atezolizumab (Rx)

All grades of severity are listed unless otherwise indicated

>10% (NSCLC [in combination with bevacizumab, paclitaxel, and carboplatin])

Anemia (67-83%)

Hyperglycemia (61%)

Neuropathy (56%)

Increased BUN (52%)

Neutropenia (52%)

Fatigue/asthenia (44-50%)

Lymphocytopenia (49%)

Alopecia (48%)

Lymphopenia (48%)

Hypoalbuminemia (40-48%)

Hyponatremia (38-42%)

Myalgia/pain (42%)

Hypomagnesemia (26-42%)

Increased AST (31-40%)

Nausea (18-39%)

Increased alkaline phosphatase (39%)

Increased ALT (27-37%)

Diarrhea (16-33%)

Neutropenia, Grade 3 or 4 (31%)

Increased TSH (30%)

Constipation (18-30%)

Decreased appetite (23-29%)

Hyperkalemia (28%)

Increased creatinine (23-28%)

Hypocalcemia (26%)

Arthralgia (26%)

Cough (20-26%)

Hypertension (25%)

Hyperphosphatemia (25%)

Hypophosphatemia (25%)

Hypokalemia (23%)

Rash (12-23%)

Dyspnea (22%)

Pyrexia (18-19%)

Vomiting (19%)

Epistaxis (17%)

Lymphopenia, Grade 3 or 4 (17%)

Proteinuria (16%)

Headache (16%)

Arthralgia (1-12%)

>10% (TNBC)

Alopecia (56%)

Fatigue (47%)

Peripheral neuropathies (47%)

Nausea (46%)

Diarrhea (33%)

Anemia (28%)

Constipation (25%)

Headache (23%)

Neutropenia (21%)

Vomiting (20%)

Decreased appetite (20%)

Pyrexia (19%)

Arthralgia (18%)

Rash (17%)

Peripheral edema (15%)

Back pain (15%)

Myalgia (14%)

Pruritus (14%)

Dizziness (14%)

Dysgeusia (14%)

Hypothyroidism (14%)

Decreased neutrophils (13%)

Urinary tract infection (12%)

Asthenia (12%)

Pain in extremity (11%)

Upper respiratory infection (11%)

Nasopharyngitis (11%)

>10% (SCLC)

Anemia (94%)

Neutropenia (73%)

Hyperglycemia (67%)

Thrombocytopenia (58%)

Lymphopenia (46%)

Neutropenia, Grade 3-4 (45%)

Increased alkaline phosphatase (38%)

Fatigue/asthenia (39%)

Nausea (38%)

Alopecia (37%)

Hyponatremia (34%)

Hypoalbuminemia (32%)

Hypomagnesemia (31%)

Decreased TSH (28%)

Decreased appetite (27%)

Constipation (26%)

Hypocalcemia (26%)

Increased ALT (26%)

Increased AST (22%)

Increased blood creatinine (22%)

Neutropenia (22%)

Hyperphosphatemia (21%)

Increased TSH (21%)

Thrombocytopenia, Grade 3-4 (20%)

Vomiting (20%)

Anemia, Grade 3-4 (17%)

Hyponatremia, Grade 3-4 (15%)

Lymphopenia, Grade 3-4 (14%)

Hyperglycemia, Grade 3-4 (10%)

>10% (HCC)

Increased AST (86%)

Increased alkaline phosphatase (70%)

Decreased platelet (68%)

Decreased lymphocytes (62%)

Increased ALT (62%)

Decreased albumin (60%)

Decreased hemoglobin (58%)

Decreased sodium (54%)

Increased glucose (48%)

Decreased leukocytes (32%)

Decreased calcium (30%)

Hypertension (30%)

Decreased phosphorus (26%)

Fatigue/asthenia (26%)

Decreased neutrophil (23%)

Increased potassium (23%)

Hypomagnesemia (22%)

Proteinuria (20%)

Pruritus (19%)

Diarrhea (19%)

Decreased appetite (18%)

Pyrexia (18%)

Increased AST, Grade 3-4 (16%)

