On October 21, 2022, tremelimu-mab-actl was approved by the U.S. Food and Drug Administration (FDA) for use in combination with durvalumab in the treatment of unresectable hepatocellular carcinoma.1
Supporting Efficacy Data
Approval was based on a comparison of overall survival in the tremelimumab/durvalumab group vs the sorafenib group in the open-label, three-arm HIMALAYA trial (ClinicalTrials.gov identifier NCT03298451). In the two groups, 782 patients with no prior systemic treatment for hepatocellular carcinoma were randomly assigned to receive tremelimumab at 300 mg as a one-time single intravenous (IV) infusion plus durvalumab at 1,500 mg on the same day, followed by durvalumab at 1,500 mg every 4 weeks (n = 393) or sorafenib at 400 mg twice daily (n = 389) until disease progression or unacceptable toxicity.
The median overall survival was 16.4 months (95% confidence interval [CI] = 14.2–19.6 months) in the tremelimumab/durvalumab group vs 13.8 months (95% CI = 12.3–16.1 months) in the sorafenib group (stratified hazard ratio [HR] = 0.78, 95% CI = 0.66–0.92, P = .0035). Median progression-free survival was 3.8 months (95% CI = 3.7–5.3 months) vs 4.1 months (95% CI = 3.7–5.5 months; stratified HR = 0.90, 95% CI = 0.77–1.05). Objective response rate was 20.1% vs 5.1%.
How It Is Used
The recommended tremelimumab dose for patients weighing at least 30 kg is 300 mg IV as a single dose combined with durvalumab at 1,500 mg on cycle 1/day 1, followed by durvalumab at 1,500 mg every 4 weeks. For those weighing less than 30 kg, the recommended tremelimumab dose is 4 mg/kg IV as a single dose in combination with durvalumab at 20 mg/kg, followed by durvalumab at 20 mg/kg every 4 weeks.
In HIMALAYA, the most common (≥ 20%) adverse events of any grade in the tremelimumab/durvalumab group were rash (32% vs 57% in the sorafenib group), diarrhea (27% vs 45%), fatigue (26% vs 30%), pruritus (23% vs 6%), musculoskeletal pain (22% vs 17%), and abdominal pain (20% vs 24%). The most common grade 3 or 4 adverse events in the tremelimumab/durvalumab group included diarrhea (6%) and fatigue (3.9%); those in the sorafenib group included rash (12%) and fatigue (6%). The most common grade 3 or 4 laboratory abnormalities in both groups were increased aspartate aminotransferase (27% vs 21%) and increased alanine aminotransferase (18% vs 12%).
Tremelimumab has warnings/precautions for immune-mediated adverse reactions, infusion-related reactions, and embryofetal toxicity.
In the tremelimumab/durvalumab group, serious adverse events occurred in 41% of patients, most commonly hemorrhage (6%) and diarrhea (4%). Adverse events led to discontinuation of treatment in 14% of patients. Fatal adverse events occurred in 8% of patients, with causes including intracranial hemorrhage, cardiac arrest, pneumonitis, hepatic failure, and immune-mediated hepatitis.
Tremelimumab has warnings/precautions for immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis, endocrinopathies, dermatologic reactions, nephritis with renal dysfunction, and pancreatitis; infusion-related reactions; and embryofetal toxicity. Patients should be advised not to breastfeed while receiving tremelimumab.
1. Imjudo (tremelimumab-actl) injection, for intravenous use, prescribing information, AstraZeneca, October 2022. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761289lbl.pdf. Accessed November 1, 2022.