Atezolizumab

Mechanism of Action

Many immune and tumor-infiltrating cells express programmed cell death-ligand 1 (PD-L1), which negatively regulates the activation of cytotoxic T lymphocytes 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.[9]

Data from various clinical trials have shown that agents targeting 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, preventing tumor-specific cytotoxic T-cell immunity and allowing (or inducing) the normal pathway of tumor cell killing to proceed.[10]

Administration

Available Dosage Forms and Strengths

Atezolizumab is available as a 15-mL subcutaneous injection containing 1,875 mg of atezolizumab and 30,000 units of hyaluronidase (TECENTRIQ HYBREZA). Atezolizumab is also available in 2 intravenous, single-dose solutions:

• TECENTRIQ 840 mg/14 mL (60 mg/mL)
• TECENTRIQ 1200 mg/20 mL (60 mg/mL)

Adult Dosage

TECENTRIQ HYBREZA (SQ): Remove the vial from the refrigerator and allow the atezolizumab solution to acclimate to room temperature. Discard the vial if the solution is discolored, cloudy, or visible particles are observed. Do not freeze, shake, or dilute at any point in time. The unpunctured vial can be stored at room temperature under ambient lighting for a maximum of 4 hours before preparation for administration. After priming the administration needle, expel excess from the syringe to ensure it contains exactly 15 mL of solution and administer it immediately to avoid needle clogging.

• Do not store the prepared syringe attached to a primed subcutaneous administration set.
• The capped syringe may be stored at room temperature (up to 25 °C in ambient room lighting) for up to 8 hours or in the refrigerator (2 °C to 8 °C) for up to 72 hours, allowing it to acclimate to room temperature before administration.

TECENTRIQ (IV): Injection vials should be diluted with 0.9 % sodium chloride injection. Mix the solution with gentle inversion, and do not shake it. Administer the diluted solution immediately once dispensed. If the diluted infusion solution is not used immediately, store it at room temperature for no more than 6 hours from the dilution, including time for administering the infusion. The dilution can be refrigerated at 2 to 8 °C for no more than 24 hours after being prepared; it should not be frozen. The initial infusion should occur over 60 minutes; if this is well tolerated, subsequent doses can be administered over 30 minutes. Patients should be closely monitored for infusion-related reactions. Severe reactions are indications to temporarily interrupt, slow, or permanently discontinue the infusion.

IV infusion (monotherapy) 

For most indicated cancers, the dose is generally 1200 mg every 3 weeks. For unresectable or metastatic melanoma, the dose is 840 mg every 2 weeks. However, depending on the diagnosis and institution, the dose can vary from this standard regimen. The clinician should always consult the drug package insert and institutional protocols before determining a dosing regimen for any patient. The following dosing recommendations are valid unless disease progression (or recurrence) or unacceptable toxicity is encountered.

Metastatic NSCLC:

• 840 mg every 2 weeks, or
• 1200 mg every 3 weeks, or
• 1680 mg every 4 weeks

Adjuvant treatment of NSCLC: Up to 1 year

• 840 mg every 2 weeks, or
• 1200 mg every 3 weeks, or
• 1680 mg every 4 weeks

Adults with ASPS:

• 840 mg every 2 weeks, or
• 1200 mg every 3 weeks, or
• 1680 mg every 4 weeks

IV infusion (in combination therapy)

NSCLC: Administer atezolizumab before chemotherapy and bevacizumab when given on the same day until disease progression or unacceptable toxicity.

• 840 mg every 2 weeks, or
• 1200 mg every 3 weeks, or
• 1680 mg every 4 weeks

SCLC: Administer atezolizumab before chemotherapy when given on the same day.

• 840 mg every 2 weeks, or
• 1200 mg every 3 weeks, or
• 1680 mg every 4 weeks

HCC: Administer atezolizumab before bevacizumab when given on the same day. Bevacizumab is administered at 15 mg/kg every 3 weeks.

• 840 mg every 2 weeks, or
• 1200 mg every 3 weeks, or
• 1680 mg every 4 weeks

Melanoma: Administer atezolizumab with cobimetinib 60 mg orally once daily (21 days on and 7 days off) and vemurafenib 720 mg orally twice daily. Before initiating atezolizumab, patients should receive a 28-day treatment cycle of cobimetinib 60 mg orally once daily (21 days on and 7 days off) and vemurafenib 960 mg orally twice daily from Days 1 to 21 and vemurafenib 720 mg orally twice daily from Days 22 to 28.

• 840 mg every 2 weeks, or
• 1200 mg every 3 weeks, or
• 1680 mg every 4 weeks

SQ injection 

This is administered subcutaneously in the thigh over approximately 7 minutes every 3 weeks. 

