Atezolizumab

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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Atezolizumab 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 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 a drug that is used in the management and treatment of various neoplastic conditions. It is in the monoclonal antibody class of medications. This activity covers the indications, contraindications, adverse events, and other therapeutic factors clinicians need to know to drive patient outcomes effectively.

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. 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.[x]’ Atezolizumab was granted FDA approval on 18 October 2016.[rx]

Mechanism of Action

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. This drug has a long duration of action as it is usually given every 3-4 weeks. Atezolizumab should not be used in patients with immune-mediated pneumonitis, hepatitis, colitis, and some endocrinopathies.

Atezolizumab is a humanized IgG antibody that binds PD-L1, preventing its interaction with PD-1 and B7-1. 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.

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.
  • Atezolizumab has also indicated the first line for nonsmall cell lung cancer in combination with bevacizumab, paclitaxel, and carboplatin with no EGFR or ALK genomic abnormalities. It can be used in patients with disease progression during or after platinum-containing chemotherapy even if they have EGFR and ALK abnormalities.
  • Atezolizumab is indicated in combination with paclitaxel protein-bound to treat locally advanced or metastatic triple-negative breast cancer expressing PD-L1. Finally, atezolizumab is indicated in combination with carboplatin and etoposide as first-line treatment for extensive stage small cell lung cancer.
  • 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.

Contraindications

  • 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

Atezolizumab is FDA-approved for intravenous use only.

  • It is available in two different concentrated strength solutions of 840 mg/14 mL (60 mg/mL) and 1200 mg/20 mL (60 mg/mL) in a single-dose vial. Atezolizumab is recommended to be administered as an IV infusion after dilution with 0.9 % sodium chloride injection. The infusion’s initial rate should be over 60 minutes, and if well tolerated, subsequent doses can be administered over 30 minutes. Patients should be closely monitored for infusion-related reactions, based on the severity of which the infusion rate must be interrupted temporarily, or the infusion rate must be slowed or permanently discontinued.
  • Dosing is generally 1200 mg IV every three weeks for most indicated cancers (unresectable or metastatic melanoma dosing is 840 mg IV every two weeks); depending on the diagnosis and institution, dosing can vary from this standard regimen. The clinician should always consult the drug package insert and institutional protocols before designing a dosing regimen for any patient.

Side Effects

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 a 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 images are crucial in patients receiving atezolizumab.

  • Patients should be monitored for signs and symptoms of exfoliative dermatological manifestations, autoimmune colitis, endocrinopathies, and 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 pneumonitides.

Immune-Mediated Hepatitis

  • After ruling out viral hepatitis and other etiologies of elevated liver function tests, vedolizumab 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 Grades 3 and 4 for 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)

     

Drug Interactions

 

Pregnancy and Lactation

TGA pregnancy category: D
US FDA pregnancy category: Not assigned.

-Based on animal studies, this drug impairs fertility in females of reproductive potential.
-Based on its mechanism of action, this drug can cause harm to a developing fetus.

  • Animal reproduction studies have not been conducted to evaluate the effect on reproduction and fetal development. A literature-based assessment of the effects on reproduction demonstrated that a central function of the PD-L1/PD-1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to a fetus. Blockage of PD-L1 signaling has been shown to disrupt tolerance to a fetus and to result in an increase in fetal loss. There are no controlled data on human pregnancy. It is not known whether this drug can cause fetal harm or adversely affect reproductive capacity in humans.
  • AU TGA pregnancy category D: Drugs which have caused, are suspected to have caused, or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.
  • US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help healthcare providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

Lactation

  • There is no information regarding the presence of this drug in human milk or the effects on milk production; because human IgG is excreted in human milk, the potential for absorption and harm to the infant is unknown.
    -Lactating women should not breastfeed during therapy and for at least 5 months after.

References

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