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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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Cemiplimab

Last Update: June 23, 2022.

OVERVIEW

Introduction

Cemiplimab is a human monoclonal antibody to the programmed cell death receptor 1 (PD-1) and a checkpoint inhibitor that is used in the immunotherapy of advanced and metastatic cancer. Cemiplimab therapy has many adverse events and particularly immune related conditions including acute hepatocellular and cholestatic liver injury which can be serious and even life threatening.

Background

Cemiplimab (ce mip' li mab) is a human recombinant monoclonal IgG4 antibody to the programmed cell death receptor 1 (PD-1), which has distinctive immunomodulatory activity and is used in cancer immunotherapy. PD-1 is an important checkpoint molecule that is expressed on activated T and B cells and macrophages. Engagement of the PD-1 receptor modulates and down regulates T cell responses. Binding of the monoclonal antibody to the PD-1 receptor prevents ligand attachment and activation of the programmed cell death pathways, thereby allowing for a continued activation and proliferation of T cells. The subsequent enhancement of cytotoxic reactivity may play a beneficial role in cancer immunotherapy by breaking immunological tolerance to cancer cell neo-antigens. In prelicensure clinical studies, cemiplimab therapy resulted in objective responses in patients with advanced, metastatic cutaneous squamous cell carcinoma, and a proportion of patients had a long term remission. Cemiplimab was approved for use in cutaneous squamous cell carcinoma in the United States in 2018 and indications were subsequently expanded to include advanced or metastatic, refractory basal cell carcinoma and non-small cell lung cancer (NSCLC). It is under evaluation in several other forms of cancer, including renal, ovarian and uterine carcinoma, lymphomas and multiple myeloma. Cemiplimab is available in solution in single use vials of 350 mg in 7 mL (50 mg/mL) under the brand name Libtayo. The recommended dose in adults is 350 mg given intravenously over 30 minutes every 3 weeks.

As with most checkpoint inhibitors, side effects of cemiplimab 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 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 drug 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 cemiplimab 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 cemiplimab include infusion reactions and embryo-fetal toxicity.

Hepatotoxicity

Mild-to-moderate serum aminotransferase elevations are common (10% to 20%) during cemiplimab therapy but are usually self-limited and resolve even with continuing cyclic therapy. Serum ALT elevations above 5 times the upper limit of normal (ULN) occur in 1% to 4% of patients, and a proportion of these individuals develop clinically apparent immune related liver injury that can be severe. Typically, onset of immune mediated liver injury arises after 2 to 6 cycles of checkpoint inhibitor therapy. The pattern of enzyme elevation is usually hepatocellular but may be mixed or even cholestatic. Monitoring of serum enzymes is recommended with dose interruption for values above 3 times the ULN and discontinuation for values above 8 times the ULN. When serum aminotransferase levels remain elevated despite discontinuation or with development of symptoms or jaundice, early intervention with immunosuppressive therapy is prudent and generally results in rapid resolution. Liver histology usually demonstrates an acute hepatitis-like pattern with focal or confluent necrosis and prominent lymphocytic infiltrates of activated T cells, which is compatible with an immune mediated hepatic injury. Autoantibodies are usually not present and immunoglobulin levels may not be elevated. Restarting monoclonal antibody therapy can result in recurrence of injury. Immune mediated hepatitis appears to be more frequent with anti-CTLA-4 than with anti-PD-1 or anti-PD-L1 checkpoint inhibitors. Among 810 patients treated with cemiplimab in prelicensure studies, 16 (2%) developed an immune related hepatitis, all of whom required corticosteroid therapy and that was fatal in 1 (0.2%).

A proportion of patients receiving checkpoint inhibitors 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-1 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 cemiplimab in regard to the risk of reactivation of hepatitis B to provide rates of reactivation with and without antiviral prophylaxis.

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

Mechanism of Injury

The mechanism of liver injury due to cemiplimab is likely to be immunologically mediated, and many cases of checkpoint related, immune mediated hepatitis have appeared to respond to corticosteroid or immunosuppressive therapy. Liver biopsies in cases of hepatocellular injury and bile duct epithelial cell biopsies in cases with 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 cemiplimab 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. 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 withdrawn within 1 to 3 months. In some cases, adding a second agent (such as mycophenolate mofetil, azathioprine, antithymocyte globulin, or tacrolimus) 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 had refractory cholestatic liver injury, or had a delay in starting corticosteroid therapy. Patients with immune related adverse events due to cemiplimab can restart therapy once the adverse event has resolved, although concurrent immunosuppressive therapy may be necessary. Switching to another type of checkpoint inhibitor (anti-CTLA-4 or anti-PD-L1) is likely to be better tolerated.

Drug Class: Antineoplastic Agents, Monoclonal Antibodies, Checkpoint Inhibitors

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Cemiplimab – Libtayo®

DRUG CLASS

Antineoplastic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NO.MOLECULAR FORMULASTRUCTURE
Cemiplimab 1801342-60-8 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 115 patients with metastatic cutaneous squamous cell carcinoma treated with cemiplimab objective responses occurred in 45%, and 98% of subjects had adverse events including fatigue, diarrhea, nausea and rash; ALT elevations occurred in 5 patients [4.3%] but none were above 5 times ULN).
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    (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).
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    (Among 608 women with refractory cervical cancer treated with cemiplimab or chemotherapy, the median overall survival was 12 vs 8.5 months and ALT elevations arose in 4.3% with cemiplimab vs 6.9% with conventional chemotherapy, ALT values above 5 times ULN in 0.7% in both groups, while immune mediated hepatitis arose in 4 cemiplimab-treated [1.3%] but no control patients).
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