FDA News: Issue 22-1 December 2022

Author: [AUTHOR] Published on 12/2/2022 5:00:00 AM

FDA Approves IMJUDO (Tremelimumab-actl) in Combination with Durvalumab for the Treatment of Adult Patients with Unresectable Hepatocellular Carcinoma (uHCC)

On October 21, 2022, the US Food and Drug Administration (FDA) approved IMJUDO (tremelimumab-actl) in combination with durvalumab, for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC).

The approved recommended dosage of IMJUDO is listed below. IMJUDO should be administered as an intravenous infusion over 60 minutes after dilution.
  • Weight 30 kg and more: IMJUDO 300 mg as a single dose in combination with durvalumab 1,500 mg at Cycle 1/Day 1, followed by durvalumab as a single agent every 4 weeks until disease progression or unacceptable toxicity
  • Weight less than 30 kg: IMJUDO 4 mg/kg as a single dose in combination with durvalumab 20 mg/kg at Cycle 1/Day 1, followed by durvalumab as a single agent every 4 weeks until disease progression or unacceptable toxicity

Additional information regarding dosage and administration as well as warnings and precautions about severe and fatal immune-mediated adverse reactions, infusion-related reactions, and embryo-fetal toxicity can be found in the full prescribing information linked below.

Mechanism of Action (MOA) and Pharmacokinetics (PK)
MOA: Tremelimumab-actl is a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blocking antibody.

General PK: The PK of tremelimumab-actl was studied in patients with other solid tumors following administration of doses 1 mg/kg, 3 mg/kg, and 10 mg/kg administered once every 4 weeks for 4 doses. The PK of tremelimumab-actl as a single dose of 300 mg were evaluated in patients with HCC. The AUC of tremelimumab-actl increased proportionally from 1 mg/kg to 10 mg/kg every 4 weeks and steady state was achieved at approximately 12 weeks.

Distribution: The geometric mean (% coefficient of variation [CV%]) of tremelimumab-actl for central (V1) and peripheral (V2) volume of distribution was 3.45 (24%) and 2.66 (34%) L, respectively.

Elimination: The geometric mean (CV%) terminal half-life of tremelimumab-actl was 16.9 (19%) days after a single dose and 18.2 (19%) days during steady state. The geometric mean (CV%) clearance of tremelimumab-actl was 0.286 (32%) L/day after a single dose and 0.263 (32%) L/day during steady state.

Immunogenicity: Of the 182 uHCC patients in the randomized, open-label, multicenter study who were treated with a single dose of tremelimumab-actl in combination with durvalumab once every 4 weeks and evaluable for the presence of anti-drug antibodies (ADAs) against tremelimumab-actl at predose week 0 and week 4, 11% (20/182) of patients tested positive for the ADAs. Among the 20 patients who tested positive for ADAs 40% (8/20) tested positive for neutralizing antibodies. There was no identified clinically significant effect of the ADAs on the pharmacokinetics or safety of tremelimumab-actl; however, the effect of ADAs and neutralizing ADAs on the effectiveness of tremelimumab-actl is unknown.

Use in Specific Populations
There were no clinically significant differences in the PK of tremelimumab-actl based on body weight (34 to 149 kg), age (18 to 87 years), sex, race (White, Black, Asian, Native Hawaiian, Pacific Islander, or American Indian), serum albumin levels (0.3 to 396 g/L), lactate dehydrogenase levels (12 to 5570 U/L), soluble PD-L1 (67 to 349 pg/mL), organ dysfunction including mild to moderate renal impairment (CLcr 30 to 89 mL/min), and mild to moderate hepatic impairment (bilirubin < 3 x ULN and any AST).

The effect of severe renal impairment (CLcr 15 to 29 mL/min) or severe hepatic impairment (bilirubin > 3 times ULN and any AST) on the PK of tremelimumab-actl is unknown.

Efficacy and Safety
The efficacy of IMJUDO in combination with durvalumab was evaluated in the HIMALAYA study, a randomized (1:1:1), open-label, multicenter study in patients with confirmed uHCC who had not received prior systemic treatment for HCC. The major efficacy outcome was overall survival (OS). Additional information regarding the efficacy trial can be found in the full prescribing information linked below.

Most common adverse reactions (≥ 20%) observed in the patients with uHCC were rash, diarrhea, fatigue, pruritus, musculoskeletal pain, and abdominal pain.

Most common laboratory abnormalities (≥ 40%) in patients with uHCC were AST increased, ALT increased, hemoglobin decreased, sodium decreased, bilirubin increased, alkaline phosphatase increased, and lymphocytes decreased.

Full prescribing information is available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761270s000lbl.pdf.

Visit Drugs@FDA at https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval. 

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

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