Hypertension, Grade 3-4 (15%)

Constipation (13%)

Decreased lymphocytes, Grade 3-4 (13%)

Decreased sodium, Grade 3-4 (13%)

Abdominal pain (12%)

Nausea (12%)

Rash (12%)

Cough (12%)

Infusion-related reactions (11%)

>10% (Melanoma [in combination with cobimetinib and vemurafenib])

Increased creatine kinase (88%)

Decreased lymphocytes (80%)

Increased AST (80%)

Increased ALT (79%)

Decreased hemoglobin (77%)

Increased triacylglycerol lipase (75%)

Increased alkaline phosphatase (73%)

Decreased phosphorus (67%)

Musculoskeletal pain (62%)

Increased amylase (51%)

Fatigue (51%)

Hepatotoxicity (50%)

Pyrexia (49%)

Increased blood urea nitrogen (47%)

Decreased albumin (43%)

Increased bilirubin (42%)

Decreased calcium (41%)

Decreased sodium (40%)

Decreased thyroid stimulating hormone (TSH) (38%)

Increased TSH (37%)

Decreased potassium (36%)

Decreased platelet (34%)

Increased triiodothyronine (33%)

Increased free thyroxine (32%)

Decreased total triiodothyronine (32%)

Nausea (30%)

Increased potassium (29%)

Decreased triiodothyronine (27%)

Decreased neutrophils (26%)

Edema (26%)

Stomatitis (23%)

Hypothyroidism (22%)

Increased Sodium (20%)

Hyperthyroidism (18%)

Hypertension (17%)

Grade 3 or 4

• Increased triacylglycerol lipase (46%)
• Decreased lymphocytes (24%)
• Increased creatinine kinase (22%)
• Decreased phosphorus (22%)
• Hepatoxicity (21%)
• Increased ALT (18%)
• Increased AST (13%)
• Increased amylase (13%)

1-10% (NSCLC [in combination with bevacizumab paclitaxel, and carboplatin])

Hyponatremia, Grade 3 or 4 (10%)

Anemia, Grade 3 or 4 (10%)

Hypertension, Grade 3 or 4 (9%)

Hypokalemia, Grade 3 or 4 (7%)

Fatigue/asthenia, Grade 3 or 4 (6%)

Diarrhea, Grade 3 or 4 (6%)

Increased ALT, Grade 3 or 4 (6%)

Nausea, Grade 3 or 4 (4%)

Decrease appetite, Grade 3 or 4 (4%)

Increased AST, Grade 3 or 4 (4%)

Hypophosphatemia, Grade 3 or 4 (4%)

Hyperkalemia, Grade 3 or 4 (3%)

Neuropathy, Grade 3 or 4 (3%)

Myalgia/pain, Grade 3 or 4 (1.3-3%)

Proteinuria, Grade 3 or 4 (3%)

Hypoalbuminemia, Grade 3 or 4 (3%)

Hypocalcemia, Grade 3 or 4 (3%)

Dyspnea, Grade 3 or 4 (2.8%)

Rash, Grade 3 or 4 (2%)

Hypomagnesemia, Grade 3 or 4 (2%)

Increased alkaline phosphatase, Grade 3 or 4 (2%)

Vomiting, Grade 3 or 4 (1%)

Epistaxis, Grade 3 or 4 (1%)

Increased creatinine (1%)

1-10% (TNBC)

Increased ALT (10%)

Abdominal pain (10%)

Neutropenia, Grade 3 or 4 (8%)

Decreased neutrophils, Grade 3 or 4 (4.6%)

Anemia, Grade 3 or 4 (2.9%)

Diarrhea, Grade 3 or 4 (1.3%)

Nausea, Grade 3 or 4 (1.1%)

1-10% (SCLC)

Fatigue/asthenia, Grade 3-4 (5%)

Hypomagnesemia, Grade 3-4 (5%)

Pneumonia (4.5%)

Increased blood creatinine, Grade 3-4 (4%)

Neutropenia, Grade 3 or 4 (3.5%)

Hypocalcemia, Grade 3-4 (3%)

