction, immune-mediated hepatitis is classified into four types:

    • Grade 1: Elevation of AST/ALT < 3 times the upper limit of normal(ULN) and/or total bilirubin <1.5 times ULN
    • Grade 2: Elevation of AST/ALT 3 to 5 times ULN and/or total bilirubin >1.5 to ≤ 3 times ULN
    • Grade 3: Elevation of AST/ALT AST/ALT > 5 to 20 times ULN and/or total bilirubin 3–10x ULN
    • Grade 4: AST/ALT > 20x ULN, and/or total bilirubin >10x ULN associated with signs and symptoms of liver dysfunction.

Immune-mediated Pneumonitis or Interstitial Lung Disease

  • Immune-Mediated pneumonitis is characterized by nonproductive cough, shortness of breath, and radiological abnormalities of the lung.
  • Based on clinical severity and radiological involvement, immune-mediated pneumonitis is classified into four different types:

    • Grade 1: asymptomatic and limited to <25% involvement of the lung parenchyma or one lobe of the lung
    • Grade 2: moderate symptoms and involvement of 25 to 50% of the lung parenchyma or more than one lobe of the lung
    • Grade 3: severe symptoms and involvement of >50% of the lung parenchyma or all lung lobes
    • Grade 4: acute respiratory distress requiring mechanical ventilation.

Immune-mediated Renal Dysfunction and Nephritis

  • Immune-mediated renal dysfunction  typically manifests with increased creatinine levels and is graded into four types of severity based on the renal function:

    • Grade 1: An increase in creatinine level >0.3 mg/dL or 1.5 to 2.0 times compared to a baseline value
    • Grade 2: An increase in creatinine level 2 to 3 times compared to a baseline value
    • Grade 3: An increase in creatinine level  >4.0 mg/dL or >3 times compared to a baseline value
    • Grade 4: Worsening renal function requiring hemodialysis)

Immune-mediated Neurological Toxicities

The incidence of immune-mediated neurological toxicity is 1 % and is characterized by clinical symptoms of polyneuropathy, facial nerve palsy, aseptic meningitis, transverse myelitis, myasthenia gravis, Guillain Barre syndrome(GBS), or posterior reversible leukoencephalopathy.

Other common adverse reactions that occurred with atezolizumab as a single agent in clinical trials participants include:

  • Musculoskeletal (back pain, neck pain)
  • Metabolism (decreased appetite, hyperglycemia, hyponatremia, hyperkalemia, hypermagnesemia, hypophosphatemia)
  • Dermatologic (pruritus, rash)
  • Respiratory (cough, dyspnea)
  • General (fatigue, pyrexia, asthenia)
  • Gastrointestinal (abdominal pain, diarrhea, constipation, nausea)
  • Endocrine (hypothyroidism)
  • Infectious (pneumonia, urinary tract infection)
  • Blood/lymphatic (anemia, thrombocytopenia, lymphopenia)
  • Hepatobiliary (elevated liver function tests)
  • Renal (increase serum creatinine)

Monitoring

Patients receiving atezolizumab are at risk of developing immune-mediated adverse reactions anytime during therapy and after treatment discontinuation. Early identification and management of imAEs are crucial in patients receiving atezolizumab.

  • Patients should be monitored for signs and symptoms of exfoliative dermatological manifestations, autoimmune colitis, endocrinopathies, immune-mediated neurological and cardiovascular involvement.
  • Laboratory tests such as blood glucose level, renal function, liver function, and thyroid function should be performed at baseline before initiation of treatment and during treatment to evaluate for new-onset diabetes, adverse reactions such as immune-mediated nephritis, immune-mediated hepatitis, and immune-mediated thyroid dysfunction, respectively.
  • Atezolizumab must be held in Grade 2 immune-mediated adverse reactions and should be permanently discontinued in Grade 3 and Grade 4 immune-mediated adverse reactions unless indicated by the oncology team.

Toxicity

There is no available data regarding the safety of atezolizumab in pediatric patients and pregnant or breastfeeding women. There is also no available data about the drug-drug interaction potential of atezolizumab.

Immune-Mediated Colitis

  • Grade 1 colitis should be treated with symptomatic management.
  • Atezolizumab must be held in Grade 2 and Grade 3 colitis, and patients should be started on steroids with a slow taper.
  • Atezolizumab should be permanently discontinued in Grade 4 colitis.

Immune-Mediated Pneumonitis

  • Tapering corticosteroids is recommended if there is evidence of pneumonitis or interstitial lung disease on lung imaging.
  • Atezolizumab should be held for Grade 2 pneumonitis and permanently discontinued if there is evidence of Grade 3 or 4 pneumonitis.

Immune-Mediated Hepatitis

  • After ruling out viral hepatitis and other etiologies of elevated liver function tests, atezolizumab must be held in Grade 2 hepatitis. Patients should be started on oral or IV steroids followed by a slow taper.
  • Atezolizumab must be permanently discontinued in Grade 3 and 4 immune mediated-hepatitis, and patients should be started on IV steroids.

Immune-Mediated Endocrinopathies

  •  Thyroid Disorders

    • If clinically indicated, consider thyroid hormone replacement therapy in hypothyroidism or medical management of hyperthyroidism.
  • Adrenal Insufficiency/Hypophysitis

    • Consider initiating stress dose corticosteroids and hormone replacement therapy as clinically indicated.
  • Type 1 Diabetes Mellitus

    • Consider starting insulin if indicated.
  • Atezolizumab should be held in Grades 2 to 4 endocrinopathies.
  • Immune-mediated Renal Dysfunction and Nephritis

    • Atezolizumab should be held with grade ≥2 toxicities, and corticosteroid administration should be considered.
  • Immune-mediated Cutaneous Adverse Reactions

    • Topical steroids are indicated for Grade 1/Grade 2 toxicity.
    • Atezolizumab must be held in Grade 2 and Grade 3 toxicity; patients with Grade 2 toxicity should be treated with PO steroids.
    • Atezolizumab must be permanently discontinued in patients with Grade 4 immune toxicity, and patients should be treated with IV steroids in an intensive care unit(ICU)

References

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