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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Atezolizumab

Last Update: June 23, 2022.

OVERVIEW

Introduction

Atezolizumab is a humanized monoclonal antibody to programmed death-ligand 1 (PD-L1), which acts as a checkpoint inhibitor and is used in the immunotherapy of several forms of advanced or metastatic cancer. Atezolizumab like other checkpoint inhibitors has major side effects and particularly immune related conditions, including acute hepatocellular and cholestatic liver injury that can be serious and even life threatening.

Background

Atezolizumab (a" te zoe liz' ue mab) is a humanized monoclonal immunoglobulin G1 antibody to the programmed cell death ligand 1 (PD-L1) which has distinctive immunomodulatory activity and is used as a checkpoint inhibitor in cancer immunotherapy. The programmed cell death receptor 1 (PD-1) is an important checkpoint protein that is expressed on activated T and B cells. Binding of the ligand to PD-1 activates programmed cell death pathways that terminate or down regulate cytotoxic T cell responses. Monoclonal antibody binding to the PD-L1 by atezolizumab prevents its engagement with the PD receptor and subsequent induction of the cellular pathways that down regulate T cell responses. Inhibition of this pathway allows for a continued activation and proliferation of cytotoxic T cells and proinflammatory cytokines. The enhancement of cytotoxic reactivity may play a beneficial role in cancer immunotherapy by breaking immunological tolerance to cancer cell neoantigens. Atezolizumab has been shown to improve response rates and survival in several forms of advanced and metastatic cancer and was approved for use in the United States in 2016, the fourth monoclonal antibody checkpoint inhibitor introduced into cancer immunotherapy, the others being ipilimumab (anti-CTLA-4: 2011), pembrolizumab (anti-PD-1: 2014), and nivolumab (anti-PD-1: 2015). Clinical indications of atezolizumab now include advanced forms of urothelial carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), hepatocellular carcinoma (HCC), and melanoma. Atezolizumab is available in solution for injection in single use vials of 840 mg in 14 mL and 1200 mg in 20 mL (both 60 mg/mL) under the brand name Tecentriq. The dose and timing of injections varies by indication; typical regimens are 840 mg every 2 weeks, 1200 mg every 3 weeks or 1680 mg every 4 weeks until disease progression or unacceptable toxicity.

As with most checkpoint inhibitors, side effects of atezolizumab are common and can include fatigue, headache, musculoskeletal pain, arthralgia, abdominal pain, diarrhea, nausea, vomiting, decreased appetite, weight loss, fever, cough, dyspnea, pruritus, and rash. Importantly, as a result of the immune enhancement, between 15% and 25% of treated patients develop immune related side effects. These reactions are high grade in 10% of patients and can include enterocolitis, dermatitis, endocrinopathy, pneumonitis, neuropathy, nephritis and hepatitis. Most of these reactions respond to discontinuation and immunosuppressive therapy, but some have resulted in fatalities and some have required permanent discontinuation of the checkpoint inhibitor and long term immunosuppressive therapy. Baseline screening and regular monitoring for these adverse events during atezolizumab therapy is recommended. Early recognition and prompt management of side effects is an integral component of proper use of checkpoint inhibitors. Checkpoint inhibitors should be used only by health care professionals with training in immunotherapy and experience in the management of the side effects of immunomodulatory agents. Other rare but potentially severe adverse effects of atezolizumab include infusion reactions and embryo-fetal toxicity.

Hepatotoxicity

In preregistration controlled trials of atezolizumab in various forms of metastatic cancer, serum aminotransferase elevations occurred in 20% to 30% of patients but were generally transient, mild and not associated with symptoms or jaundice. These rates of serum enzyme elevations are similar to those with other forms of chemotherapy for advanced malignancies. Serum ALT elevations above 5 times the upper limit of normal (ULN) occurred in 1% to 4% of patients and generally led to temporary or permanent discontinuation. Importantly, in 1% to 2% of patients the serum enzyme elevations evolved into clinically apparent immune mediated liver injury. The onset of injury was usually after 2 to 4 cycles or 1 to 3 months after starting treatment. The pattern of enzyme elevation was usually hepatocellular but was sometimes mixed and even cholestatic. Liver histology usually demonstrated a pan-lobular hepatitis with focal or confluent necrosis and prominent lymphocytic infiltrates of activated T cells, compatible with an immune mediated hepatic injury. More severe forms of hepatitis can demonstrate centrilobular (zone 3) necrosis. Despite features of immune mediated liver injury, autoantibodies are generally not present and immunoglobulin levels are normal. Because of the serious nature of the liver injury, monitoring with routine liver tests (including alkaline phosphatase) is recommended for patients who receive checkpoint inhibitor therapy. Treatment with corticosteroids generally results in a rapid improvement, allowing for their discontinuation within 1 to 2 months. In some instances, however, the clinical and biochemical response is inadequate, calling for addition of a second immunosuppressive agent such as azathioprine or mycophenolate mofetil. Restarting atezolizumab or another checkpoint inhibitor after resolution of the hepatic injury is sometimes possible, but can result in recurrence of injury and has not been shown to improve outcome of the cancer chemotherapy.

