Introduction

Tremelimumab is a monoclonal antibody check point inhibitor that is used in combination with durvalumab, a second check point inhibitor, in the therapy of unresectable hepatocellular carcinoma (HCC) and non-small cell lung cancer (NSCLC). The combination of tremelimumab and durvalumab is associated with a relatively high rate of serum aminotransferase elevations during therapy and an appreciable rate of clinically apparent immune mediated liver injury which can be severe and even fatal.

Background

Tremelimumab (tre” me lim’ ue mab) is an IgG2 monoclonal antibody to the cytotoxic T lymphocyte antigen-4 (CTLA-4) which is used in combination with durvalumab, a monoclonal antibody to the programmed cell death receptor ligand-1 (PD-L1), as immune therapy of HCC and NSCLC. Both tremelimumab and durvalumab are check point inhibitors that act by inhibition of cellular pathways that down-regulate immune reactions, thus helping to break tolerance and lead to immune clearance of cancer cells by promoting T cell activation and unleashing cytotoxic antitumor activity. Breaking tolerance, however, can also lead to unintended immune mediated injury to normal tissue. Like other combinations of monoclonal antibody inhibitors of the checkpoint proteins, CTLA-4 and anti-PD-1, tremelimumab combined with durvalumab has enhanced potency but also increased adverse events compared to either agent alone. The combination of tremelimumab with durvalumab has been shown to increase the clinical response rate to chemotherapy in patients with several forms of advanced or metastatic cancer. The combination was given accelerated approval as therapy of unresectable HCC and NSCLC in 2022 and continues to be under evaluation as therapy of other neoplastic diseases. Tremelimumab is available in single use vials of 25 mg in 1.25 mL and 300 mg in 15 mL (both at 20 mg/mL) under the brand name Imjudo. Both agents are administered intravenously and the recommended dose regimen varies by indication and body weight. For adults with body weight more than 30 kg, tremelimumab is recommended in doses of 300 mg and durvalumab in doses of 1500 mg. For HCC, a single priming dose of tremelimumab is given while durvalumab is administered every 4 weeks continuing until disease progression or intolerable toxicity arises. For NSCLC, the combination of tremelimumab 75 mg with durvalumab 1500 mg is given every 3 weeks for 4 cycles, then durvalumab every 4 weeks. Side effects of the combination are common and can include rash, diarrhea, abdominal pain, nausea, vomiting, pruritus, fatigue. More severe adverse events include immune mediated reactions of various organs including pneumonitis, dermatitis, colitis, nephritis, hepatitis and thyroiditis. Because tremelimumab is given in combination with durvalumab, side effects of therapy cannot be reliably attributed to one or the other agent, but durvalumab being given long term is probably responsible for most adverse events. Other severe adverse events with this combination include hypersensitivity reactions, tumor lysis syndrome and embryo-fetal injury.

Hepatotoxicity

Serum enzyme elevations occur in 41% to 56% of patients taking the combination of tremelimumab and durvalumab and rise to above 5 times the upper limit of normal (ULN) in 8% to 18% of patients. Immune mediated reactions are reported to occur in up to 36% of patients, which are liver related in 7.5% of patients with HCC but less frequently in those with other malignancies. The immune mediated liver injury can be severe, and fatal instances have been reported. Most instances of immune mediated hepatitis ultimately require corticosteroid therapy and result in high discontinuation rates. The immune mediated liver injury typically arises after 1 to 3 infusions and is usually hepatocellular in pattern and may be more related to durvalumab than tremelimumab. Rare instances of cholestatic immune mediated injury have been reported with checkpoint inhibitors, which is typically more severe and protracted and less likely to respond to immunosuppressive therapy. Monitoring of liver tests at the time of monthly infusions is recommended and stopping therapy early may play an important role in preventing severe and fatal outcomes.

The effects of combined CTLA-4 and 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 tremelimumab and durvalumab 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 immune mediated clinically apparent liver injury).

Mechanism of Injury

The mechanism of tremelimumab immune mediated organ damage is due to inhibition of checkpoint proteins that results in breaking tolerance to self-antigens and T cell activation. Off target T cell activation leads to immune-relayed adverse events such as hepatitis. Liver related immune reactions usually respond to immunosuppressive therapy.

Outcome and Management

The severity of tremelimumab and durvalumab induced liver injury ranges from transient, asymptomatic elevations in serum enzymes to acute liver injury with jaundice to severe acute liver failure and death. Guidelines for management of patients receiving the combination of tremelimumab and durvalumab 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 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 or severe acute hepatitis resistant to immunosuppressive therapy. Restarting tremelimumab or durvalumab after severe liver injury requiring corticosteroid therapy can be followed by recurrence of liver injury and is not recommended.

Drug Class: Antineoplastic Agents, Monoclonal Antibodies, Checkpoint Inhibitors

Other Related Drugs: Atezolizumab, Avelumab, Cemiplimab, Cetuximab, Dostarlimab, Durvalumab, Ipilimumab, Nivolumab, Pembrolizumab