Atezolizumab is an IgG1 kappa monoclonal antibody that binds to and blocks programmed death-ligand 1 (PD-L1). It is indicated in adult patients for certain types of melanoma, hepatocellular cancer, non-small cell lung cancer, and small cell lung cancer. Atezolizumab is also indicated in adult and pediatric patients aged 2 years and older for the treatment of unresectable or metastatic alveolar soft part sarcoma. Treatment with atezolizumab may result in severe immune-related adverse reactions requiring interruption or discontinuation of therapy, as well as treatment with high-dose corticosteroids. Infusion-related reactions may also occur.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Emetic Risk
-Minimal
Route-Specific Administration
Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
Dilution
-Withdraw the required volume of atezolizumab from the vial(s).
-Dilute to a final concentration between 3.2 mg/mL and 16.8 mg/mL in a polyvinyl chloride (PVC), polyethylene (PE), or polyolefin (PO) infusion bag containing 0.9% Sodium Chloride Injection.
-Mix by gentle inversion; do not shake.
-Storage after dilution: Store diluted solution at room temperature for no more than 6 hours (including infusion time), or under refrigeration (2 to 8 degrees C; 36 to 46 degrees F) for no more than 24 hours from the time of preparation.
Infusion
-Administer atezolizumab prior to chemotherapy or other antineoplastic agents when given on the same day.
-Do not infuse through the same IV line with other drugs.
-Administer the first dose intravenously, with or without a sterile, non-pyrogenic, low protein-binding in-line filter (0.2 to 0.22 micron), over 60 minutes; do not administer atezolizumab as an IV push or bolus. If tolerated, all subsequent infusions may be infused over 30 minutes.
-Interrupt or slow administration for grade 2 infusion-related reactions; the infusion may resume when symptoms have resolved to grade 0 or 1.
-Permanently discontinue atezolizumab for grade 3 or 4 infusion-related reactions.
Immune-mediated pneumonitis or interstitial lung disease requiring the use of systemic corticosteroids has occurred in patients treated with atezolizumab, including fatal cases; the incidence is higher in patients who have received prior thoracic radiation. Monitor patients for signs and symptoms of pneumonitis; if suspected, confirm with radiographic imaging. Atezolizumab therapy may need to be temporarily withheld or permanently discontinued; treatment with corticosteroids may be necessary. Pneumonitis occurred in 1.6% to 3.8% (grade 3 or 4, 0.8 to 1%; grade 5, 0.2% or less) of patients with various cancers receiving atezolizumab monotherapy (n = 2,121). Systemic corticosteroids were required in 55% to 63% of patients, with resolution in 69% to 84% of these patient. Of 39 patients with advanced cancers (n = 2,616) who had an interruption of therapy for pneumonitis, 25 reinitiated treatment after symptom improvement; of these, 4% had recurrence of pneumonitis. Immune-mediated pneumonitis including interstitial lung disease occurred in 13% (grade 3 or 4, 1.3%) of patients who received atezolizumab plus cobimetinib and vemurafenib (n = 230) in a randomized trial.
Cough including upper-airway cough syndrome (12% to 45%; grade 3 or 4, less than 1%) and dyspnea (33% or less; grade 3 or 4, 4.9% or less) were reported in patients who received atezolizumab monotherapy or in combination with other anticancer therapy in clinical trials. Allergic rhinitis occurred in 16% of patients (n = 49; age range, 12 to 70 years) with unresectable or metastatic alveolar soft part sarcoma who received atezolizumab in a clinical study.
Pleural effusion occurred in more than 1% of patients with metastatic NSCLC treated with atezolizumab monotherapy (n = 609) in a randomized clinical trial.
Immune-mediated hepatitis occurred in 1.8% (grade 3 or 4, 0.7%; grade 5, less than 0.1%) of patients treated with atezolizumab monotherapy in clinical trials (n = 2,616); the incidence was higher in patients treated with atezolizumab in combination with cobimetinib and vemurafenib (n = 230) in 1 clinical trial (6.1%; grade 3 or 4, 3%). Monitor liver function tests; treatment with corticosteroids and an interruption or discontinuation of atezolizumab therapy may be necessary. Systemic corticosteroids were required in 25% of patients receiving monotherapy and in 50% of those who received atezolizumab plus cobimetinib/vemurafenib; resolution occurred in 50% and 93% of patients, respectively. Four of 6 patients who had an interruption of atezolizumab monotherapy due to hepatitis reinitiated treatment after symptom improvement; none had recurrence of hepatitis. Three of the 4 patients treated with atezolizumab/cobimetinib/vemurafenib who had an interruption of therapy due to hepatitis reinitiated therapy after symptom improvement; 33% had recurrence of hepatitis. Monitor liver function tests during therapy.
Immune-mediated colitis occurred in 1% (grade 3, 0.5%) of patients treated with atezolizumab monotherapy in clinical trials (n = 2,616); colitis can present with diarrhea, stomach pain, or lower gastrointestinal bleeding. Systemic corticosteroids were required in 50% of patients with colitis, with resolution occurring in 73% of patients. Of the 12 patients who had an interruption of therapy for colitis, 8 reinitiated therapy; 25% of these patients had a recurrence of colitis. Consider repeating an infectious workup in patients with corticosteroid-refractory immune-mediated colitis, as cytomegalovirus (CMV) infections/reactivations have been reported in these patients. Diarrhea including autoimmune colitis and enterocolitis occurred in 11% to 27% (grade 3 or 4, 2% or less) of patients with advanced hepatocellular cancer (in combination with bevacizumab), non-small cell lung cancer (NSCLC), or alveolar soft part sarcoma who received atezolizumab in clinical trials; the incidence was higher in advanced NSCLC patients treated with atezolizumab in combination with carboplatin and paclitaxel or nab-paclitaxel (33% to 43%; grade 3 or 4, 6%).
Constipation was reported in 12% to 18% (grade 3 or 4, 1% or less) of patients with non-small cell lung cancer treated with atezolizumab monotherapy in clinical trials. The incidence was similar in patients with hepatocellular cancer treated with atezolizumab in combination with bevacizumab (13%). Constipation occurred in 33% of patients (n = 49; age range, 12 to 70 years) with unresectable or metastatic alveolar soft part sarcoma who received atezolizumab in a clinical study. The addition of atezolizumab to chemotherapy has a small, but inconsistent effect on constipation compared to chemotherapy alone. In patients with metastatic NSCLC, more patients who received atezolizumab added to either bevacizumab/paclitaxel/carboplatin (30% vs. 23%; grade 3 or 4, 0.3% vs. 0.3%) or nab-paclitaxel/carboplatin (36% vs. 31%; grade 3 or 4, 1.1% vs. 0%) experienced constipation compared to chemotherapy alone. In patients with SCLC, patients treated with atezolizumab plus carboplatin/etoposide had a lower incidence of constipation compared to placebo plus carboplatin/etoposide (26% vs. 30%; grade 3 or 4, 1% vs. 1%). Fatal cases of GI obstruction and intestinal/bowel ischemia have been reported.
Abdominal pain was reported in 12% of patients with hepatocellular cancer receiving atezolizumab in combination with bevacizumab in a clinical trial. Abdominal pain occurred in 25% of patients (n = 49; age range, 12 to 70 years) with unresectable or metastatic alveolar soft part sarcoma who received atezolizumab in a clinical study.
Nausea occurred in 14% to 18% (grade 3 or 4, less than 1%) patients with advanced non-small cell lung cancer (NSCLC) treated with atezolizumab monotherapy in clinical trials. Neither nausea nor vomiting were reported in patients receiving adjuvant treatment for NSCLC with atezolizumab following completion of platinum-based chemotherapy. Nausea (12%) and vomiting (10%) were reported in patients with hepatocellular cancer treated with atezolizumab in combination with bevacizumab. Nausea (43%) and vomiting (37%) occurred in patients (n = 49; age range, 12 to 70 years) with unresectable or metastatic alveolar soft part sarcoma who received atezolizumab in a clinical study. The addition of atezolizumab to chemotherapy (e.g., bevacizumab/paclitaxel/carboplatin, nab-paclitaxel/carboplatin, or carboplatin/etoposide) increased the incidence of nausea and vomiting by less than 10% each compared to chemotherapy alone in 3 clinical trials. Nausea occurred less often in melanoma patients treated with atezolizumab plus cobimetinib and vemurafenib compared with those who received placebo plus cobimetinib and vemurafenib (30% vs. 32%; grade 3 or 4, less than 1% vs. 2.5%). Stomatitis occurred in 23% (grade 3 or 4, 1.3%) of patients in the atezolizumab arm of this trial and in 15% (grade 3 or 4, less than 1%) of those in the placebo arm including mucosal inflammation, aphthous ulcer, mouth/oral ulceration, cheilitis, and glossitis; oropharyngeal pain was also reported in less than 10% of patients in the atezolizumab arm.
Dehydration was reported as leading to a discontinuation of therapy in more than 1% of patients with metastatic non-small cell lung cancer treated with either bevacizumab/paclitaxel, carboplatin or nab-paclitaxel/carboplatin in clinical trials.
Immune-mediated endocrinopathies have been reported in patients treated with atezolizumab. Adrenocortical insufficiency occurred in 0.4% to 1.2% (grade 3, 0.4% or less) of patients treated with atezolizumab monotherapy across clinical trials and indications (n = 2,616). Systemic corticosteroids were required in 82% to 83% of patients; 7 of these 17 patients remained on systemic corticosteroids. Grade 2 hypophysitis was also reported in 2 patients (less than 0.1%) receiving atezolizumab monotherapy. One of these patients required treatment with systemic corticosteroids; hypophysitis did not resolve in either patient. Monitor patients for signs and symptoms of hypophysitis and adrenal insufficiency; an interruption or discontinuation of therapy may be necessary. Administer corticosteroids and hormone replacement as clinically indicated.
