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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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Avelumab

Last Update: June 23, 2022.

OVERVIEW

Introduction

Avelumab is a human monoclonal antibody to programmed cell 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. Avelumab therapy has major side effects and particularly immune related conditions, including acute hepatocellular and cholestatic liver injury which can be serious and even life threatening.

Background

Avelumab (av el' ue mab) is a human recombinant monoclonal IgG1 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 molecule 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 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 T cell responses. The subsequent enhancement of cytotoxic reactivity may play a beneficial role in cancer immunotherapy by breaking immunological tolerance to cancer cell neo-antigens. In several multicenter studies, avelumab therapy resulted in objective responses in patients with advanced, metastatic or unresectable malignant neoplasms, and a proportion of patients had a long term remission. Avelumab was approved for use in metastatic Merkel cell carcinoma and advanced, refractory urothelial bladder carcinoma in the United States in 2017, and was subsequently approved for use in combination with axitinib in advanced renal cell carcinoma. Avelumab is available in single use 10 mL vials of 200 mg (20 mg/mL) under the brand name Bavencio. The recommended dose is 800 mg as an intravenous infusion every 2 weeks. Premedication with acetaminophen and antihistamines is recommended for the first 4 infusions.

As with most checkpoint inhibitors, side effects of avelumab are common and can include fatigue, headache, musculosketetal 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 30% of avelumab treated patients develop immune related side effects, including enterocolitis, dermatitis, endocrinopathy, pneumonitis, neuropathy, nephritis and hepatitis. Most of these reactions respond to discontinuation of avelumab and initiation of 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 avelumab 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 avelumab include infusion reactions and embryo-fetal toxicity.

Hepatotoxicity

Mild-to-moderate serum aminotransferase elevations are not uncommon during avelumab therapy, but are usually self-limited and resolve even with continuing cyclic therapy. 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) occur in 1% to 4% of patients and generally lead to temporary discontinuation. Importantly, in 1% to 2% of patients receiving checkpoint inhibitor therapy, the serum enzyme elevations evolve into an immune mediated liver injury that can be clinically apparent and can be severe. The onset of injury is usually after 2 to 4 cycles or 1 to 3 months after starting treatment. The pattern of enzyme elevation is usually hepatocellular but can be mixed or even cholestatic. Liver histology generally demonstrates 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 may demonstrate centrilobular (zone 3) necrosis. Despite features of immune mediated liver injury, autoantibodies are usually 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 avelumab 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 avelumab 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 immunosuppression 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 avelumab 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 immune mediated liver injury and possible cause of reactivation of hepatitis B).

Mechanism of Injury

The liver injury due to avelumab is likely 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 avelumab 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 high or 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. 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 a cholestatic form of liver injury or delay in receiving corticosteroids. Restarting avelumab 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

