Active Ingredient: Tremelimumab
Tremelimumab in combination with durvalumab is indicated for the first line treatment of adults with advanced or unresectable hepatocellular carcinoma (HCC).
For this indication, competent medicine agencies globally authorize below treatments:
For:
Regimen A: In case that patient weight is ≥ 40 kg, intravenous, 300 milligrams tremelimumab, one dose.
Regimen B: In case that patient weight is ≤ 40 kg, intravenous, 4 milligrams tremelimumab per kilogram of body weight, one dose.
The recommended dose of tremelimumab is presented in Table 1.
Table 1. Recommended dose of tremelimumab:
| Indication | Recommended tremelimumab dosage | Duration of Therapy |
|---|---|---|
| Advanced or unresectable HCC | Tremelimumab 300 mga as a single dose administered in combination with durvalumab 1500 mga at Cycle 1/Day 1, followed by durvalumab monotherapy every 4 weeks | Until disease progression or unacceptable toxicity |
a For tremelimumab, HCC patients with a body weight of 40 kg or less must receive weight-based dosing, equivalent to tremelimumab 4 mg/kg until weight is greater than 40 kg. For durvalumab, patients with a body weight of 30 kg or less must receive weight-based dosing, equivalent to durvalumab 20 mg/kg until weight is greater than 30 kg.
Dose escalation or reduction is not recommended during treatment with tremelimumab in combination with durvalumab. Treatment withholding or discontinuation may be required based on individual safety and tolerability.
Guidelines for management of immune-mediated adverse reactions are described in Table 2 (refer to section 4.4 for further management recommendations, monitoring, and evaluation information). Refer also to the SmPC for durvalumab.
Table 2. Treatment modifications for tremelimumab in combination with durvalumab:
| Adverse reactions | Severitya | Treatment modification |
|---|---|---|
| Immune-mediated pneumonitis/interstitial lung disease | Grade 2 | Withhold doseb |
| Grade 3 or 4 | Permanently discontinue | |
| Immune-mediated hepatitis | ALT or AST > 3 - ≤ 5 x ULN or total bilirubin > 1.5 - ≤ 3 x ULN | Withhold doseb |
| ALT or AST > 5 - ≤ 10 x ULN | Withhold durvalumab and permanently discontinue tremelimumab (where appropriate) | |
| Concurrent ALT or AST > 3 x ULN and total bilirubin > 2 x ULNc | Permanently discontinue | |
| ALT or AST > 10 x ULN or total bilirubin > 3 x ULN | ||
| Immune-mediated hepatitis in HCC (or secondary tumour involvement of the liver with abnormal baseline values)d | ALT or AST > 2.5 - ≤ 5 x BLV and ≤ 20 x ULN | Withhold doseb |
| ALT or AST > 5 – 7 x BLV and ≤ 20 x ULN or concurrent ALT or AST 2.5 – 5 x BLV and ≤ 20 x ULN and total bilirubin > 1.5 - < 2 x ULNc | Withhold durvalumab and permanently discontinue tremelimumab (where appropriate) | |
| ALT or AST > 7 x BLV or > 20 x ULN whichever occurs first or bilirubin > 3 x ULN | Permanently discontinue | |
| Immune-mediated colitis or diarrhoea | Grade 2 | Withhold doseb |
| Grade 3 or 4 | Permanently discontinue | |
| Intestinal perforation | ANY grade | Permanently discontinuee |
| Immune-mediated hyperthyroidism, thyroiditis | Grade 2-4 | Withhold dose until clinically stable |
| Immune-mediated hypothyroidism | Grade 2-4 | No changes |
| Immune-mediated adrenal insufficiency, hypophysitis/hypopituitarism | Grade 2-4 | Withhold dose until clinically stable |
| Immune-mediated Type 1 diabetes mellitus | Grade 2-4 | No changes |
| Immune-mediated nephritis | Grade 2 with serum creatinine > 1.5-3 x (ULN or baseline) | Withhold doseb |
| Grade 3 with serum creatinine > 3 x baseline or > 3-6 x ULN; Grade 4 with serum creatinine > 6 x ULN | Permanently discontinue | |
| Immune-mediated rash or dermatitis (including pemphigoid) | Grade 2 for > 1 week or Grade 3 | Withhold doseb |
| Grade 4 | Permanently discontinue | |
| Immune-mediated myocarditis | Grade 2-4 | Permanently discontinue |
| Immune-mediated myositis/polymyositis | Grade 2 or 3 | Withhold doseb,f |
| Grade 4 | Permanently discontinue | |
| Infusion-related reactions | Grade 1 or 2 | Interrupt or slow the rate of infusion |
| Grade 3 or 4 | Permanently discontinue | |
| Immune-mediated myasthenia gravis | Grade 2-4 | Permanently discontinue |
| Immune-mediated meningitis | Grade 2 | Withhold doseb |
| Grade 3 or 4 | Permanently discontinue | |
| Immune-mediated encephalitis | Grade 2-4 | Permanently discontinue |
| Immune-mediated Guillain- Barré syndrome | Grade 2-4 | Permanently discontinue |
| Other immune-mediated adverse reactionsg | Grade 2 or 3 | Withhold doseb |
| Grade 4 | Permanently discontinue | |
| Non-immune-mediated adverse reactions | Grade 2 and 3 | Withhold dose until ≤ Grade 1 or return to baseline |
| Grade 4 | Permanently discontinueh |
a Common Terminology Criteria for Adverse Events, version 4.03. ALT: alanine aminotransferase; AST: aspartate aminotransferase; ULN: upper limit of normal; BLV: baseline value.
b After withholding, tremelimumab and/or durvalumab can be resumed within 12 weeks if the adverse reactions improved to ≤ Grade 1 and the corticosteroid dose has been reduced to ≤10 mg prednisone or equivalent per day. Tremelimumab and durvalumab should be permanently discontinued for recurrent Grade 3 adverse reactions, as applicable.
c For patients with alternative cause follow the recommendations for AST or ALT increases without concurrent bilirubin elevations.
d If AST and ALT are less than or equal to ULN at baseline in patients with liver involvement, withhold or permanently discontinue durvalumab based on recommendations for hepatitis with no liver involvement.
e Permanently discontinue tremelimumab for Grade 3; however, treatment with durvalumab can be resumed once event has resolved
f Permanently discontinue tremelimumab and durvalumab if the adverse reaction does not resolve to ≤ Grade 1 within 30 days or if there are signs of respiratory insufficiency.
g Includes immune thrombocytopenia, pancreatitis, cystitis noninfective, immune-mediated arthritis, and uveitis.
h With the exception of Grade 4 laboratory abnormalities, about which the decision to discontinue treatment should be based on accompanying clinical signs/symptoms and clinical judgment.
Administer tremelimumab as a separate intravenous infusion prior to durvalumab on the same day.
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