Immune-mediated hypothyroidism occurred in 4.9% to 25% (grade 3, 0.2% or less) of patients treated with atezolizumab monotherapy in clinical trials; hypothyroidism can follow a patient being hyperthyroid. Immune-mediated thyroiditis occurred in 0.2% to 1.2% of patients in these trials. Hypothyroidism was more common in patients receiving atezolizumab in combination with platinum-based chemotherapy (11%; grade 3 or 4, 0.3% or less) or in combination with cobimetinib and vemurafenib (22% to 26%). Hormone replacement therapy was required in 52% to 81% of patients with hypothyroidism and in 67% to 75% of those with thyroiditis; systemic corticosteroids were necessary in 25% to 33% of patients with thyroiditis. Thyroiditis resolved in 50% of patients. The majority of patients with hypothyroidism remained on long-term thyroid hormone replacement. Evaluate thyroid function at baseline and monitor periodically during treatment. Begin hormone replacement for hypothyroidism as clinically indicated. Atezolizumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may also be necessary. Increased TSH occurred more often when atezolizumab was added to platinum-based chemotherapy compared to chemotherapy alone (21% to 30% vs. 5% to 20%) or added to cobimetinib/vemurafenib versus placebo plus cobimetinib/vemurafenib (37% vs. 33%). Decreased triiodothyronine (27% vs. 21%) and decreased total triiodothyronine (32% vs. 8%) also occurred more frequently in patients who received atezolizumab plus cobimetinib/vemurafenib compared with placebo plus cobimetinib/vemurafenib.
Immune-mediated hyperthyroidism occurred in 0.8% to 6% (grade 3, 0.4% or less) of patients who received atezolizumab monotherapy in clinical trials (n = 3,111); it was more common in patients who received atezolizumab in combination with cobimetinib and vemurafenib (19%; grade 3, 0.9%). Antithyroid therapy was required in 29% to 38% of patients who received monotherapy and in 53% of those who received atezolizumab plus cobimetinib and vemurafenib; the majority of patients remained on antithyroid treatment. Evaluate thyroid function at baseline and monitor periodically during treatment. Begin medical management of hyperthyroidism as clinically indicated. Atezolizumab therapy may need to be interrupted or discontinued depending on severity. Decreased TSH was reported more often in patients treated with atezolizumab in combination with carboplatin/etoposide compared with placebo plus carboplatin/etoposide (28% vs. 15) or in combination with cobimetinib/vemurafenib compared with placebo plus cobimetinib/vemurafenib (38% vs. 23%) in randomized clinical trials. Increased triiodothyronine (33% vs. 18%) and increased free thyroxine (32% vs. 21%) also occurred more frequently in patients who received atezolizumab plus cobimetinib/vemurafenib compared with placebo plus cobimetinib/vemurafenib.
Hyperglycemia has been reported with atezolizumab therapy. Monitor for hyperglycemia or other signs and symptoms of diabetes and initiate treatment with insulin as clinically indicated; an interruption or discontinuation of therapy may be necessary. Type 1 diabetes mellitus occurred in 0.3% (grade 3, 0.2%) of patients treated with atezolizumab as monotherapy in clinical trials (n = 2,616); diabetic ketoacidosis may also occur. Hyperglycemia (78%) and hypoglycemia (33%) including decreased fasting glucose level (25%) occurred in patients (n = 49; age range, 12 to 70 years) with unresectable or metastatic alveolar soft part sarcoma who received atezolizumab in a clinical study. The incidence of hyperglycemia was similar when atezolizumab was added to platinum-based chemotherapy compared with placebo plus platinum-based chemotherapy (61% to 75% vs. 60% to 66%; grade 3 or 4, 10% or less vs. 8% or less). Hyperglycemia occurred in 48% (grade 3 or 4, 43%) patients with hepatocellular cancer treated with atezolizumab plus bevacizumab compared with 43% (grade 3 or 4, 4.6%) of those treated with sorafenib. Hyperglycemia was reported in less than 10% of melanoma patients who received atezolizumab in combination with cobimetinib/vemurafenib.
Lymphopenia occurred in 47% (grade 3 or 4, 9%) of patients with treatment-naive advanced non-small cell lung cancer (NSCLC) treated with atezolizumab monotherapy; it was not reported in patients receiving adjuvant atezolizumab monotherapy for early NSCLC. When administered in combination with chemotherapy, the effect of atezolizumab on hematologic parameters reflects the effect of concomitant chemotherapy. The addition of atezolizumab to chemotherapy (e.g., bevacizumab, bevacizumab/carboplatin/paclitaxel, nab-paclitaxel/carboplatin, etoposide/cisplatin, and cobimetinib/vemurafenib) increased the incidence of neutropenia, lymphopenia, and leukopenia by up to 10% (grade 3 or 4, 11% or less). Febrile neutropenia also occurred in at least 1.9% of patients treated with atezolizumab plus chemotherapy (e.g., bevacizumab/paclitaxel/carboplatin, nab-paclitaxel/carboplatin, and etoposide/carboplatin); some cases were fatal. Immune-mediated hemophagocytic lymphohistiocytosis occurred in less than 1% of patients receiving atezolizumab or other PD-1/PD-L1 inhibitors. An interruption or discontinuation of therapy and treatment with systemic corticosteroids may be necessary for patients who develop immune-mediated reactions.
Immune-mediated aplastic anemia and hemolytic anemia were each reported in less than 1% of patients who received atezolizumab or other PD-1/PD-L1 inhibitors in clinical trials. An interruption or discontinuation of therapy and treatment with systemic corticosteroids may be necessary for patients who develop immune-mediated reactions. Anemia (63% to 69%; grade 3 or 4, 3% or less) occurred in patients with advanced non-small cell lung cancer (NSCLC) and alveolar soft part sarcoma treated with atezolizumab monotherapy; it was not reported in patients receiving adjuvant atezolizumab monotherapy for early NSCLC. When administered in combination with chemotherapy, the effect of atezolizumab on hematologic parameters reflects the effect of concomitant chemotherapy. The addition of atezolizumab to chemotherapy (e.g., bevacizumab, bevacizumab/carboplatin/paclitaxel, nab-paclitaxel/carboplatin, etoposide/cisplatin, and cobimetinib/vemurafenib) increased the incidence of anemia by up to 5% (grade 3 or 4, 8% or less).
Immune thrombocytopenic purpura occurred in less than 1% of patients who received atezolizumab or other PD-1/PD-L1 inhibitors in clinical trials. An interruption or discontinuation of therapy and treatment with systemic corticosteroids may be necessary for patients who develop immune-mediated reactions. Thrombocytopenia (27%) and thrombocytosis (29%) occurred in patients (n = 49; age range, 12 to 70 years) with unresectable or metastatic alveolar soft part sarcoma who received atezolizumab in a clinical study. When administered in combination with chemotherapy, the effect of atezolizumab on hematologic parameters reflects the effect of concomitant chemotherapy. The addition of atezolizumab to chemotherapy (e.g., bevacizumab, nab-paclitaxel/carboplatin, etoposide/cisplatin, and cobimetinib/vemurafenib) increased the incidence of thrombocytopenia by 5% to 14% (grade 3 or 4, 0.9% to 6%).
Immune-related meningitis and encephalitis occurred in less than 1% of patients treated with atezolizumab or were reported with the use of other PD-1/PD-L1 inhibitors. Monitor patients for clinical signs and symptoms of meningitis or encephalitis/encephalopathy; discontinuation of therapy and treatment with corticosteroids may be necessary.
Immune-mediated myasthenic syndrome/myasthenia gravis, Guillain-Barre syndrome, myelitis and demyelination, and nerve paresis have each occurred in less than 1% of patients treated with atezolizumab or were reported with the use of other PD-1/PD-L1 inhibitors. Monitor patients for symptoms of motor disorders. An interruption or discontinuation of therapy may be necessary, along with treatment with high-dose corticosteroids.
Peripheral neuropathy occurred in 12% (grade 3 or 4, 0.4%) of patients receiving adjuvant treatment of non-small cell lung cancer (NSCLC) with atezolizumab monotherapy following the completion of platinum-based chemotherapy, including paresthesias, hypoesthesia, polyneuropathy, dysesthesia, neuralgia, and axonal neuropathy. The addition of atezolizumab to chemotherapy (bevacizumab/carboplatin/paclitaxel or nab-paclitaxel/carboplatin) increased the incidence of neuropathy by 5% to 9% (grade 3 or 4, 0.3% or less) compared with chemotherapy alone in 2 clinical trials. Autoimmune neuropathy occurred in less than 1% of patients treated with atezolizumab or was reported with the use of other PD-1/PD-L1 inhibitors. Monitor patients for symptoms of motor and sensory neuropathy. An interruption or discontinuation of therapy may be necessary, along with treatment with high-dose corticosteroids.
