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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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Last Update: May 1, 2016.



Pembrolizumab is a humanized monoclonal antibody to programmed cell death receptor 1 (PD-1), which results in an increased immune reactivity that can break tolerance and is used in the immunotherapy of cancer. Pembrolizumab therapy has many adverse events and particularly immune related conditions, including acute hepatitis and acute liver injury which can be serious and even life threatening.


Pembrolizumab (pem" broe liz' ue mab) is a humanized recombinant monoclonal IgG4 kappa-isotype 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 modulates and down regulates T cell responses. Inhibition of PD-1 receptors on the surface of activated T cells prevents their binding to the PD ligand which ordinarily terminates the activation and proliferation of T cells. Without the PD-1 receptor engagement, T cell responses remained activated. 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 large multicenter studies, pembrolizumab therapy resulted in a prolongation of survival in patients with advanced, metastatic or unresectable malignant melanoma, and a proportion of patients had a long term remission. Pembrolizumab was approved for use in advanced melanoma in the United States in 2014 and for advanced non-small cell lung cancer (NSCLC) in 2015. It is also under active investigation in several other forms of cancer, including breast and renal cancer and lymphomas. Pembrolizumab is available in single use vials both as a powder for reconstitution and as a liquid solution (25 mg/mL) under the brand name Keytruda. The typical regimen is 2 mg/kg as an intravenous infusion every 3 weeks. Side effects are common and can be severe. As many as half of treated patients develop immune related side effects as a result of immune enhancement including enterocolitis, dermatitis, endocrinopathy, pneumonitis, neuropathy, nephritis and hepatitis. Most of these reactions respond to immunosuppressive therapy, but some have resulted in fatalities and some have required long term therapy. Early recognition and prompt management of these side effects is an integral component of proper use of checkpoint inhibitors such as pembrolizumab.


Mild-to-moderate serum aminotransferase elevations are not uncommon (~10%) during pembrolizumab 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 0.5% to 1.5% of patients, and a proportion of these individuals develop clinically apparent liver injury that can be severe. The onset of such injury is usually after 2 to 6 cycles or 1 to 3 months after initiation of treatment. The pattern of enzyme elevation is usually hepatocellular. Monitoring of serum enzymes is recommended and early intervention with immunosuppressive therapy generally results in rapid resolution. However, without treatment the abnormalities can progress to clinically apparent liver injury with jaundice. Liver histology 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 pembrolizumab can result in recurrence of injury, although corticosteroid treatment may block recurrence.

The effects of PD-1 inhibition on chronic hepatitis B have not been reported as enrollment criteria in the clinical trials of pembrolizumab have usually excluded patients with chronic viral hepatitis. However, it is possible that anti-PD-1 treatment would exacerbate chronic hepatitis B by enhancing T cell cytotoxicity to viral antigens. Interestingly, checkpoint immunotherapy has not been found to be deleterious in patients with chronic hepatitis C and in some cases resulted in a decrease in viral levels.

Likelihood score: E* (although no specific cases have been described in the literature, this is a relatively recently approved medication and is likely to be a not uncommon cause of clinically apparent acute liver injury).

Mechanism of Injury

The mechanism of liver injury due to pembrolizumab is likely to be immunologically mediated and some cases have appeared to respond to corticosteroid or immunosuppressive therapy, allowing for continuation or restarting of pembrolizumab therapy.

Outcome and Management

Guidelines for management of patients receiving pembrolizumab recommend monitoring of liver tests and use of corticosteroids for patients who develop serum aminotransferase elevations above 5 times the ULN, 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 pembrolizumab 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 delay in starting corticosteroid therapy. Patients with immune related adverse events due to pembrolizumab can frequently restart therapy once the adverse event has resolved, although concurrent immunosuppressive therapy may be necessary.

Drug Class: Antineoplastic Agents, Monoclonal Antibodies, Checkpoint Inhibitors



Pembrolizumab – Keytruda®


Antineoplastic Agents


Product labeling at DailyMed, National Library of Medicine, NIH


Pembrolizumab1374853-91-4Monoclonal AntibodyNot Available


References updated: 01 May 2016

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    (Among 41 patients with advanced cancers with or without mismatch repair deficiency, response rates to pembrolizumab were higher in those with mismatch repair deficiency [53%] than in those without [0%]; adverse events occurred in 98% of patients; ALT elevations occurred in 3 [7%] patients and were greater than 5 times ULN in 2 [5%]).
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