Durvalumab is a human monoclonal antibody to programmed cell death receptor ligand 1 (PD-L1), which results in an increased immune reactivity which can break tolerance and is used in the immunotherapy of cancer. Durvalumab therapy has many adverse events and particularly immune related conditions, including acute liver injury which can be serious and even life threatening.
Durvalumab (dur val" ue mab) is a human recombinant monoclonal IgG1 kappa-isotype antibody to the ligand for programmed cell death receptor-1 (PD-L1) which leads to enhanced T cell responses against cancer cells and is used in cancer immunotherapy. PD-1 is an important checkpoint molecule that modulates and down regulates T cell responses. Inhibition of the PD-L1 prevents its binding to the programmed cell death receptor 1 which is responsible for down regulating T cell responses. Inhibition of this pathway allows 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 several large multicenter studies, durvalumab therapy resulted in a prolongation of survival in patients with advanced, metastatic or unresectable urothelial carcinoma, and a proportion of patients had a long term remission. Durvalumab was approved for use in advanced urothelial cancer in the United States in 2017 and it continues to be assessed for efficacy in several other solid tumors and lymphomas including advanced non-small cell lung cancer (NSCLC). Durvalumab is available as a solution in single use vials of 120 and 500 mg (50 mg/mL) under the brand name Imfinzi. The typical regimen is 10 mg/kg by intravenous infusion over 60 minutes every 2 weeks until disease progression or intolerance. Side effects are common and can be severe. Common adverse reactions include fatigue, musculoskeletal pain, constipation, anorexia, nausea, and peripheral edema. 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 avelumab.
In the preregistration clinical trials of durvalumab, mild-to-moderate serum aminotransferase elevations were not uncommon (~10%), although most abnormalities were self-limited and resolved even with continuing cyclic therapy. Serum ALT elevations above 5 times the upper limit of normal (ULN) occurred in 0.5% to 1.5% of patients, and a proportion of these individuals develop clinically apparent liver injury that was severe in some instances. The onset of such injury was usually after 2 to 6 cycles or 1 to 3 months after initiation of treatment. The pattern of enzyme elevation was usually hepatocellular. For this reason, 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 durvalumab can result in recurrence of injury, although corticosteroid treatment may block recurrence.
The effects of PD-L1 inhibition on chronic hepatitis B have not been reported as enrollment criteria in the clinical trials of durvalumab have usually excluded patients with chronic viral hepatitis. However, it is likely that anti-PD-L1 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: C (although no specific cases have been described in the literature, 4 cases of immune mediated hepatitis were described in the FDA review of durvalumab; the incidence of hepatitis in the preregistration studies was 1% and clinically apparent injury occurred despite careful monitoring and regimens of dose interruption and discontinuation based upon monitoring of liver tests every 2 to 4 weeks).
Mechanism of Injury
The liver injury due to durvalumab is likely immunologically mediated and some cases have appeared to respond to corticosteroid or immunosuppressive therapy, allowing for continuation or restarting of durvalumab therapy.
Outcome and Management
Guidelines for management of patients receiving durvalumab recommend monitoring of liver tests at the time of the infusions for the first 4 cycles and then monthly thereafter and as clinically indicated. Most cases of hepatitis due to durvalumab 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 durvalumab can frequently restart therapy once the adverse event has resolved, although concurrent immunosuppressive therapy may be necessary.
REPRESENTATIVE TRADE NAMES
Durvalumab – Imfinzi®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 20 July 2017
Abbreviations used: CTLA-4, cytotoxic T lymphocyte-associated antigen 4; PD-L1, programmed cell death receptor ligand one; NSCLC, non-small cell lung cancer.
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Massard C, Gordon MS, Sharma S, Rafi S, Wainberg ZA, Luke J, et al. Safety and efficacy of durvalumab (MED 14736), an anti-programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer. J Clin Oncol 2016; 34: 3119-25. PubMed Citation (Among 41 patients with advanced, refractory urothelial bladder cancer treated with durvalumab for up to 12 months, the objective response rate was 31% and adverse event rate 64%; most frequently fatigue [13%], diarrhea [10%] and anorexia [8%]; no mention of ALT elevations or hepatotoxicity).
Antonia S, Goldberg SB, Balmanoukian A, Chaft JE, Sanborn RE, Gupta A, Narwal R, et al. Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol 2016; 17: 299-308. PubMed Citation (Among 102 patients with refractory NSCLC treated with various doses of durvalumab [anti-PD-L1] and temelimumsb [anti-CTLA-4], side effects were common leading to discontinuations in 28% and ALT elevations in 0% to 12% of regimens).
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