Immune-mediated pancreatitis including hyperamylasemia and increases in serum lipase levels have occurred in less than 1% of patients treated with atezolizumab in clinical trials. Monitor patients for signs and symptoms of acute pancreatitis. An interruption or discontinuation of therapy may be necessary, as well as treatment with high dose corticosteroids. Decreased amylase level (40%), increased amylase level/hyperamylasemia (grade 3 or 4, 20%) and increased lipase level (grade 3 or 4, 25%) occurred in patients (n = 49; age range, 12 to 70 years) with unresectable or metastatic alveolar soft part sarcoma who received atezolizumab in a clinical study. Pancreatitis occurred in less than 10% of patients with advanced melanoma treated with atezolizumab plus cobimetinib and vemurafenib in a clinical trial; increased amylase (51% vs. 45%; grade 3 or 4, 13% vs. 13%) and triacylglycerol lipase (75% vs. 62%; grade 3 or 4, 46% vs. 35%) levels from baseline were more common in patients who received atezolizumab plus cobimetinib and vemurafenib compared with placebo plus cobimetinib and vemurafenib.
Immune-mediated uveitis, iritis, and other ocular inflammatory toxicities each occurred in less than 1% of patients who received atezolizumab or other PD-1/PD-L1 inhibitors in clinical trials; 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, evaluate for Vogt-Koyanagi-Harada syndrome; treatment with systemic steroids may be necessary to reduce the risk of permanent vision loss. Uveitis occurred in less than 10% of patients with advanced melanoma who received atezolizumab plus cobimetinib and vemurafenib (n = 230) in a randomized trial.
Infection has been reported across clinical trials of patients treated with atezolizumab. Serious cases of pneumonia occurred in 1% to 6% of lung cancer patients who received atezolizumab as monotherapy or in combination with chemotherapy. Serious infections occurred in 6% of patients with hepatocellular cancer treated with atezolizumab and bevacizumab. Serious cases of pneumonia occurred in 4.3% of melanoma patients treated with atezolizumab in combination with cobimetinib and vemurafenib; urinary tract infection occurred in less than 10% of these patients. Influenza-like illness occurred in 18% of patients (n = 49; age range, 12 to 70 years) with unresectable or metastatic alveolar soft part sarcoma who received atezolizumab in a clinical study. Systemic inflammatory response syndrome (SIRS) and histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis) have also been reported in less than 1% of patients treated with atezolizumab or were reported with the use of other PD-1/PD-L1 inhibitors.
Severe or life-threatening infusion-related reactions have been reported with atezolizumab therapy. Infusion-related reactions occurred in 1.3% (grade 3, 0.2%) of patients who received atezolizumab monotherapy across clinical trials and indications (n = 2,616); the frequency and severity were similar when atezolizumab was administered in combination with other antineoplastic agents and across the recommended dose range. Monitor for signs and symptoms of infusion-related reactions; interrupt, slow the rate of, or discontinue atezolizumab depending on the severity; consider using premedications with subsequent doses for mild (grade 1 or 2) infusion reactions. Infusion-related reactions were more common when atezolizumab was administered with bevacizumab to patients with hepatocellular cancer in one randomized clinical trial (11%; grade 3 or 4, 2.4%). Infusion-related reactions including hypersensitivity occurred in 10% (grade 3 or 4, 2.6%) of patients with advanced melanoma who received atezolizumab plus cobimetinib and vemurafenib (n = 230) in a randomized trial.
Immune-mediated dermatologic/skin toxicity occurred in 0.6% (grade 3, less than 1%) of patients who received atezolizumab monotherapy in clinical trials (n = 2,616). Exfoliative dermatitis, including Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis, has occurred with PD-1/PD-L1 inhibitors. Topical emollients and/or topical corticosteroids may be adequate to treat mild-to-moderate non-exfoliative rashes. Atezolizumab therapy may need to be interrupted or discontinued depending on the severity of rash; treatment with systemic corticosteroids may also be necessary. In clinical trials, 20% of patients who experienced skin toxicity received systemic corticosteroids; skin toxicity resolved in 87% of patients. Rash occurred in 12% to 23% (grade 3 or 4, 2% or less) of patients who treated with atezolizumab as monotherapy or in combination with chemotherapy (e.g., bevacizumab/carboplatin/paclitaxel, nab-paclitaxel/carboplatin), including acneiform rash, contact dermatitis, exfoliative dermatitis, asteatotic and dyshidrotic eczema, genital rash, erythematous rash, lichen planus-like eruption, maculopapular rash, palmar-plantar erythrodysesthesia (hand and foot syndrome), pemphigoid, pruritic rash, psoriaform rash, pustular rash, and seborrheic dermatitis; pruritus occurred in 10% to 19% (grade 3 or 4, less than 1%) of these patients. Additionally, rash occurred in 47% (grade 3 or 4, 2%) of patients (n = 49; age range, 12 to 70 years) with unresectable or metastatic alveolar soft part sarcoma who received atezolizumab in a clinical study. Rash including the previous terms as well as nodular rash, morbilliform rash, and erythema multiforme (75% vs. 72%; grade 3 or 4, 27% vs. 23%) and pruritus (26% vs. 17%; grade 3 or 4, less than 1% vs. less than 1%) were more common in melanoma patients treated with atezolizumab plus cobimetinib and vemurafenib but occurred with a similar frequency in the control arm (placebo plus cobimetinib and vemurafenib); photosensitivity (21% vs. 25%; grade 3 or 4, less than 1% vs. 3.2%) and vitiligo (less than 10%) were also reported in atezolizumab-treated patients in this trial.
Alopecia has been reported with atezolizumab therapy when combined with chemotherapy, although the incidence is not meaningfully different than chemotherapy alone. The incidence of alopecia for regimens with and without atezolizumab are as follows: bevacizumab/paclitaxel/carboplatin (48% vs. 46%), nab-paclitaxel (56% vs. 58%; grade 3 or 4, less than 1% vs. less than 1%), carboplatin/etoposide (37% vs. 35%), and nab-paclitaxel/carboplatin (32% vs. 27%).
Immune-mediated interstitial nephritis with renal dysfunction was reported in 1 patient (less than 0.1%) treated with atezolizumab monotherapy in clinical trials (n = 2,616); this was a grade 3 event. This patient required treatment with systemic corticosteroids; nephritis did not resolve. The incidence was higher (grade 2, 1.3%) in patients treated with atezolizumab in combination with cobimetinib and vemurafenib; 2 of these 3 patients required treatment with systemic corticosteroids with resolution occurring in all 3 patients. Atezolizumab therapy may need to be interrupted or discontinued depending on the severity of renal impairment; treatment with systemic corticosteroids may also be necessary. Monitor renal function at baseline and periodically during treatment. Renal failure (unspecified) has been reported with atezolizumab; some cases were fatal. An increase in creatinine occurred in 31% or less (grade 3 or 4, 2% or less) of patients treated with atezolizumab monotherapy. The addition of atezolizumab to chemotherapy (bevacizumab/carboplatin/paclitaxel; nab-paclitaxel/carboplatin; etoposide cisplatin) increased the incidence of increased creatinine by 7% to 9% (grade 3 or 4, 3% or less). Patients treated with atezolizumab in combination with cobimetinib and vemurafenib or in combination with bevacizumab, carboplatin, and paclitaxel also experienced increased BUN (47% to 52%).
Proteinuria occurred in 16% to 20% of patients with non-small cell lung cancer (NSCLC) or hepatocellular cancer treated with atezolizumab in combination with bevacizumab in 2 clinical trials (grade 3 or 4, 3%); the patients with NSCLC additionally received paclitaxel and carboplatin.
Electrolyte abnormalities have been reported with atezolizumab therapy in clinical trials. Hyperkalemia occurred in 29% or less (grade 3 or 4, 3.9% or less) of patients receiving atezolizumab monotherapy or in combination with other anticancer therapies in clinical trials. Patients with advanced disease receiving atezolizumab monotherapy also experienced hyponatremia (42% to 44%; grade 3 or 4, 9% or less), hypocalcemia (47% or less; grade 3 or 4, 1.4% or less), hypomagnesemia (26% or less; grade 3 or 4, 1% or less), and hypophosphatemia (27% or less; grade 3 or 4, 5% or less). Hypercalcemia (25%; grade 3 or 4, 14%) and hypermagnesemia (grade 3 or 4, 26% or less) were reported in patients (n = 49; age range, 12 to 70 years) with unresectable or metastatic alveolar soft part sarcoma who received atezolizumab in a clinical study. The addition of atezolizumab to chemotherapy (e.g., bevacizumab/carboplatin/paclitaxel, nab-paclitaxel/carboplatin) increased the incidence of electrolyte abnormalities by 9% or less (grade 3 or 4, 4% or less). Hypokalemia (26% vs. 24%; grade 3 o 4, 6% vs. 4.4%) and hyperphosphatemia (21% to 26% vs. 13% to 28%; grade 3 or 4, 3% or less vs. 5% or less) were also reported in patients treated with atezolizumab in combination with nab-paclitaxel and carboplatin or etoposide and cisplatin compared with chemotherapy alone. Decreases from baseline in sodium (54% vs. 49%; grade 3 or 4, 13% vs. 9%) were more common in patients with hepatocellular cancer treated with atezolizumab plus bevacizumab versus sorafenib; increased potassium from baseline also occurred in these patients (23% vs. 16%; grade 3 or 4, 1.9% vs. 2%). Decreases from baseline in phosphorous (67% vs. 64%; grade 3 or 4, 22% vs. 14%), calcium (41% vs. 28%; grade 3 or 4, 1.3% vs. 0%), sodium (40% vs. 34%; grade 3 or 4, 5% vs. 7%), and potassium (36% vs. 22%; grade 3 or 4, 5% vs. 4.3%) and increases from baseline in potassium (29% vs. 19%; grade 3 or 4, 1.3% vs. 1.4%) and sodium (hypernatremia) (20% vs. 13%; grade 3 or 4, 0% vs. 0.4%) were more common in advanced melanoma patients treated with atezolizumab in combination with cobimetinib and vemurafenib compared with those who received placebo plus cobimetinib and vemurafenib.