A proportion of patients receiving atezolizumab develop cholestatic rather than hepatocellular liver injury. Cholestatic forms of immune mediated liver injury generally arise later than the hepatocellular forms (after 3 to 10 cycles) and are often accompanied by abdominal pain and jaundice. Alkaline phosphatase levels are markedly elevated while aminotransferase levels are only modestly increased. Imaging studies may show irregular dilatation of the intra- and/or extra-hepatic bile ducts and thickening of the gall bladder and bile duct wall, but without evidence of frank obstruction. Liver biopsy shows portal inflammation and bile duct injury and endoscopic biopsy of the bile duct epithelium shows inflammation and scarring. The general features suggest a secondary form of sclerosing cholangitis referred to as checkpoint inhibitor cholangiopathy. Therapy with corticosteroids may improve alkaline phosphatase and bilirubin levels but rarely leads to complete recovery, and long term cholestasis and hepatic failure can occur. Some patients with a cholestatic form of immune related hepatitis do not manifest the large bile duct changes but demonstrate loss and paucity of the smaller, intrahepatic portal bile ducts resulting in a vanishing bile duct syndrome similar to primary biliary cholangitis (PBC).

The effects of PD-L1 inhibition on chronic hepatitis B are not well defined but convincing examples of reactivation of hepatitis B have been described due to other checkpoint inhibitors. Most cases have occurred in patients with preexisting HBsAg, but rare instances were reported in individuals suspected of having with anti-HBc without HBsAg. Thus, screening patients for HBsAg, anti-HBc and anti-HBs is appropriate before initiating immunotherapy with checkpoint inhibitors. Patients with HBsAg should be considered for prophylaxis with an antiviral agent with potent activity against HBV such as entecavir or tenofovir. In patients with anti-HBc without HBsAg, monitoring and close attention to liver test abnormalities is probably adequate if antiviral therapy can be introduced rapidly for early evidence of reactivation. There has not been adequate experience with atezolizumab in regard to the risk of reactivation of hepatitis B to provide rates of reactivation with and without antiviral prophylaxis.

Likelihood score: B (likely cause of clinically apparent liver injury and probable cause of reactivation of hepatitis B).

Mechanism of Injury

The mechanism of liver injury due to atezolizumab is likely to be immunologically mediated and is usually at least partially responsive to corticosteroid or immunosuppressive therapy. Liver biopsies in cases of hepatocellular injury and bile duct epithelial cell biopsies in cholangiopathic injury demonstrate necrosis and inflammatory cell infiltration with cytotoxic CD8+ T cells, suggesting that the checkpoint inhibition allowed for activation of T cells directed at hepatocyte or cholangiocyte cell surface antigens.

Outcome and Management

Guidelines for management of patients receiving atezolizumab recommend monitoring of liver tests and interrupting therapy for patients who develop serum aminotransferase elevations above 3 times the ULN, and discontinuing treatment for values above 8 times the ULN in patients without preexisting abnormalities or tumor involvement of the liver (in whom elevations of 5 and 10 times the ULN are used). Corticosteroid therapy can be considered for patients with persistent ALT elevations or if symptoms or jaundice arise, initiating therapy with high dose 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 checkpoint inhibitors resolve with prompt institution of immunosuppressive therapy which can be discontinued in 1 to 3 months. In some cases, adding a second agent (such as mycophenolate mofetil, azathioprine, antithymocyte globulin, infliximab or tacrolimus) and prolonged immunosuppression may be necessary. The few fatal cases that have been reported during immunotherapy with checkpoint inhibitors occurred in patients who had other severe immune related adverse events (Stevens Johnson syndrome, capillary leak syndrome) or who had an immune related cholangiopathy resistant to immunosuppressive therapy. Restarting atezolizumab after severe liver injury requiring corticosteroid therapy can be followed by recurrence of liver injury and is not recommended. Switching to other checkpoint inhibitors (ipilimumab or anti-PD-1 inhibitors) is more likely to be tolerated. However, survival rates do not seem to be improved by re-introduction of checkpoint inhibitor therapy after severe immune related adverse events. Thus, restarting therapy should be undertaken only after careful evaluation of the residual cancer status.

Drug Class: Antineoplastic Agents, Monoclonal Antibodies, Checkpoint Inhibitors

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Atezolizumab – Tecentriq®

DRUG CLASS

Antineoplastic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NO.MOLECULAR FORMULASTRUCTURE
Atezolizumab 1380723-44-3 Monoclonal AntibodyNot Available

ANNOTATED BIBLIOGRAPHY

References updated: 23 June 2022

Abbreviations used: CPI, checkpoint inhibitor; CTLA-4, cytotoxic T lymphocyte associated antigen 4; HCC, hepatocellular carcinoma; irAE, immune related adverse event; PD-1, programmed cell death receptor 1; PD-L1, programmed cell death receptor ligand-1; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer.