NSCLC: Administer as monotherapy for up to 1 year unless there is disease recurrence or unacceptable toxicity.

Metastatic NSCLC: Administer atezolizumab as monotherapy for up to 1 year until disease progression or unacceptable toxicity.

NSCLC: Administer atezolizumab before chemotherapy and bevacizumab when given on the same day. Treat until disease progression or unacceptable toxicity.

SCLC: Administer atezolizumab before chemotherapy when given on the same day. Treat until disease progression or unacceptable toxicity.

HCC: Administer atezolizumab before bevacizumab when given on the same day. Bevacizumab is administered intravenously at 15 mg/kg every 3 weeks. Treat until disease progression or unacceptable toxicity.

Melanoma: Before initiating atezolizumab, patients should receive the following 28-day cobimetinib and vemurafenib treatment cycle. Treat until disease progression or unacceptable toxicity.

• Days 1 to 21: cobimetinib 60 mg orally once daily in combination with 960 mg of oral vemurafenib twice daily
• Days 22 to 28: withhold cobimetinib and administer vemurafenib 720 mg orally twice daily

ASPS: Administer atezolizumab monotherapy until disease progression or unacceptable toxicity.

Specific Patient Populations

Pregnancy considerations: Before starting treatment with atezolizumab, confirm the pregnancy status of women who could become pregnant. Inform these women about the possible risks to a fetus and recommend the use of effective contraception during treatment and for 5 months following the last dose. There is a lack of data regarding its use in pregnancy. However, based on its mechanism of action, it can potentially cause fetal harm. Animal studies show that blocking the PD-L1/PD-1 pathway could enhance the possibility of immune-related rejection of the fetus, leading to fetal death.

Breastfeeding considerations: Breastfeeding is not recommended while on therapy with atezolizumab and at least for 5 months after the last dose.

Pediatric patients: The dosage for children aged 2 and older with ASPS is 15 mg/kg (maximum 1200 mg) every 3 weeks.

Adverse Effects

As with other approved PD-1/PD-L1-targeted therapies, the administration 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.[11][12][13]

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, 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 4 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) 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 4 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, hypothyroidism, hypophysitis, and diabetes, either alone related to one endocrine organ or in combination.

Immune-mediated hepatitis

• Immune-mediated hepatitis typically manifests with elevated liver function markers.
• Based on the severity of liver test abnormalities and hepatic dysfunction, immune-mediated hepatitis is classified into 4 grades:
  • Grade 1: Elevation of AST/ALT <3 times (3x) the upper limit of normal (ULN) or total bilirubin <1.5x ULN
  • Grade 2: Elevation of AST/ALT 3x to 5x ULN or total bilirubin >1.5 to ≤ 3x ULN
  • Grade 3: Elevation of AST/ALT >5x to 20x ULN or total bilirubin 3 to 10x ULN
  • Grade 4: AST/ALT > 20x ULN or total bilirubin >10x ULN (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 4 grades: 
  • Grade 1: asymptomatic and limited to <25% involvement of the lung parenchyma or 1 lobe of the lung
  • Grade 2: moderate symptoms and involvement of 25% to 50% of the lung parenchyma or more than 1 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 4 types based on renal function: 
  • Grade 1: An increase in creatinine level >0.3 mg/dL or 1.5 to 2.0 times compared to the patient's baseline value
  • Grade 2: An increase in creatinine level 2x to 3x baseline
  • Grade 3: An increase in creatinine level >4.0 mg/dL or >3x baseline
  • Grade 4: Worsening renal function requiring hemodialysis

Immune-mediated neurological toxicities

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

Other common adverse reactions that occurred in patients receiving atezolizumab monotherapy during clinical trials are listed by system below.[14][2]

• Musculoskeletal: back pain, neck pain
• Metabolic: 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: decreased hemoglobin, anemia, thrombocytopenia, lymphopenia
• Hepatobiliary: elevated liver function markers
• Renal: elevated serum creatinine

Contraindications

Contraindications

TECENTRIQ HYBREZA should not be used in individuals with a known allergy to hyaluronidase or any of its components.