Edema occurred in 26% (grade 3 or 4, less than 1%) of patients with advanced melanoma who received atezolizumab plus cobimetinib and vemurafenib in a randomized trial compared with 21% of patients who received placebo plus cobimetinib and vemurafenib. The term edema included peripheral edema; lymphoedema; face, eyelid, and periorbital edema; and lip edema.
Pulmonary embolism occurred in greater than 1% of NSCLC patients receiving atezolizumab monotherapy and in 3% of NSCLC patients receiving atezolizumab in combination with nab-paclitaxel/carboplatin, and has been fatal in some cases.
In a single arm clinical trial, grade 3 or 4 confusion was reported in greater than 2% of patients with progressive locally advanced or metastatic urothelial carcinoma who were treated with atezolizumab (n = 310), and lead to an interruption of therapy in greater than 1%.
Treatment-emergent antibody formation has been reported in 13% to 36% of patients who received atezolizumab in clinical trials. At any post-treatment follow-up, 4.3% to 27.5% of neutralizing antibody (NAb)-evaluable patients had a positive NAb status. There was lower efficacy (effect on overall survival) in the subset of patients with treatment-emergent atezolizumab antibodies in exploratory analyses of 2 clinical trials in patients with non-small cell lung cancer and hepatocellular carcinoma. The presence of drug antibodies did not have a clinically significant effect on the incidence or severity of adverse reactions.
Immune-mediated cardiovascular toxicity that was reported in less than 1% of patients who received atezolizumab or that occurred with the use of other PD-1/PD-L1 blocking antibodies include myocarditis, pericarditis, and vasculitis; cases may be severe or fatal. Atezolizumab therapy may need to be interrupted or discontinued in patients who develop immune-mediated toxicity, depending on the severity of the reaction. Treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary. Pericarditis, pericardial effusion, and cardiac tamponade have been reported in postmarketing experience with atezolizumab.
Hypertension occurred in 25% to 30% of patients with non-small cell lung cancer (NSCLC) or hepatocellular cancer treated with atezolizumab in combination with bevacizumab in 2 clinical trials (grade 3 or 4, 9% to 15%); the patients with NSCLC additionally received paclitaxel and carboplatin. Hypertension including hypertensive crisis occurred in 17% (grade 3 or 4, 10%) of patients with advanced melanoma who received atezolizumab plus cobimetinib and vemurafenib in a randomized trial compared with 18% (grade 3 or 4, 7%) of those treated with cobimetinib and vemurafenib without atezolizumab. Cardiac arrhythmias, decreased ejection fraction, and QT prolongation on electrocardiogram occurred in less than 10% of patients who received atezolizumab in this trial. Cardiac arrhythmias including atrial fibrillation, sinus bradycardia, ventricular tachycardia, and sinus tachycardia (22%; grade 3 or 4, 2%) and hypertension (43%; grade 3 or 4, 6%) occurred in patients (n = 49; age range, 12 to 70 years) with unresectable or metastatic alveolar soft part sarcoma who received atezolizumab in a clinical study.
Arthralgia including arthritis occurred in 11% to12% (grade 3 or 4, 0.5% to 0.6%) of patients with non-small cell lung cancer treated with atezolizumab monotherapy; the incidence was higher in patients treated with atezolizumab in combination with bevacizumab, carboplatin, and paclitaxel. The terms musculoskeletal pain and myalgia were used similarly in clinical trials and included back pain, bone pain, extremity pain, muscle stiffness, myalgia, neck pain, noncardiac chest pain, and spinal pain. Musculoskeletal pain occurred in 67% (grade 3 or 4, 8%) of patients (n = 49; age range, 12 to 70 years) with unresectable or metastatic alveolar soft part sarcoma who received atezolizumab in a clinical study. Musculoskeletal pain/myalgia was reported in 14% to 20% (grade 3 or 4, 0.8% to 1.3%) of patients who received atezolizumab monotherapy and in 38% to 42% (grade 3 or 4, 3%) of patients who received atezolizumab in combination with bevacizumab/carboplatin/paclitaxel or nab-paclitaxel/carboplatin. The incidence was higher in patients treated with atezolizumab in combination with cobimetinib and vemurafenib (62%; grade 3 or 4, 4.3%) and also included immune-mediated arthralgia, arthritis, and joint stiffness; increased creatine kinase occurred in 88% (grade 3 or 4, 22%) of atezolizumab-treated patients in this trial compared with 81% (grade 3 or 4, 18%) of patients in the control arm.
Immune-mediated myositis/polymyositis, rhabdomyolysis, polymyalgia rheumatic, and sarcoidosis occurred in less than 1% of patients treated with atezolizumab or were reported with the use of other PD-1/PD-L1 inhibitors.
Headache was reported in 16% (grade 3 or 4, 0.8%) of patients with metastatic non-small cell lung cancer treated with atezolizumab plus bevacizumab, paclitaxel, and carboplatin (n = 393) compared with 13% of those treated with bevacizumab, paclitaxel, and carboplatin without atezolizumab (n = 394) in a randomized clinical trial. Headache occurred in 43% (grade 3 or 4, 4%) of patients (n = 49; age range, 12 to 70 years) with unresectable or metastatic alveolar soft part sarcoma who received atezolizumab in a clinical study.
Dizziness and syncope were each reported in less than 10% of patients with advanced melanoma who received atezolizumab plus cobimetinib and vemurafenib (n = 230) in a randomized clinical trial. Dizziness including vertigo occurred in 29% (grade 3 or 4, 4%) of patients (n = 49; age range, 12 to 70 years) with unresectable or metastatic alveolar soft part sarcoma who received atezolizumab in a clinical study.
Epistaxis occurred in 10% to 17% of patients with non-small cell lung cancer (NSCLC) or hepatocellular cancer treated with atezolizumab in combination with bevacizumab in 2 clinical trials (grade 3 or 4, 1% or less); the patients with NSCLC additionally received paclitaxel and carboplatin. More than 2% of patients with NSCLC who received atezolizumab plus bevacizumab experienced hemoptysis.
Fatal cerebrovascular accident (stroke) and intracranial bleeding were reported in patients with metastatic non-small cell lung cancer (NSCLC) treated with atezolizumab in combination with bevacizumab, paclitaxel, and carboplatin (n = 393) in a randomized clinical trial.
Fatigue including asthenia, lethargy, and malaise was reported in 14% to 55% (grade 3 or 4, 0.6% to 4%) of patients with advanced malignancies treated with atezolizumab monotherapy in clinical trials; it was not reported in patients receiving adjuvant atezolizumab monotherapy for non-small cell lung cancer following completion of platinum-based chemotherapy. The addition of atezolizumab to chemotherapy (e.g., bevacizumab, bevacizumab/carboplatin/paclitaxel, nab-paclitaxel/carboplatin, etoposide/cisplatin, and cobimetinib/vemurafenib) increased the incidence of fatigue and/or asthenia by up to 6% (grade 3 or 4, 3% or less).
Dysgeusia occurred in less than 10% of patients with advanced melanoma who received atezolizumab plus cobimetinib and vemurafenib (n = 230) in a randomized trial.
Anorexia or decreased appetite (15% to 25%; grade 3 or 4, 2% or less) was among the most commonly reported adverse reactions in patients treated with atezolizumab monotherapy in clinical trials. The incidence was similar in patients with hepatocellular cancer treated with atezolizumab in combination with bevacizumab (18%; grade 3 or 4, 1.2%). The addition of atezolizumab to chemotherapy (e.g., bevacizumab/paclitaxel/carboplatin, nab-paclitaxel/carboplatin, or carboplatin/etoposide) increased the incidence of appetite suppression by 4% to 9% (grade 3 or 4, 3.2% or less) compared to chemotherapy alone in 3 clinical trials.
Weight gain (16%; grade 3 or 4, 6%) and weight loss (18%) occurred in patients (n = 49; age range, 12 to 70 years) with unresectable or metastatic alveolar soft part sarcoma who received atezolizumab in a clinical study. Additionally, weight loss occurred in 11% of patients with hepatocellular cancer treated with atezolizumab in combination with bevacizumab in a randomized clinical trial.
Serious cases of GI bleeding occurred in 7% of patients with hepatocellular cancer treated with atezolizumab in combination with bevacizumab in a randomized clinical trial.