Avelumab – Bavencio®

DRUG CLASS

Antineoplastic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NO.MOLECULAR FORMULASTRUCTURE
Avelumab 1537032-82-8 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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    (Among 53 patients with various refractory solid tumors treated with 1 of 4 doses of avelumab every 2 weeks, common side effects were fatigue, flu-like symptoms and fever, and 3 developed autoimmune disorders, one with ALT elevations above 5 times ULN).
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    (Systematic review of literature on check point inhibitor therapy in patients infected with hepatitis B or C identified 34 articles including 89 patients with HBV and 98 with HCV infection [67% with HCC and 25% with melanoma], among whom reactivation of hepatitis B occurred in two patients and ALT elevations arose in 14% of those with HBV versus 30% with HCV, the elevations rising above 5 times ULN in 3% and 17%).
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    (Long term outcome of a single arm study of 88 patients with metastatic Merkel cell cancer treated with avelumab found a median overall survival of 12.6 months; with no treatment related deaths, but treatment related adverse events in 77% including ALT elevations in 5% but only one patient had ALT levels above 5 times ULN).
  • Ruggiero R, Fraenza F, Scavone C, di Mauro G, Piscitelli R, Mascolo A, Ferrajolo C, et al. Immune checkpoint inhibitors and immune-related adverse drug reactions: data from Italian Pharmacovigilance Database. Front Pharmacol. 2020;11:830. [PMC free article: PMC7295943] [PubMed: 32581796]
    (Among 2088 safety reports of check point inhibitors enrolled in an Italian pharmacovigilance registry, 801 were immune related including gastrointestinal [33%], skin [17%] and liver [2.7%] due to nivolumab [70%], pembrolizumab [11%], ipilimumab [15%], atezolizumab [4%] and avelumab [<1%]).
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    (Among 700 patients with metastatic urothelial cancer treated with avelumab vs supportive care, the overall 1-year survival was 71% vs 58%, while the adverse event rate was 98% vs 78% and serious adverse events 47% vs 25%; no mention of ALT elevations or hepatotoxicity).
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    (Among 1783 patients in two large trials of avelumab in various solid tumors and Merkel cell carcinoma, adverse events arose in all patients which were immune related in 295 [16.5%] and severe in 51 [2.9%] with two deaths from liver injury; 50 and 51 year old women with metastatic breast and gastric cancer who developed acute liver failure after a 3rd and first infusion).
  • Mizuno K, Ito T, Ishigami M, Ishizu Y, Kuzuya T, Honda T, Kawashima H, et al. Real world data of liver injury induced by immune checkpoint inhibitors in Japanese patients with advanced malignancies. J Gastroenterol. 2020;55:653–661. [PubMed: 32124082]
    (Among 546 patients with advanced malignancies treated with checkpoint inhibitors at two Japanese referral centers between 2014 and 2019, high grade, immune mediated liver injury occurred in 29 [5%], mean age 69 years, 73% male, mean onset 52 [range 1-273] days, after 3 [1-15] doses of ipilimumab [6%], nivolumab [54%], pembrolizumab [30%], atezolizumab [6%], durvalumab [2.4%], combination [1.3%], presenting with hepatocellular [21%], cholestatic [59%] or mixed [21%] enzyme elevations, 4 with cholangitis and biliary dilatation without obstruction, only 1 case fatal; predictive factors for injury included ipilimumab [hazard ratio 4.2]).
  • Lee DW, Cho EJ, Lee JH, Yu SJ, Kim YJ, Yoon JH, Kim TY, et al. Phase II study of avelumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib. Clin Cancer Res. 2021;27(3):713–718. [PubMed: 33139266]
    (Among 30 patients with HCC [26 due to HBV and 3 to HCV] resistant to sorafenib who were then treated with avelumab, there were no complete and only 3 partial responses, and adverse events were frequent including ALT or AST elevations in 37% and bilirubin in 30%, but there were no episodes of reactivation or deaths due to adverse events).
  • Pujade-Lauraine E, Fujiwara K, Ledermann JA, Oza AM, Kristeleit R, Ray-Coquard IL, Richardson GE, et al. Avelumab alone or in combination with chemotherapy versus chemotherapy alone in platinum-resistant or platinum-refractory ovarian cancer (JAVELIN Ovarian 200): an open-label, three-arm, randomised, phase 3 study. Lancet Oncol. 2021;22:1034–1046. [PubMed: 34143970]
    (Among 566 woman with refractory ovarian carcinoma treated with avelumab or doxorubicin or both, avelumab alone or in combination did not improve either progression-free or overall survival and adverse events were greatest with the combination; ALT elevations arose in 1-2% of patients and one who received avelumab alone developed autoimmune hepatitis).
  • Park K, Özgüroğlu M, Vansteenkiste J, Spigel D, Yang JCH, Ishii H, Garassino M, et al. Avelumab versus docetaxel in patients with platinum-treated advanced NSCLC: 2-year follow-up from the JAVELIN lung 200 phase 3 trial. J Thorac Oncol. 2021;16:1369–1378. [PubMed: 33845211]
    (Among 792 patients with advanced, refractory NSCLC treated with avelumab or docetaxel, objective response rates were greater with avelumab than docetaxel in subjects with increased PD-L1 expression, and immune related adverse events arose in 17.3% of patients and ALT elevations in 1%).
  • D'Angelo SP, Bhatia S, Brohl AS, Hamid O, Mehnert JM, Terheyden P, Shih KC, et al. Avelumab in patients with previously treated metastatic Merkel cell carcinoma (JAVELIN Merkel 200): updated overall survival data after >5 years of follow-up. ESMO Open. 2021;6:100290. [PMC free article: PMC8564559] [PubMed: 34715570]
    (Among 88 patients with Merkel cell carcinoma treated with avelumab followed long term, the overall survival rate was 36% at 2 years and 26% at 5 years while 12% discontinued therapy because of adverse events).
  • 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: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 Korea, 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).

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