Warnings/Precautions

Immune-mediated adverse reactions

Pneumonitis:

• Grade 2: Withhold*
• Grade 3 or 4: Permanently discontinue

Colitis:

• Grade 2 or 3: Withhold*
• Grade 4: Permanently discontinue

Hepatitis with no liver tumor:

• AST or ALT >3x and <8x ULN, or total bilirubin >1.5x and <3x ULN: Withhold*
• AST or ALT >8x ULN, or total bilirubin >3x ULN: Permanently discontinue

Hepatitis with liver tumor:

• Baseline AST or ALT is >1x and <3x ULN and increases to >5x and <10x ULN, or baseline AST or ALT is >3x and <5x ULN and increases to >8x and <10x ULN: Withhold*
• AST or ALT increases to >10x ULN, or total bilirubin increases to >3x ULN: Permanently discontinue
• If baseline AST and ALT ≤ULN: withhold or permanently discontinue (based on recommendations for hepatitis with no liver involvement)

Endocrinopathy:

• Grade 3 or 4: Hold until clinically stable or permanently discontinue (depending on severity)

Nephritis with renal dysfunction:

• Grade 2 or 3 creatinine elevation: Withhold*
• Grade 4 creatinine elevation: Permanently discontinue

Exfoliative dermatologic conditions:

• Suspected SJS, TEN, or DRESS: Withhold
• Confirmed SJS, TEN, or DRESS: Permanently discontinue

Myocarditis or pericarditis:

• Grade 2, 3, or 4: Permanently discontinue

Neurological toxicity:

• Grade 2: Withhold*
• Grade 3 or 4: Permanently discontinue

Other adverse reactions

Infusion-related reactions

• Grade 1 or 2: Hold or slow the injection rate; premedication with antipyretics and antihistamines may be considered for subsequent doses.
• Grade 3 or 4: Permanently discontinue

DRESS = Drug rash with eosinophilia and systemic symptoms, SJS = Stevens-Johnson syndrome, TEN = toxic epidermal necrolysis; Based on Common Terminology Criteria for Adverse Events (CTCAE), version 5; † Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if there is no partial or full resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg daily or less (or equivalent) within 12 weeks of initiating steroids.

Complications of allogeneic HSCT

Assess the benefits and risks of using a PD-1/PD-L1 blocking antibody before or after allogeneic hematopoietic stem cell transplantation (HSCT). Monitor patients closely for signs of transplant-related complications and take action as needed.

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 for patients undergoing atezolizumab therapy.[15]

• 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 the initiation of treatment and during treatment to evaluate for new-onset diabetes and adverse reactions such as immune-mediated nephritis, immune-mediated hepatitis, and immune-mediated thyroid dysfunction, respectively.
• Atezolizumab must be held for patients experiencing grade 2 immune-mediated adverse reactions and should be permanently discontinued for grade 3 and 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.[12][11] There is also no available data about the drug-drug interaction potential of atezolizumab.[13]

Immune-mediated colitis

• Grade 1 colitis should be treated with symptomatic management.
• Atezolizumab must be held for patients experiencing grade 2 and 3 colitis, and patients should be started on steroids with a slow taper.
• Atezolizumab should be permanently discontinued for patients experiencing 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 for patients experiencing Grade 2 hepatitis. Patients should be started on oral or IV steroids followed by a slow taper.
• Atezolizumab must be permanently discontinued for patients experiencing Grade 3 and 4 immune-mediated hepatitis; these 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
  • Consider starting insulin if indicated.

• Atezolizumab should be held for patients with grade 2 to 4 endocrinopathies.

• Immune-mediated renal dysfunction and nephritis
  • Atezolizumab should be held for patients with grade 2 toxicity or higher, and corticosteroid administration should be considered.

• Immune-mediated cutaneous adverse reactions
  • Topical steroids are indicated for grade 1 or 2 toxicity.
  • Atezolizumab must be held in grade 2 and 3 toxicity; patients with grade 2 toxicity should be treated with oral 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).

Enhancing Healthcare Team Outcomes

Given its propensity to cause immune-mediated adverse reactions, the clinical use of atezolizumab requires an interprofessional team approach of healthcare professionals to enhance safety and efficacy. Clinicians prescribing this drug should educate their patients about the immediate and long-term adverse reactions. The clinical pharmacist and the nurse administering the drug infusion to the patients about the mechanism of action, recommended doses, and infusion-related adverse reactions of atezolizumab. Laboratory tests must be performed and reviewed before and during treatment with atezolizumab. This interprofessional approach will yield optimal therapeutic results.

There should be close communication between the ordering clinicians, the pharmacist, and the nurse about any infusion-related reactions or laboratory abnormalities related to the drug. Signs and symptoms of immune-mediated adverse reactions during treatment or long after discontinuation of atezolizumab should be monitored, and appropriate clinical investigations must be performed to rule out other etiologies. Detailed prescribing information and essential dose management information specific to adverse reactions should always be available for review. Applicable clinical specialties must be promptly consulted. Such a holistic approach would lead to timely identification and management of this drug's potential adverse effects, resulting in improved outcomes.