Elevated hepatic enzymes occurred in 22% to 40% (grade 3 or 4, 1% to 6%) of patients with various cancers (excluding hepatocellular cancer) treated with atezolizumab as monotherapy or in combination with bevacizumab/carboplatin/paclitaxel, nab-paclitaxel/carboplatin, or etoposide/cisplatin in clinical trials. Additionally, increased alkaline phosphatase (25% to 46%; grade 3 or 4, 2.6% or less) and hypoalbuminemia (32% to 48%; grade 3 or 4, 0.4% to 4%) were reported in patients who received atezolizumab in these trials. Decreased bilirubin level occurred in 49% of patients (n = 49; age range, 12 to 70 years) with unresectable or metastatic alveolar soft part sarcoma who received atezolizumab in a clinical study. In patients with hepatocellular cancer, transaminitis occurred in 62% to 86% (grade 3 or 4, 8% to 16%) of those who received atezolizumab plus bevacizumab; increased alkaline phosphatase occurred in 70% (grade 3 or 4, 4%), decreased albumin in 60% (grade 3 or 4, 1.5%), and increased bilirubin in 57% (grade 3 or 4, 8%) of patients in this trial. Increased AST or ALT (79% to 80%; grade 3 or 4, 13% to 18%), increased alkaline phosphatase (73%; grade 3 or 4, 6%), decreased albumin (43%; grade 3 or 4, 0.9%), and increased bilirubin (42%; grade 3 or 4, 3.1%) occurred with the highest frequency in patients with advanced melanoma treated with atezolizumab in combination with vemurafenib. Hepatotoxicity which included transaminitis, hyperbilirubinemia, hepatitis, hepatocellular injury, hepatic failure, and abnormal liver function tests, occurred in 50% (grade 3 or 4, 21%) of patients in the atezolizumab arm of this trial.
Fever has been reported in 14% to 19% (grade 3 or 4, less than 1%) of patients treated with atezolizumab, either as monotherapy or in combination with chemotherapy for non-small cell lung cancer, small cell lung cancer, or hepatocellular carcinoma. Fever occurred in 25% (grade 3 or 4, 2%) of patients (n = 49; age range, 12 to 70 years) with unresectable or metastatic alveolar soft part sarcoma who received atezolizumab in a clinical study. Additionally, fever occurred in 49% (grade 3 or 4, 1.7%) of patients with advanced melanoma who received atezolizumab plus cobimetinib and vemurafenib in a randomized trial compared with 35% (grade 3 or 4, 2.1%) of those who received placebo plus cobimetinib and vemurafenib.
Fatal and serious adverse events occurred in patients who received an allogeneic hematopoietic stem-cell transplant (HSCT) prior to and after treatment with a PD-1/PD-L1 blocking antibody, such as atezolizumab. Monitor patients closely for evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, sinusoidal obstruction syndrome (SOS) previously termed veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause); treat adverse events promptly. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT.
Immune-mediated gastritis and duodenitis each occurred in less than 1% of patients who received atezolizumab or other PD-1/PD-L1 inhibitors in clinical trials. An interruption or discontinuation of therapy and treatment with systemic corticosteroids may be necessary for patients who develop immune-mediated reactions.
Solid organ transplant rejection occurred in less than 1% of patients who received atezolizumab or other PD-1/PD-L1 inhibitors in clinical trials.
Immune-mediated hypoparathyroidism occurred in less than 1% of patients receiving atezolizumab or other PD-1/PD-L1 inhibitors.
Insomnia (27%) and anxiety (25%) occurred in patients (n = 49; age range, 12 to 70 years) with unresectable or metastatic alveolar soft part sarcoma who received atezolizumab in a clinical study.
Bleeding including pulmonary hemorrhage, hemoptysis, conjunctival/ocular hemorrhage, epistaxis, hematuria, rectal hemorrhage, and laryngeal hemorrhage occurred in 29% (grade 3 or 4, 2%) of patients (n = 49; age range, 12 to 70 years) with unresectable or metastatic alveolar soft part sarcoma who received atezolizumab in a clinical study.
Immune-mediated pneumonitis has been reported with atezolizumab therapy; some cases were fatal. The incidence of pneumonitis with other PD-1/PD-L1 inhibitors was higher in patients who have received prior thoracic radiation therapy. Monitor patients for signs and symptoms of pneumonitis (e.g., new or worsening cough, chest pain, shortness of breath). If confirmed, atezolizumab therapy may need to be interrupted or discontinued; treatment with systemic corticosteroids may be necessary.
Immune-mediated hepatitis has been reported with atezolizumab therapy; some cases were fatal. Monitor hepatic function at baseline and periodically during treatment. Atezolizumab therapy may need to be interrupted or discontinued depending on the severity of hepatitis and if there is tumor involvement of the liver; treatment with systemic corticosteroids may also be necessary.
Use atezolizumab with caution in patients who have previously had an organ transplant or who have autoimmune disease such as systemic lupus erythematosus (SLE). Immune-mediated organ transplant rejection has been reported with PD-1/PD-L1 inhibitor therapy.
Immune-mediated colitis has been reported with atezolizumab therapy. Additionally, cytomegalovirus (CMV) viral infection/reactivation has been reported in patients with steroid-refractory immune-mediated colitis. Use atezolizumab with caution in patients with pre-existing inflammatory bowel disease such as ulcerative colitis or Crohn's disease. Monitor patients for symptoms of colitis (e.g., diarrhea, severe abdominal pain). Atezolizumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may be necessary. In patients with steroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.
Primary or secondary adrenal insufficiency and immune-mediated hypophysitis can occur in patients treated with atezolizumab. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects; hypophysitis can cause hypopituitarism. Initiate symptomatic treatment including hormone replacement therapy for grade 2 or higher adrenal insufficiency and for hypophysitis as clinically indicated. Atezolizumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may also be necessary.
Type 1 diabetes mellitus, which can present with diabetic ketoacidosis, has been reported with atezolizumab therapy. Monitor patients for hyperglycemia and other signs and symptoms of diabetes. Withhold atezolizumab therapy for cases of severe hyperglycemia until blood sugar control is achieved; administer insulin as clinically indicated.
Immune-mediated reactions, which may be severe or fatal, can occur in patients treated with drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), thus removing inhibition of the immune response, such as atezolizumab. These immune-mediated reactions can occur in any organ system or tissue and can also affect more than one body system simultaneously. Although usually occurring during treatment with PD-1/PD-L1 inhibitors, immune-mediated reactions can occur at any time after starting therapy including after discontinuation of therapy. Because early identification and management is critical to safe usage of PD-1/PD-L1 inhibitors, closely monitor patients for signs and symptoms that may be clinical manifestations of underlying immune-mediated reactions. Initiate an appropriate workup to exclude alternative etiologies including infection in cases of suspected immune-mediated reaction. Begin medical management promptly, including specialty consultation as appropriate. An interruption or discontinuation of atezolizumab therapy may be necessary, depending on the severity of the reaction. In general, if an interruption or discontinuation of therapy is necessary, administer systemic corticosteroids (1 to 2 mg/kg per day of prednisone or equivalent); upon improvement to grade 1 or less, begin a steroid taper over at least 1 month. Consider additional systemic immunosuppression in patients whose symptoms are not controlled with corticosteroid therapy.
Atezolizumab can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy; hypothyroidism can follow hyperthyroidism. Evaluate thyroid function at baseline and monitor periodically during treatment. Begin hormone replacement for hypothyroidism or medical management of hyperthyroidism as clinically indicated. Atezolizumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may also be necessary.
Severe infusion-related reactions have occurred with atezolizumab. Monitor patients for signs and symptoms of infusion reactions including fever chills, wheezing, pruritus, flushing, and rash. Consider premedication with subsequent doses in patients who develop a reaction. Interrupt or slow the rate of infusion for mild or moderate infusion-related reactions (grade 1 or 2); stop the infusion and permanently discontinue atezolizumab for severe or life-threatening infusion-related reactions (grade 3 or 4).
Immune-mediated serious rash, including exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) has occurred in patients treated with PD-1/PD-L1 inhibitors. Monitor patients for suspected severe skin reactions and exclude other causes. Topical emollients and/or topical corticosteroids may be adequate to treat mild-to-moderate non-exfoliative rashes. Atezolizumab therapy may need to be interrupted or discontinued depending on the severity of rash; treatment with systemic corticosteroids may also be necessary.
Immune-mediated nephritis and renal failure have been reported with atezolizumab therapy. Monitor renal function at baseline and periodically during treatment. Atezolizumab therapy may need to be interrupted or discontinued depending on the severity of renal impairment; treatment with systemic corticosteroids may also be necessary.
Fatal and other serious complications including hyperacute, acute, and chronic graft-versus-host-disease, sinusoidal obstruction syndrome (SOS) previously termed veno-occlusive disease (VOD) after reduced intensity conditioning, and a steroid-requiring febrile syndrome (without an identified infectious cause) have been reported in patients who receive an allogeneic stem cell transplant (SCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Therefore, perform a risk/benefit analysis prior to starting treatment with a PD-1/PD-L1 blocking antibody, such as atezolizumab, in patients who may receive or who have a history of undergoing an allogeneic SCT. Monitor patients closely for evidence of transplant-related complications and intervene promptly. Complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic SCT.
Immune-mediated neurotoxicity has been reported with atezolizumab or other PD-1/PD-L1 inhibitors. Use atezolizumab with caution in patients who have a history of neurological disease such as myasthenia gravis or Guillain-Barre syndrome. Atezolizumab may need to be interrupted or discontinued depending on the severity of the neurotoxicity; treatment with systemic corticosteroids may also be necessary.
Based on its mechanism of action, atezolizumab may cause fetal harm if used during pregnancy. Atezolizumab is an immunoglobulin G1 antibody and may cross the placental barrier. Fetal exposure to atezolizumab may increase the risk of developing immune-mediated disorders or altering the normal immune response. Advise women of reproductive potential of the risk to a fetus. The PD-1 pathway is associated with decidual CD8-positive T-cell function and the PD1/PD-L1 interaction may be important in maintaining fetal tolerance during pregnancy. PD1/PDL1 Inhibitors, such as atezolizumab, may impair maternal immune tolerance resulting in spontaneous abortion, intrauterine growth restriction, or early-onset preeclampsia.