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    (77 year old Japanese woman with advanced adenocarcinoma of the lung developed nausea after 13 cycles of atezolizumab [bilirubin 2.6 mg/dL, ALT 193 UL, Alk P 2837], liver biopsy resembling sclerosing cholangitis with minimal response to ursodiol and marked response to prednisone although Alk P remained elevated).
  • Honma Y, Shibata M, Gohda T, Matsumiya H, Kumamoto K, Miyama A, Morino K, et al. Rapid progression of liver fibrosis Induced by acute liver injury due to immune-related adverse events of atezolizumab. Intern Med. 2021;60:1847–1853. [PMC free article: PMC8263175] [PubMed: 33456046]
    (72 year old Japanese woman with advanced lung cancer developed liver injury after 3 monthly cycles of atezolizumab and bevacizumab with carboplatin and paclitaxel [bilirubin 0.6 mg/dL, ALT 208 U/L, Alk P 1075 U/L, INR 1.12], biopsy showing a panlobular hepatitis, treated with ursodiol with partial effect [bilirubin 3.2 mg/dL, ALT ~180 U/L, Alk P ~850 U/L], with second biopsy showing bridging fibrosis; addition of prednisolone resulted in further but incomplete biochemical improvement).
  • Wong GL, Wong VW, Hui VW, Yip TC, Tse YK, Liang LY, Lui RN, et al. Hepatitis flare during immunotherapy in patients with current or past hepatitis B virus infection. Am J Gastroenterol. 2021;116:1274–1283. [PubMed: 33560651]
    (Among 990 patients in Hong Kong with advanced malignancies treated with checkpoint inhibitors between 2014 and 2019 [397 HBsAg positive, 482 with anti-HBc or anti-HBs, 111 negative for both at baseline], 39% of HBsAg-positive vs 30% of HBsAg-negative patients developed ALT elevations during therapy, but only two cases [both HBsAg positive and on prophylaxis] were due to HBV reactivation).
  • Mustafayev K, Torres H. Hepatitis B virus and hepatitis C virus reactivation in cancer patients receiving novel anticancer therapies. Clin Microbiol Infect. 2022 Mar 10:S1198-743X(22)00119-7. [PubMed: 35283317]
    (Review of the literature on reactivation of HBV and HCV in patients on “novel” anticancer therapy concludes that reactivation can occur with checkpoint inhibitor therapy but largely among HBsAg positive patients and only rarely in patients with resolved hepatitis B).
  • Yoo S, Lee D, Shim JH, Kim KM, Lim YS, Lee HC, Yoo C, et al. Risk of hepatitis B virus reactivation in patients treated with immunotherapy for anti-cancer treatment. Clin Gastroenterol Hepatol. 2022;20:898–907. [PubMed: 34182151]
    (Among 3,465 patients with advanced malignancies treated with checkpoint inhibitors between 2015 and 2020 at a single referral center in Korean, 511 [15%] were HBsAg positive at baseline, reactivation of HBV occurred in 5 of 511 [1%] HBsAg positive vs none of 2,954 HBsAg negative patients, arising in 2 of 464 [0.4%] patients given prophylaxis [both having stopped antivirals] vs 3 of 47 not given prophylaxis [6.4%]; reactivation arising after 3-141 weeks [median 54 weeks] of nivolumab [n=2], pembrolizumab [n=2] or ipilimumab and nivolumab [n=1] treatment, ALT peak 53 to 1768 IU/mL, HBV DNA 6,100 to 3.9 million IU/mL, resolving with 2 to 6 weeks of starting antiviral therapy).
  • Tzadok R, Levy S, Aouizerate J, Shibolet O. Acute liver failure following a single dose of atezolizumab, as assessed for causality using the updated RUCAM. Case Rep Gastrointest Med. 2022;2022:5090200. [PMC free article: PMC8967548] [PubMed: 35368450]
    (46 year old man with refractory, locally invasive adenocarcinoma of lung developed weakness and pain 2 weeks after an initial dose of atezolizumab [bilirubin 0.3 mg/dL, ALT 485 rising to 2124 U/L, Alk P 253 U/L, creatinine 2.8, INR 1.32 rising to 2.91], with progressive lactic acidosis and hepatic failure, biopsy showing severe zone 3 necrosis and slight inflammation and sinusoidal dilation but no fibrosis, dying within 5 days of presentation).
  • Kotha S, Zen Y, Berry P. Diagnostic, therapeutic and prognostic challenges in a jaundiced patient treated with a checkpoint inhibitor. Clin J Gastroenterol. 2022;15:446–450. [PubMed: 35152370]
    (42 year old man with metastatic NSCLC on treatment with maintenance atezolizumab developed jaundice, diffuse biliary dilatation without obstruction, and ascites [bilirubin 10.0 rising to 16.4 mg/dL, ALT 603 U/L, Alk P 889 U/L], biopsy showing marked cholestasis with little inflammation and malignant cells in hepatic vessels suggestive of malignant rather than checkpoint induced cholangiopathy).

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