Increased ALT, Grade 3-4 (3%)

Febrile neutropenia (2.5%)

Thrombocytopenia (2.5%)

Vomiting, Grade 3-4 (2%)

Increased AST, Grade 3-4 (1%)

Nausea, Grade 3-4 (1%)

Constipation, Grade 3-4 (1%)

Decreased appetite, Grade 3-4 (1%)

Increased alkaline phosphatase, Grade 3-4 (1%)

Hypoalbuminemia, Grade 3-4 (1%)

1-10% (HCC)

Increased glucose, Grade 3-4 (9%)

Increased ALT, Grade 3-4 (8%)

Increased bilirubin, Grade 3-4 (8%)

Decreased phosphorus, Grade 3-4 (4.7%)

Increased alkaline phosphatase, Grade 3-4 (4%)

Increased leukocytes, Grade 3-4 (3.4%)

Decreased hemoglobin, Grade 3-4 (3.1%)

Proteinuria, Grade 3-4 (3%)

Infusion-related reactions, Grade 3-4 (2.4%)

Decreased neutrophil (2.3%)

Fatigue/asthenia, Grade 3-4 (2%)

Increased potassium, Grade 3-4 (1.9%)

Diarrhea, Grade 3-4 (1.8%)

Decreased albumin, Grade 3-4 (1.5%)

Decreased appetite, Grade 3-4 (1.2%)

1-10% (Melanoma [in combination with cobimetinib and vemurafenib])

Infusion related reaction (10%)

Pneumonitis (10%)

Arrhythmias (<10%)

Ejection fraction decreased (<10%)

Electrocardiogram QT prolonged (<10%)

Uveitis (<10%)

Pancreatitis (<10%)

Pneumonia (<10%)

Urinary tract infection (<10%)

Hyperglycemia (<10%)

Dizziness (<10%)

Dysgeusia (<10%)

Syncope (<10%)

Dyspnea (<10%)

Oropharyngeal pain (<10%)

Grade 3 or 4

• Hypertension (10%)
• Increased alkaline phosphatase (6%)
• Decreased sodium (5%)
• Decreased potassium (5%)
• Musculoskeletal pain (4.3%)
• Increased bilirubin (3.1%)
• Fatigue (3%)
• Infusion-related reaction (2.6%)
• Pyrexia (1.7%)
• Stomatitis (1.3%)
• Increased potassium (1.3%)
• Decreased calcium (1.3%)
• Pneumonitis (1.3%)

<1% (NSCLC [in combination with bevacizumab paclitaxel, and carboplatin])

Headache, Grade 3 or 4

Pyrexia, Grade 3 or 4

Constipation, Grade 3 or 4

Cough, Grade 3 or 4

<1% (TNBC)

Alopecia, Grade 3 or 4

Rash, Grade 3 or 4

Pyrexia, Grade 3 or 4

Peripheral edema, Grade 3 or 4

Asthenia, Grade 3 or 4

Constipation, Grade 3 or 4

Vomiting, Grade 3 or 4

Abdominal pain, Grade 3 or 4

Headache, Grade 3 or 4

Dyspnea, Grade 3 or 4

Decreased appetite, Grade 3 or 4

Arthralgia, Grade 3 or 4

Myalgia, Grade 3 or 4

Pain in extremity, Grade 3 or 4

Urinary tract infection, Grade 3 or 4

<1% (HCC)

Decreased calcium, Grade 3-4 (0.3%)

<1% (Melanoma [in combination with cobimetinib and vemurafenib])

Grade 3 or 4

• Hyperthyroidism (<1%)
• Nausea (<1%)
• Edema (<1%)
• Decreased albumin (0.9%)

Postmarketing Reports

Cardiac: Myocarditis, pericarditis, pericardial effusion, cardiac tamponade

Dermatologic: Bullous dermatitis, pemphigoid, erythema multiforme, Stevens-Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN)

Gastrointestinal: Pancreatitis, including increases in serum amylase or lipase levels