Counsel patients about the reproductive risk and contraception requirements during atezolizumab treatment. Atezolizumab can increase the risk of fetal loss, or may result in altered immune responses in surviving fetuses, if taken by the mother during pregnancy. Females should avoid pregnancy and use effective contraception during treatment with atezolizumab and for at least 5 months after the last dose. Females of reproductive potential should undergo pregnancy testing prior to initiation of atezolizumab. Women who become pregnant while receiving atezolizumab should be apprised of the potential hazard to the fetus. In addition, atezolizumab caused irregular menstrual cycles and lack of newly formed corpora lutea in the ovaries of female monkeys; there was no effect on male reproductive organs. Atezolizumab treatment may result in impaired fertility or infertility in females of reproductive potential.
Due to the potential for serious adverse reactions in breastfed children, the manufacturer recommends that patients avoid breast-feeding during atezolizumab therapy and for 5 months after the final dose. It is not known if atezolizumab is present in human milk or if it has effects on the breastfed child or on milk production. Use atezolizumab with caution during breastfeeding, especially while nursing a newborn or preterm infant. Because atezolizumab is a large protein molecule (molecular weight of 145,000 Daltons), the amount of drug in milk is likely to be very low. It may also be partially destroyed in the gastrointestinal tract resulting in minimal absorption.
For the treatment of urothelial carcinoma*:
-for the first-line treatment of locally advanced or metastatic urothelial carcinoma, in combination with gemcitabine and cisplatin*:
Intravenous dosage:
Adults: 1,200 mg IV over 60 minutes on day 1, in combination with gemcitabine (1,000 mg/m2 IV on days 1 and 8) and cisplatin (70 mg/m2 IV on day 1), every 21 days for up to 6 cycles; may continue atezolizumab monotherapy after the completion of chemotherapy until disease progression or unacceptable toxicity. If the first atezolizumab infusion is tolerated, all subsequent infusions may be administered over 30 minutes. In a randomized phase 3 trial (the IMvigor 130 trial), the addition of atezolizumab to platinum-based chemotherapy in patients with metastatic urothelial cancer significantly improved progression-free survival (PFS) compared with platinum-based chemotherapy alone in the intent-to-treat population; the PFS benefit in the atezolizumab arm was seen across all subgroups, although it was not statistically significant in several including patients with PD-L1 0/1 expression and in patients receiving carboplatin- versus cisplatin-based regimens. At an interim analysis after 11.8 months of follow-up, overall survival was not significantly different between groups.
-for the first-line treatment of locally advanced or metastatic urothelial carcinoma, in combination with gemcitabine and carboplatin*:
Intravenous dosage:
Adults: 1,200 mg IV over 60 minutes on day 1, in combination with gemcitabine (1,000 mg/m2 IV on days 1 and 8) and carboplatin (AUC 4.5 IV on day 1), every 21 days for up to 6 cycles; may continue atezolizumab monotherapy after the completion of chemotherapy until disease progression or unacceptable toxicity. If the first atezolizumab infusion is tolerated, all subsequent infusions may be administered over 30 minutes. In a randomized phase 3 trial (the IMvigor 130 trial), the addition of atezolizumab to platinum-based chemotherapy in patients with metastatic urothelial cancer significantly improved progression-free survival (PFS) compared with platinum-based chemotherapy alone in the intent-to-treat population; the PFS benefit in the atezolizumab arm was seen across all subgroups, although it was not statistically significant in several including patients with PD-L1 0/1 expression and in patients receiving carboplatin- versus cisplatin-based regimens. At an interim analysis after 11.8 months of follow-up, overall survival was not significantly different between groups.
-for the treatment of locally advanced or metastatic urothelial carcinoma in patients whose tumors express PD-L1 (5% or more) as determined by an FDA-approved test and are ineligible for cisplatin-containing chemotherapy or in patients who are not eligible for any platinum-containing chemotherapy, regardless of PD-L1 status*:
NOTE: FDA approval was removed for this indication in December 2022 after initial accelerated approval due to failure to meet the co-primary end point of overall survival in the IMvigor130 trial.
Intravenous dosage:
Adults: Dosage not established.
-for the treatment of locally advanced or metastatic urothelial carcinoma in patients who progress during or following any platinum-containing chemotherapy*:
NOTE: FDA approval was removed for this indication in April 2021 after initial accelerated approval due to failure to meet the primary end point of overall survival in the IMvigor211 trial.
Intravenous dosage:
Adults: Dosage not established.
-for the treatment of locally advanced or metastatic urothelial carcinoma in patients who progress within 12 months of neoadjuvant or adjuvant chemotherapy*:
NOTE: FDA approval was removed for this indication in April 2021 after initial accelerated approval due to failure to meet the primary endpoint of overall survival in the IMvigor211 trial.
Intravenous dosage:
Adults: Dosage not established.
For the treatment of non-small cell lung cancer (NSCLC):
-for the adjuvant treatment of stage II to IIIA NSCLC as monotherapy in patients with PD-L1 expression on 1% or more of tumor cells, following resection and platinum-based chemotherapy:
NOTE: Patients should be selected based on the PD-L1 expression on tumor cells.
Intravenous dosage:
Adults: 840 mg IV every 2 weeks; OR 1,200 mg IV every 3 weeks; OR 1,680 mg IV every 4 weeks for up to 1 year, unless there is disease recurrence or unacceptable toxicity. In a multicenter, randomized, open-label clinical trial (IMpower010), patients with stage IB to IIIA NSCLC who had complete tumor resection and received cisplatin-based adjuvant chemotherapy were randomized to treatment with atezolizumab or best supportive care (BSC). Treatment with atezolizumab significantly improved the primary endpoint of median disease-free survival (DFS) in stage II to IIIA NSCLC patients with PD-L1 expression in 1% or more of tumor cells compared with BSC (not reached vs. 35.3 months). In a prespecified secondary subgroup analysis of stage II to IIIA NSCLC patients with PD-L1 expression in 50% or more of tumor cells, median DFS was not reached versus 35.7 months, respectively; median DFS was 32.8 months versus 31.4 months, respectively, in an exploratory subgroup analysis of patients with PD-L1 expression in 1% to 49% of tumor cells.
-for the first-line treatment of metastatic non-small cell lung cancer (NSCLC) without EGFR or ALK mutations, in patients whose tumors have high PD-L1 expression (at least 50% of tumor cells, or PD-L1 stained tumor-infiltrating immune cells covering at least 10% of the tumor area), as monotherapy:
NOTE: Patients should be selected based on the PD-L1 expression on tumor cells or on tumor-infiltrating immune cells. Information on FDA-approved tests for the determination of PD-L1 expression in NSCLC is available at www.fda.gov/CompanionDiagnostics.
Intravenous dosage:
Adults: 840 mg IV every 2 weeks; OR 1,200 mg IV every 3 weeks; OR 1,680 mg IV every 4 weeks until disease progression or unacceptable toxicity. Treatment with atezolizumab significantly improved median overall survival compared with platinum-based chemotherapy (20.2 months vs. 13.1 months) in patients with metastatic NSCLC and high PD-L1 expression, without EGFR or ALK mutations in a randomized, open-label trial (IMpower110). Investigator-assessed median progression-free survival was 8.1 months in the atezolizumab arm compared with 5 months in the chemotherapy arm; the confirmed objective response rate was 38% versus 29%, respectively.
-for the first-line treatment of metastatic nonsquamous non-small cell lung cancer (NSCLC) without EGFR or ALK mutations, in combination with bevacizumab, paclitaxel, and carboplatin:
Intravenous dosage:
Adults: 840 mg IV every 2 weeks; OR 1,200 mg IV every 3 weeks; OR 1,680 mg IV every 4 weeks until disease progression or unacceptable toxicity. Administer in combination with bevacizumab (15 mg/kg IV), paclitaxel (200 mg/m2 IV, or 175 mg/m2 IV in Asian patients), and carboplatin (AUC 6 IV), every 3 weeks for a maximum of 4 to 6 cycles of chemotherapy. Administer atezolizumab prior to bevacizumab and chemotherapy when given on the same day. In a multicenter, randomized, open-label, phase 3 clinical trial (IMpower150), treatment with atezolizumab plus bevacizumab/paclitaxel/carboplatin (ABCP) significantly improved overall survival in patients with metastatic nonsquamous NSCLC compared with BCP without atezolizumab (19.2 months vs. 14.7 months); overall survival with atezolizumab/paclitaxel/carboplatin was not significantly different from BCP. Progression-free survival was also significantly improved in the ABCP arm compared with BCP (8.5 months vs. 7 months). The objective response rate was 55% (complete response [CR], 4%) versus 42% (CR, 1%), respectively, for a median duration of 10.8 months and 6.5 months, respectively.
-for the first-line treatment of metastatic nonsquamous non-small cell lung cancer (NSCLC) without EGFR or ALK mutations, in combination with nanoparticle albumin-bound (nab) paclitaxel and carboplatin:
Intravenous dosage:
Adults: 840 mg IV every 2 weeks; OR 1,200 mg IV every 3 weeks; OR 1,680 mg IV every 4 weeks until disease progression or unacceptable toxicity. Administer in combination with nab-paclitaxel (100 mg/m2 on days 1, 8, and 15) and carboplatin (AUC 6 IV on day 1), every 3 weeks for a maximum of 4 to 6 cycles of chemotherapy. Administer atezolizumab prior to chemotherapy when given on the same day. First-line treatment of EGFR- and ALK-negative metastatic NSCLC with atezolizumab plus nab-paclitaxel and carboplatin significantly improved median overall survival (18.6 months vs. 13.9 months) and median progression-free survival (7.2 months vs. 6.5 months) compared with nab-paclitaxel and carboplatin alone in a multicenter, randomized, open-label trial (IMpower130). The overall response rate was 46% (complete response [CR], 5%) in the atezolizumab arm compared with 32% (CR, 1%) in the control arm, for a median duration of 10.8 months versus 7.8 months, respectively.
