Supporting Efficacy Data
Approval was based on response rate and duration of response in a multicenter single-arm phase II trial in 310 patients.2,3 Patients with a history of autoimmune disease or who required systemic immunosuppressive medications were excluded from the study. Treatment consisted of intravenous infusion of atezolizumab at 1,200 mg every 3 weeks. Overall, 78% of patients had visceral metastases, 40% had received at least two prior regimens in the metastatic setting, and 19% had progressed after neoadjuvant or adjuvant therapy.
The confirmed objective response rate on independent review was 14.8% (95% confidence interval = 11.1%–19.3%). Median duration of response was not reached, with response durations of 2.1+ to 13.8+ months at the time of analysis. Of 46 responders, 37 had an ongoing response for at least 6 months and 6 had an ongoing response for at least 12 months. Response rates were 26.0% among patients with PD-L1 expression ≥ 5% (32% of all patients) and 9.5% in those with PD-L1 expression < 5%. Response durations in these subgroups were similar.
How It Works
Atezolizumab is a PD-L1–blocking monoclonal antibody that binds to PD-L1 and inhibits its interactions with PD-1 (programmed cell death protein 1) and B7.1 receptors. This action releases the PD-L1/PD-1–mediated inhibition of the immune response, including activation of an antitumor immune response without inducing antibody-dependent cellular cytotoxicity. PD-L1 may be expressed on tumor cells or tumor-infiltrating immune cells and can contribute to the inhibition of an antitumor immune response in the tumor microenvironment. Binding of PD-L1 to PD-1 and B7.1 receptors on T cells and antigen-presenting cells results in suppression of cytotoxic T-cell activity, T-cell proliferation, and cytokine production. In syngeneic mouse tumor models, blocking PD-L1 activity resulted in decreased tumor growth.
How It Is Used
The recommended dose of atezolizumab is 1,200 mg via intravenous infusion over 60 minutes every 3 weeks until disease progression or unacceptable toxicity. If the first infusion is tolerated, all subsequent infusions can be given over 30 minutes. Infusion should be interrupted or slowed for mild or moderate infusion reactions and discontinued for more severe reactions. No dose reductions of atezolizumab are recommended. Testing of PD-L1 expression in tumor specimens is not required for use of atezolizumab but may guide in patient selection. The Ventana PD-L1 (SP142) Assay is approved for PD-L1 testing on tumor-infiltrating immune cells.
Atezolizumab should be withheld for the following conditions: grade 2 pneumonitis; aspartate transaminase (AST) or alanine transaminase (ALT) > 3 and up to 5 times the upper limit of normal or total bilirubin > 1.5 and up to 3 times the upper limit of normal; grade 2 or 3 diarrhea or colitis; symptomatic hypophysitis, adrenal insufficiency, hypothyroidism, hyperthyroidism, or grade 3 or 4 hyperglycemia; grade 2 ocular inflammatory toxicity; grade 2 or 3 pancreatitis or grade 3 or 4 increases in amylase or lipase levels (> 2.0 times the upper limit of normal); grade 3 or 4 infection; grade 2 infusion-related reactions; and grade 3 rash. Treatment may be resumed with recovery of adverse reactions to grade 0 or 1.
Atezolizumab should be permanently discontinued for the following conditions: grade 3 or 4 pneumonitis; AST or ALT > 5 times the upper limit of normal or total bilirubin > 3 times the upper limit of normal; grade 4 diarrhea or colitis; grade 4 hypophysitis; any grade myasthenic syndrome/myasthenia gravis, Guillain-Barré, or meningoencephalitis; grade 3 or 4 ocular inflammatory toxicity; grade 4 pancreatitis or any grade of recurrent pancreatitis; grade 3 or 4 infusion-related reactions; and grade 4 rash.
In the single-arm trial, the most common adverse events of any grade were fatigue (52%), decreased appetite (26%), nausea (25%), urinary tract infection (22%), pyrexia (21%), and constipation (21%). Grade 3 or 4 adverse events occurred in 50% of patients, with the most common being urinary tract infection (9%), fatigue (6%), abdominal pain (4%), and dyspnea (4%). Infection and immune-related adverse events including pneumonitis, hepatitis, colitis, thyroid disease, adrenal insufficiency, diabetes, pancreatitis, and dermatitis/rash were observed. The most common grade 3 or 4 lab abnormalities were lymphopenia (10%), hyponatremia (10%), and anemia (8%).
Serious adverse events occurred in 45% of patients, with the most common (> 2%) being urinary tract infection, hematuria, acute kidney injury, intestinal obstruction, pyrexia, venous thromboembolism, urinary obstruction, pneumonia, dyspnea, abdominal pain, sepsis, and confusional state. Adverse events led to interruption of treatment in 27%, with the most common reasons (> 1%) being liver enzyme increase, urinary tract infection, diarrhea, fatigue, confusional state, urinary obstruction, pyrexia, dyspnea, venous thromboembolism, and pneumonitis. Adverse events led to discontinuation of treatment in 3.2%; sepsis led to discontinuation of treatment in two patients (0.6%). Three patients (0.9%) had sepsis, pneumonitis, or intestinal obstruction that led to death.
Atezolizumab carries warnings/precautions for the following conditions: immune-related pneumonitis; immune-related hepatitis; immune-related colitis; immune-related endocrinopathies, including hypophysitis, thyroid disorders, adrenal insufficiency, and type 1 diabetes; immune-related myasthenic syndrome/myasthenia gravis, Guillain-Barré or meningoencephalitis; ocular inflammatory toxicity; immune-related pancreatitis; infection; infusion reaction; and embryofetal toxicity. ■
1. U.S. Food and Drug Administration: Atezolizumab for urothelial carcinoma. Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm501878.htm. Accessed May 26, 2016.
2. Tecentriq (atezolizumab) injection prescribing information, May 2016, Genentech, Inc. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761034s000lbl.pdf. Accessed May 26, 2016.
3. Rosenberg JE, Hoffman-Censits J, Powles T, et al: Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: A single-arm, multicentre, phase 2 trial. Lancet 387:1909-1920, 2016.