Atezolizumab is a humanized monoclonal antibody to programmed death-ligand 1 (PD-L1) that increases immune reactivity to tumor neoantigens and is used as immunotherapy of selected cancers of the bladder and lung. Atezolizumab has been associated with a low rate of serum enzyme elevations during therapy and with uncommon instances of clinically apparent, immune-mediated liver injury.
Atezolizumab (a" te zoe liz' ue mab) is a humanized monoclonal immunoglobulin G1 antibody to the programmed cell death ligand 1 (PD-L1) that is used in cancer immunotherapy. Inhibition of PD-L1 overcomes the usual block ("check point") in immune surveillance of tumor cell neoantigens and can induce remissions in several forms of advanced, metastatic cancer including urothelial (bladder and urethral) carcinoma and non-small cell lung cancer (NSCLC). In clinical trials, atezolizumab led to prolongation of recurrence free survival as well as overall survival in patients with bladder cancer and NSCLC. Response rates to atezolizumab were somewhat higher in patients who expressed high levels of PD-L1 in tumor-infiltrating immune cells. Atezolizumab was approved for use in the United States in 2016, the fourth monoclonal antibody check point inhibitor introduced into cancer immunotherapy, the others being ipilimumab (anti-CTLA-4: 2011), pembrolizumab (anti-PD-1: 2014), and nivolumab (anti-PD-1: 2015). Atezolizumab is available in single use vials of 1200 mg (in 20 mL) and the recommended dose is 1200 mg intravenously every 3 weeks. Adverse events can include fatigue, nausea, anorexia, diarrhea, fever, dyspnea and rash. Most challenging, however, are the various immune-mediated adverse events such as hypothyroidism, colitis, pneumonitis and hepatitis. Early recognition and prompt management of these side effects (usually with corticosteroids) is an integral component of proper use of check point inhibitors.
In preregistration controlled trials of atezolizumab in various forms of metastatic cancer, serum aminotransferase elevations occurred in 2% to 6% of patients and were above 5 times the ULN in 1% to 2%. In addition, several instances of immune-mediated hepatitis were reported, although the clinical features were not described in any detail. In most instances, the liver injury from check point inhibitors arises within 1 to 3 months of starting therapy and is marked by prominent elevations in serum ALT and AST with minimal increases in alkaline phosphatase. Although apparently immune mediated, most patients do not develop conventional autoantibodies. The liver tests abnormalities usually resolve with stopping therapy, but improvement is more rapid with corticosteroid therapy, which can also allow continuation of the immunotherapy of the cancer. Because patients in these clinical trials were prospectively monitored, atezolizumab was withdrawn once liver test abnormalities were detected and, perhaps as a consequence, severe liver injury with jaundice was not reported. In clinical practice, use of the check point inhibitors with less rigorous monitoring may result in continuation of therapy despite early evidence of injury and more prominent instances of clinically apparent liver injury. However, rates of clinically apparent liver injury from atezolizumab appear to be lower than those associated with ipilimumab, the initial check point inhibitor.
The effects of anti-PD-L1 inhibition on hepatitis B have not been reported as enrollment criteria in the clinical trials of atezolizumab typically excluded patients with hepatitis B or C or preexisting liver disease. However, it is likely that check point inhibitors could exacerbate chronic hepatitis B and C by enhancing T cell cytotoxicity to viral antigens.
Likelihood score: D (possible cause of clinically apparent liver injury).
Mechanism of Injury
The mechanism of liver injury due to atezolizumab is likely to be immunologically mediated and cases have appeared to respond to corticosteroid or immunosuppressive therapy allowing for continuation of atezolizumab therapy.
Outcome and Management
Guidelines for management of patients receiving monoclonal antibody check point inhibitors recommend corticosteroids for patients who develop persistent serum aminotransferase elevations above 5 times the ULN, initiating therapy with high doses of intravenous methylprednisolone and switching to oral prednisone after 1 to 2 days, continuing tapering doses for at least 30 days. Most cases of hepatitis due to atezolizumab resolve with prompt institution of immunosuppressive therapy. The few fatal cases associated with check point inhibitors that have been reported occurred in patients who had other severe immune related adverse events (Stevens Johnson syndrome, capillary leak syndrome) or who had a delay in starting corticosteroid therapy.
REPRESENTATIVE TRADE NAMES
Atezolizumab – Tecentriq®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 06 December 2016
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