-for the treatment of metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-containing chemotherapy, and after progression on FDA-approved EGFR- or ALK-targeted therapy if applicable, as monotherapy:
Intravenous dosage:
Adults: 840 mg IV every 2 weeks until disease progression or unacceptable toxicity; alternatively, atezolizumab may be dosed at 1,200 mg IV every 3 weeks OR atezolizumab 1,680 mg IV every 4 weeks. In clinical trials, atezolizumab could be continued beyond disease progression, as long as clinical benefit was evident. In a multicenter, randomized, open-label phase 2 clinical trial, second-line treatment of platinum-resistant NSCLC with atezolizumab significantly improved overall survival compared with docetaxel (12.6 months vs. 9.7 months); progression-free survival (PFS) and objective response rate (ORR) were not significantly different. In a pre-planned subgroup analysis, the benefit of atezolizumab was greater in patients with 1% or more PD-L1 expressing tumor cells or tumor-infiltrating cells. Atezolizumab was better tolerated than docetaxel.
For the treatment of renal cell cancer*:
-for the first-line treatment of advanced or metastatic renal cell cancer, in combination with bevacizumab*:
Intravenous dosage:
Adults: 1,200 mg IV over 60 minutes plus bevacizumab (15 mg/kg IV over 90 minutes), repeated every 3 weeks until disease progression or unacceptable toxicity. If the first atezolizumab infusion is tolerated over 60 minutes, all subsequent infusions may be infused over 30 minutes. If the first bevacizumab infusion is tolerated over 90 minutes, the second infusion may be given over 60 minutes and if well-tolerated, subsequent bevacizumab infusions may be given over 30 minutes. In a randomized, phase 3 clinical trial, first-line treatment with atezolizumab plus bevacizumab significantly improved median investigator-assessed PFS in patients with advanced or metastatic RCC compared with sunitinib; however, these results were not supported by an independent review committee (IRC) which found a nonsignificant trend toward improved PFS. An exploratory analysis found that treatment with atezolizumab plus bevacizumab significantly improved investigator-assessed PFS in intent-to-treat patients with sarcamoid histology, which has a particularly poor prognosis. Treatment with atezolizumab plus bevacizumab did not significantly improve overall survival compared with sunitinib in this patient population, but patients who received combination therapy experienced a longer time to clinically relevant decline.
For the treatment of small cell lung cancer (SCLC):
Atezolizumab is designated as an orphan drug by the FDA for this indication.
-for the first-line treatment of extensive-stage small cell lung cancer (SCLC), in combination with carboplatin and etoposide:
Intravenous dosage:
Adults: 840 mg IV every 2 weeks; OR 1,200 mg IV every 3 weeks; OR 1,680 mg IV every 4 weeks until disease progression or unacceptable toxicity. Administer in combination with carboplatin (AUC 5 IV on day 1) and etoposide (100 mg/m2 IV on days 1, 2, and 3), every 3 weeks for 4 cycles. Administer atezolizumab prior to chemotherapy when given on the same day. In a randomized, double-blind, phase 3 clinical trial (IMpower133), the addition of atezolizumab to carboplatin plus etoposide significantly improved overall survival (12.3 months vs. 10.3 months) and progression-free survival (5.2 months vs. 4.3 months) compared with placebo plus carboplatin/etoposide. Survival at 1 year was 51.7% versus 38.2%, respectively. Treatment was well-tolerated, with 56.5% of patients in the atezolizumab arm experiencing grade 3 or 4 adverse reactions compared with 56.1% of those in the placebo arm. Immune-related adverse reactions occurred in 39.9% versus 24.5% of patients, respectively.
For the treatment of breast cancer*:
-for the neoadjuvant treatment of hormone receptor (HR)-negative, HER2-negative (triple-negative) breast cancer, in combination with sequential nab-paclitaxel followed by cyclophosphamide plus doxorubicin (dose-dense AC)*:
NOTE: Do not substitute nab-paclitaxel with paclitaxel. In a phase 3 clinical trial (the IMpassion131 trial), treatment with atezolizumab and paclitaxel increased the risk of death compared with placebo and paclitaxel in the PD-L1-positive population.
Intravenous dosage:
Adults: 840 mg IV every 2 weeks in combination with nab-paclitaxel (125 mg/m2 once weekly) for 12 weeks, followed by atezolizumab 840 mg IV every 2 weeks in combination with doxorubicin (60 mg/m2 IV) plus cyclophosphamide (600 mg/m2 IV every 2 weeks) for 8 weeks (dose-dense AC), followed by surgery. After surgery, continue atezolizumab 1,200 mg IV every 3 weeks for 11 cycles to complete approximately 12 months of atezolizumab therapy. In a randomized, phase 3 clinical trial (IMpassion031), neoadjuvant treatment with atezolizumab plus sequential nab-paclitaxel and AC chemotherapy significantly improved pCR compared with neoadjuvant placebo plus sequential nab-paclitaxel and AC chemotherapy in patients with early TNBC, regardless of PD-L1 status.
-for the treatment of unresectable locally advanced or metastatic hormone receptor (HR)-negative, HER2-negative (triple-negative) breast cancer, in patients whose tumors express PD-L1 (1% or more) as determined by an FDA-approved test, in combination with nab-paclitaxel*:
NOTE: FDA approval was removed for this indication in August 2021 after initial accelerated approval due to failure to meet the primary end point of progression-free survival in the IMpassion131 trial.
Intravenous dosage:
Adults: Dosage not established.
For the treatment of hepatocellular cancer:
-for the treatment of unresectable or metastatic hepatocellular cancer (HCC) in patients who have not received prior systemic therapy, in combination with bevacizumab:
NOTE: Atezolizumab in combination with bevacizumab is designated by the FDA as an orphan drug for this indication.
Intravenous dosage:
Adults: 840 mg IV every 2 weeks; OR 1,200 mg IV every 3 weeks; OR 1,680 mg IV every 4 weeks. Administer in combination with bevacizumab 15 mg/kg IV every 3 weeks until disease progression or unacceptable toxicity. Administer atezolizumab prior to bevacizumab when given on the same day. In a multicenter, randomized, open-label clinical trial (IMbrave150), treatment with atezolizumab followed by bevacizumab significantly improved overall survival (not estimable vs. 13.2 months) and progression-free survival (6.8 months vs. 4.3 months) compared with sorafenib in patients with unresectable or metastatic HCC who have not received prior systemic therapy. The overall response rate was also significantly improved for patients treated with bevacizumab/atezolizumab by both RECIST1.1 criteria (28% vs. 12%; complete response [CR], 7% vs. 0%) and mRECIST criteria (33% vs. 13%; CR, 11% vs. 1.8%); the median duration of response was not estimable versus 6.3 months, respectively.
For the treatment of malignant melanoma:
Note: Atezolizumab has been designated by the FDA as an orphan drug for the treatment of stage llb, llc, lll, and IV melanoma.
-for the treatment of BRAF V600 mutation-positive unresectable or metastatic melanoma, in combination with cobimetinib and vemurafenib:
NOTE: Patients should be selected using an FDA-approved test confirming the presence of a BRAF V600 mutation. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at www.fda.gov/CompanionDiagnostics.
Intravenous dosage:
Adults: 840 mg IV every 2 weeks; OR 1,200 mg IV every 3 weeks; OR 1,680 mg IV every 4 weeks, starting on cycle 2 (28 days after starting cobimetinib and vemurafenib therapy). Administer in combination with cobimetinib (60 mg orally once daily on days 1 to 21, every 28 days) and vemurafenib (720 mg orally twice daily). Cycle 1 consists of cobimetinib and vemurafenib only given as follows: cobimetinib 60 mg orally once daily on days 1 to 21 and vemurafenib 960 mg orally twice daily on days 1 to 21 and then 720 mg orally twice daily on days 22 to 28. At a median follow-up time of 18.9 months, the investigator-assessed median progression-free survival (PFS) time was significantly longer in patients who received atezolizumab, vemurafenib, and cobimetinib compared with placebo, vemurafenib, and cobimetinib (15.1 months vs. 10.6 months; hazard ratio (HR) = 0.78; 95% CI, 0.63 to 0.97) in an international, randomized, double-blind, placebo-controlled, phase 3 trial (n = 514; IMspire150 trial). When PFS was assessed by an independent review committee, the median PFS time was not significantly improved in the atezolizumab arm (16.1 months vs. 12.3 months; HR = 0.85; 95% CI, 0.67 to 1.07). Additionally, the median overall survival (OS) time was not significantly improved in patients who received atezolizumab compared with placebo (39 months vs. 25.8 months; HR = 0.84; 95% CI, 0.66 to 1.06) in an interim OS analysis of the IMspire150 trial performed at median follow-up times of 29.1 and 22.8 months, respectively. Patients (median age 54 years; range, 43 to 64 years) in this trial had BRAF V600 mutation-positive unresectable stage IIIc or stage IV melanoma and had not received previous systemic therapy for metastatic disease.
For the treatment of soft-tissue sarcoma:
NOTE: Atezolizumab is designated as an orphan drug by the FDA for this indication.