General: Systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis

Hematological: Autoimmune hemolytic anemia, immune thrombocytopenic purpura

Musculoskeletal: Myositis, rhabdomyolysis

Neurological: Guillain-Barre syndrome, myasthenia syndrome/myasthenia gravis, demyelination, immune-related meningoencephalitis, aseptic meningitis, encephalitis, facial and abducens nerve paresis, polymyalgia rheumatica, autoimmune neuropathy, and Vogt-Koyanagi- Harada syndrome

Ophthalmological: Uveitis, iritis

Renal: Nephrotic syndrome, nephritis

Vascular: Vasculitis

Hyperthyroidism

Increased transaminases or alkaline phosphate

Infusion-related reactions

Contraindications

None

Cautions

Immune-mediated pneumonitis or interstitial lung disease occurred; monitor for signs and symptoms of pneumonitis; incidence of pneumonitis is higher in patient who have received thoracic radiation

May cause liver test abnormalities and immune-mediated hepatitis; fatal cases reported; monitor for signs and symptoms of hepatitis, during and after discontinuation of therapy, including clinical chemistry monitoring

Immune-mediated colitis or diarrhea reported

May cause severe or life-threatening infusion-related reactions; monitor for signs and symptoms of infusion-related reactions

Severe infections (eg, sepsis, herpes encephalitis, mycobacterial infection) leading to retroperitoneal hemorrhage reported; most common infection was upper respiratory tract infection; monitor for signs and symptoms of infection

Hematologic/immune effects may include hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection

Uveitis, iritis, and other ocular inflammatory toxicities can occur; some cases can be associated with retinal detachment; various grades of visual impairment, including blindness, can occur; if uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss

Do not substitute paclitaxel protein-bound with paclitaxel in combination with drug in clinical practice for metastatic TNBC outside of controlled trials

Can cause fetal harm; advise females of reproductive potential of potential risk to a fetus and use of effective contraception

Immune-related endocrinopathies

• Immune-related myasthenic syndrome/myasthenia gravis, Guillain-Barré syndrome, or meningoencephalitis reported; permanently discontinue for any grade
• Monitor for clinical signs and symptoms of meningitis or encephalitis
• Monitor for symptoms of motor and sensory neuropathy
• Symptomatic pancreatitis without an alternative etiology occurred in 0.1% of patients across clinical trials; pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis; monitor for signs and symptoms of acute pancreatitis
• Monitor for signs and symptoms of myocarditis
• Thyroid disorders may occur; thyroiditis can present with or without endocrinopathy; not reported to lead to permanent discontinuation; hypothyroidism can follow hyperthyroidism monitor thyroid function prior to and periodically during treatment; initiate hormone replacement therapy or medical management of hyperthyroidism as clinically indicated; continue therapy for hypothyroidism and interrupt for hyperthyroidism or permanently discontinue therapy based on severity
• Adrenal insufficiency may occur; monitor patients for clinical signs and symptoms of adrenal insufficiency
• Type 1 diabetes mellitus reported; monitor for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated; interrupt treatment based on severity
• Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatic reported
• Hypoparathyroidism may occur
• Hypophysitis/hypopituitarism may occur; hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts; hypophysitis can cause hypopituitarism; withhold or permanently discontinue therapy depending on severity; for Grade 2 or higher hypophysitis, initiate prednisone 1-2 mg/kg/day or equivalents, followed by a taper and hormone replacement therapy as clinically indicated

FDA Safety Alert

• On 9/8/2020, FDA alerted health care professionals, oncology clinical investigators, and patients that the combination of atezolizumab and paclitaxel in previously untreated inoperable locally advanced or metastatic TNBC was ineffective
• Alert was based on results from the IMpassion131 trial, a doubled-blind, multicenter, placebo-controlled trial comparing atezolizumab or placebo in combination with paclitaxel for patients with metastatic TNBC
• In this trial, atezolizumab and paclitaxel did not significantly reduce the risk of cancer progression and death compared with placebo and paclitaxel in PD-L1-positive population
• Increase in risk of death observed in patients treated with atezolizumab plus paclitaxel compared with placebo and paclitaxel in PD-L1-positive population; the efficacy of atezolizumab in combination with paclitaxel in patients with unresectable locally advanced or metastatic TNBC has not been demonstrated
• Interim overall survival results favored paclitaxel and placebo, over paclitaxel and atezolizumab in both the PD-L1-positive population and total population