-for the treatment of unresectable or metastatic alveolar soft part sarcoma:
Intravenous dosage:
Adults: 840 mg IV every 2 weeks; OR 1,200 mg IV every 3 weeks; OR 1,680 mg IV every 4 weeks until disease progression or unacceptable toxicity. The objective response rate was 37% (complete response rate, 2%) in 52 patients (age range, 12 to 70 years) with unresectable or metastatic alveolar soft part sarcoma who received atezolizumab in a multicenter, single-arm, phase 2 (ML39345) study. At a median follow-up time of 13.2 (range, 1.8 to 58) months, the median duration of response was 24.7 (range, 4.1 to 55.8) months. Additionally, the median progression-free survival time was 20.8 months.
Children and Adolescents 2 years and older: 15 mg/kg (maximum dose of 1,200 mg) every 3 weeks until disease progression or unacceptable toxicity. The efficacy of atezolizumab in pediatric patients is supported by evidence from a study in adults with alveolar soft part sarcoma (ASPS), 2 adolescent pediatric patients with metastatic ASPS, and pharmacokinetic and safety data in pediatric patients aged 2 to 16 years.
Therapeutic Drug Monitoring:
Management of Treatment-Related Toxicity
Immune-Mediated Reactions
NOTE: Corticosteroid therapy consists of prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper starting when the toxicity resolves to grade 1 or less. Consider starting other systemic immunosuppressants if toxicity is not controlled by corticosteroids. Permanently discontinue atezolizumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids.
Colitis
-Grade 2 or 3 toxicity: Hold atezolizumab and administer corticosteroids. Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper.
-Grade 4 toxicity: Permanently discontinue atezolizumab and administer corticosteroids.
Endocrinopathies (including Type 1 diabetes, Hypophysitis, Hypothyroidism, Hyperthyroidism, and Adrenal Insufficiency)
-Grade 3 or 4 toxicity: Hold atezolizumab until the patient is clinically stable; administer appropriate treatment (e.g., hormone replacement therapy, corticosteroids, insulin). Permanently discontinue atezolizumab for severe toxicity.
Exfoliative Skin Reactions
-Suspected Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), or drug reaction with eosinophilia and systemic symptoms (DRESS): Hold atezolizumab and administer corticosteroids as applicable.
-Confirmed SJS, TEN, or DRESS: Permanently discontinue atezolizumab and administer corticosteroids.
Infusion-Related Reactions
-Grade 1 or 2 toxicity: Hold atezolizumab or slow the infusion rate.
-Grade 3 or 4 toxicity: Permanently discontinue atezolizumab.
Myocarditis or Pericarditis
Grade 2, 3, or 4 toxicity: Permanently discontinue atezolizumab and administer corticosteroids.
Neurologic Toxicity
-Grade 2 toxicity: Hold atezolizumab and administer corticosteroids. Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper.
-Grade 3 or 4 toxicity: Permanently discontinue atezolizumab and administer corticosteroids.
Pneumonitis
-Grade 2 toxicity: Hold atezolizumab and administer corticosteroids. Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper.
-Grade 3 or 4 toxicity: Permanently discontinue atezolizumab and administer corticosteroids.
Other Immune-Mediated Adverse Reactions
-Grade 3 toxicity: Hold atezolizumab and administer corticosteroids. Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper.
-Recurrent grade 3 toxicity that requires treatment with other systemic immunosuppressants: Permanently discontinue atezolizumab.
-Grade 4 toxicity: Permanently discontinue atezolizumab and administer corticosteroids.
Maximum Dosage Limits:
-Adults
840 mg IV every 2 weeks; 1,200 mg IV every 3 weeks; OR 1,680 mg IV every 4 weeks.
-Geriatric
840 mg IV every 2 weeks; 1,200 mg IV every 3 weeks; OR 1,680 mg IV every 4 weeks.
-Adolescents
15 mg/kg (maximum of 1,200 mg) IV every 3 weeks.
-Children
2 years and older: 15 mg/kg (maximum of 1,200 mg) IV every 3 weeks.
1 year: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Treatment-Related Immune-Mediated Hepatitis
No Tumor Involvement of the Liver
AST or ALT level of more than 3 to 8 times the ULN or a total bilirubin level of more than 1.5 to 3 times the ULN: Hold atezolizumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue atezolizumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids.
AST or ALT level more than 8 times the ULN or a total bilirubin level more than 3-times the ULN: Permanently discontinue atezolizumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper starting when the toxicity resolves to grade 1 or less).
Tumor Involvement of the Liver
Baseline AST or ALT level at the ULN or less: Hold or permanently discontinue atezolizumab based on recommendations for hepatitis with no tumor involvement of the liver.
Baseline AST or ALT level of more than 1 to 3 times the ULN
AST or ALT level of more than 5 to 10 times the ULN: Hold atezolizumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue atezolizumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids.
Baseline AST or ALT level of more than 3 to 5 times the ULN
AST or ALT level of more than 8 to 10 times the ULN: Hold atezolizumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue atezolizumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids.
Any Baseline AST or ALT level
AST or ALT level more than 10 times the ULN or a total bilirubin level to more than 3 times the ULN: Permanently discontinue atezolizumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper starting when the toxicity resolves to grade 1 or less).
Patients with Renal Impairment Dosing
Treatment-Related Immune-Mediated Nephritis with Renal Dysfunction
Grade 2 or 3 increased serum creatinine (SCr) level: Hold atezolizumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue atezolizumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids.
Grade 4 increased SCr level: Permanently discontinue atezolizumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper starting when the toxicity resolves to grade 1 or less).
*non-FDA-approved indication
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Atezolizumab is an Fc-engineered, humanized, non-glycosylated IgG1 kappa monoclonal antibody that inhibits programmed death ligand 1 (PD-L1) interactions with the PD-1 and B7.1 receptors. PD-L1 may be expressed on tumor cells and/or tumor-infiltrating immune cells, and can contribute to inhibition of the anti-tumor immune response in the tumor microenvironment; PD-1 and B7.1 receptors are found on T-cells and antigen-presenting cells. The PD-1 pathway regulates the balance between T-cell activation and protection of healthy tissues from immune-mediated damage. In cancer, the PD-1 pathway is thought to play an important role in the interaction of tumor cells with the host immune response. Binding of PD-L1 to the PD-1 and B7.1 receptors suppresses cytotoxic T-cell activity, T-cell proliferation, and cytokine production; PD-L1 expression in a tumor cell may provide adaptive immune resistance and lead to poor outcomes. Atezolizumab binds to PD-L1 and prevents its interaction with both PD-1 and B7.1 receptors, releasing the PD-L1/PD-1 mediated inhibition of an anti-tumor immune response without inducing antibody-dependent cellular cytotoxicity. In syngeneic mouse tumor models, blocking PD-L1 activity resulted in decreased tumor growth.
Atezolizumab is administered intravenously. Exposure to atezolizumab increases in a dose-proportional manner over a range of 1 mg/kg to 20 mg/kg, including the recommended fixed dose of 1,200 mg. Clearance was 0.2 L/day (CV, 29%) and volume of distribution (Vd) at steady-state was 6.9 L. Atezolizumab clearance was found to decrease over time, with a mean maximal reduction (% coefficient of variation; CV%) from baseline value of 17% (CV%, 41%); however, this was not considered statistically relevant. The terminal half-life was 27 days, with steady-state reached after 6 to 9 weeks following multiple doses.
-Route-Specific Pharmacokinetics
Intravenous Route
The systemic accumulation ratio for atezolizumab was 3.3-fold when administered every 2 weeks and 1.9-fold when administered every 3 weeks.
-Special Populations
Hepatic Impairment
Neither mild hepatic impairment (bilirubin less than or equal to the upper limit of normal (ULN) and AST greater than ULN; OR bilirubin greater than 1 to 1.5 times ULN and any AST), moderate hepatic impairment (bilirubin 1.6 to 3 times ULN and any AST), nor albumin levels significantly affected the systemic exposure of atezolizumab. The effect of severe hepatic impairment on the pharmacokinetics of atezolizumab is unknown.
Renal Impairment
Mild or moderate renal impairment (estimated glomerular filtration rate (eGFR) 30 to 89 mL/min/1.73 m2) did not significantly affect the systemic exposure of atezolizumab. The effect of severe renal impairment on the pharmacokinetics of atezolizumab is unknown.
Pediatrics
Serum concentrations were comparable following the administration of atezolizumab 15 mg/kg (maximum dose, 1,200 mg) every 3 weeks in pediatric patients aged 2 to 16 years and atezolizumab 1,200 mg every 3 weeks in adult patients with relapsed or progressive solid tumors and lymphomas. Atezolizumab exposure trended lower in pediatric patients less than 12 years of age; this is not considered to be clinically relevant.
Geriatric
Age (up to 89 years) did not significantly affect the systemic exposure of atezolizumab.
Gender Differences
Gender did not significantly affect the systemic exposure of atezolizumab.
Ethnic Differences
Ethnicity did not significantly affect the systemic exposure of atezolizumab.
Obesity
Body weight did not significantly affect the systemic exposure of atezolizumab.
Other
Neither tumor burden, level of PD-L1 expression, or performance status significantly affected the systemic exposure of atezolizumab.
Treatment-Emergent Anti-Drug Antibodies (ADA)
The median atezolizumab clearance was 19% (range, 18% to 49%) higher in patients who developed treatment-emergent ADA compared with patients who did not develop treatment-emergent ADA in clinical trials.