Immune-mediated adverse reactions

• Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue; reactions can occur at any time after starting a PD­1/PD-L1 blocking antibody
• While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies
• Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies; monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions
• Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment; in cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection
• Institute medical management promptly, including specialty consultation as appropriate; withhold or permanently discontinue therapy depending on severity; in general, if therapy requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less
• Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month; consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy

Complications of allogeneic HSCT

• Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody
• Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause)
• These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT
• Follow patients closely for evidence of transplant-related complications and intervene promptly; consider benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT

Colitis

• Drug can cause immune-mediated colitis that can present with diarrhea, abdominal pain, and lower gastrointestinal (GI) bleeding
• Cytomegalovirus (CMV) infection/ reactivation reported in patients with corticosteroid-refractory immune-mediated colitis
• In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies

Pregnancy

Based on its mechanism of action, can cause fetal harm when administered during pregnancy

No available data on use in pregnant women

Animal data

• Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of immune-related rejection of the developing fetus, resulting in fetal death

Contraception

• Advise females of reproductive potential to use effective contraception during treatment and for at least 5 months following the last dose

Infertility

• 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, potential for absorption and harm to the infant is unknown

Advise lactating woman not to breastfeed during treatment and for at least 5 months after the last dose

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Monoclonal antibody to programmed cell death ligand-1 protein (PDL1); binding PDL1 blocks the interaction between PDL-1 and its ligands (including B7.1 receptors)

PDL-1

• PDL1 is expressed on the surface of activated T cells under normal conditions; binding PDL1 inhibits immune activation and reduces T-cell cytotoxic activity when bound
• This negative feedback loop is essential for maintaining normal immune responses and limits T-cell activity to protect normal cells during chronic inflammation
• Tumor cells may circumvent T-cell–mediated cytotoxicity by expressing PDL1 on the tumor itself or on tumor-infiltrating immune cells, resulting in the inhibition of immune-mediated killing of tumor cells

Absorption

Systemic accumulation over 2-3 cycles of repeated dosing

• Peak plasma concentration: 1.91-fold
• Minimum plasma concentration: 1.46-fold
• AUC: 2.75-fold

Steady state: 6-9 weeks

Distribution

Vd: 6.9 L

Elimination

Half-life: 27 days

Clearance: 0.2 L/day

IV Compatibilities

0.9% NaCl

IV Preparation

Visually inspect solution for particulate matter and discoloration prior to administration

Solution should appear colorless to slightly yellow; discard if cloudy, discolored, or particles observed

Do NOT shake vial

Dilution

• Withdraw required amount from vial
• Dilute to a final concentration between 3.2-16.8 mg/mL in a polyvinyl chloride, polyethylene, or polyolefin infusion bag containing 0.9% NaCl
• Dilute with 0.9% NaCl only
• Gently invert diluted solution; do not shake
• Discard partially used or empty vial

IV Administration

For IV infusion only; do not give as IV bolus or IV push

Administer through an IV line with or without a sterile, nonpyrogenic, low-protein binding in-line filter (pore size of 0.2-0.22 micron)

First IV infusion: Infuse over 60 min

Subsequent IV infusions: If first infusion is tolerated, may administer subsequent doses over 30 min

When administering in combination with chemotherapy, administer atezolizumab before chemotherapy when given on the same day

Do not coadminister with other drugs through the same IV line

Storage

Contains no preservatives

Do not freeze

Do not shake

Unopened vials

• Refrigerate at 2-8°C (36-46°F) in original carton to protect from light

Diluted infusion solution

• Administer immediately once prepared

• If not used immediately, it can be stored by either:

  • At room temperature for no more than 6 hr from time of preparation (includes infusion time) OR
  • Refrigerate at 2-8°C (36-46°F) for no more than 24 hr