Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: AstraZeneca AB, SE-151 85 Södertälje, Sweden
Pharmacotherapeutic group: Other monoclonal antibodies and antibody drug conjugates
ATC code: L01FX20
Cytotoxic T lymphocyte-associated antigen (CTLA-4) is primarily expressed on the surface of T lymphocytes. Interaction of CTLA-4 with its ligands, CD80 and CD86, limits effector T-cell activation, through a number of potential mechanisms, but primarily by limiting co-stimulatory signalling through CD28.
Tremelimumab is a selective, fully human IgG2 antibody that blocks CTLA-4 interaction with CD80 and CD86, thus enhancing T-cell activation and proliferation, resulting in increased T-cell diversity and enhanced antitumour activity.
The combination of tremelimumab, a CTLA-4 inhibitor and durvalumab, a PD-L1 inhibitor results in improved anti-tumour responses in metastatic non-small cell lung cancer In murine syngeneic tumour models, dual blockade of PD-L1 and CTLA-4 resulted in enhanced anti-tumour activity.
The efficacy of IMJUDO 300 mg as a single dose in combination with durvalumab was evaluated in the HIMALAYA Study, a randomised, open-label, multicentre study in patients with confirmed uHCC who did not receive prior systemic treatment for HCC. The study included patients with Barcelona Clinic Liver Cancer (BCLC) Stage C or B (not eligible for locoregional therapy) and Child-Pugh Score Class A.
The study excluded patients with brain metastases or a history of brain metastases, co-infection of viral hepatitis B and hepatitis C; active or prior documented gastro-intestinal (GI) bleeding within 12 months; ascites requiring non-pharmacologic intervention within 6 months; hepatic encephalopathy within 12 months before the start of treatment; active or prior documented autoimmune or inflammatory disorders.
Patients with esophageal varices were included except those with active or prior documented GI bleeding within 12 months prior to study entry.
Randomisation was stratified by macrovascular invasion (MVI) (yes vs. no), aetiology of liver disease (confirmed hepatitis B virus vs. confirmed hepatitis C virus vs. others) and ECOG performance status (0 vs. 1). The HIMALAYA study randomized 1171 patients 1:1:1 to receive:
Tumour assessments were conducted every 8 weeks for the first 12 months and then every 12 weeks thereafter. Survival assessments were conducted every month for the first 3 months following treatment discontinuation and then every 2 months.
The primary endpoint was Overall Survival (OS). Secondary endpoints included Progression-Free Survival (PFS), Investigator-assessed Objective Response Rate (ORR) and Duration of Response (DoR) according to RECIST v1.1.
The demographics and baseline disease characteristics were well balanced between study arms. The baseline demographics of the overall study population were as follows: male (83.7%), age <65 years (50.4%) White (44.6%), Asian (50.7%), Black or African American (1.7%), Other race (2.3%), ECOG PS 0 (62.6%); Child-Pugh Class score A (99.5%), macrovascular invasion (25.2%), extrahepatic spread (53.4%), baseline AFP <400 ng/ml (63.7%), baseline AFP ≥400 ng/ml (34.5%), viral aetiology; hepatitis B (30.6%), hepatitis C (27.2%), uninfected (42.2%), evaluable PD-L1 data (86.3%), PD-L1 Tumour area positivity (TAP) ≥1% (38.9%), PD-L1 TAP <1% (48.3%) [Ventana PD-L1 (SP263) assay].
Results are presented in Table 4 and Figure 1.
Table 4. Efficacy Results for the HIMALAYA Study for IMJUDO 300 mg with durvalumab vs. S:
| IMJUDO 300 mg + durvalumab (n=393) | S (n=389) | |
|---|---|---|
| Follow-up duration | ||
| Median follow-up (months)a | 33.2 | 32.2 |
| OS | ||
| Number of deaths (%) | 262 (66.7) | 293 (75.3) |
| Median OS (months) (95% CI) | 16.4 (14.2, 19.6) | 13.8 (12.3, 16.1) |
| HR (95% CI) | 0.78 (0.66, 0.92) | |
| p-valueb | 0.0035 | |
| PFS | ||
| Number of events (%) | 335 (85.2) | 327 (84.1) |
| Median PFS (months) (95% CI) | 3.78 (3.68, 5.32) | 4.07 (3.75, 5.49) |
| HR (95% CI) | 0.90 (0.77, 1.05) | |
| ORR | ||
| ORR n (%)c | 79 (20.1) | 20 (5.1) |
| Complete Response n (%) | 12 (3.1) | 0 |
| Partial Response n (%) | 67 (17.0) | 20 (5.1) |
| DoR | ||
| Median DoR (months) | 22.3 | 18.4 |
a Calculated using reverse the Kaplan-Meier technique (with censor indicator reversed).
b Based on a Lan-DeMets alpha spending function with O’Brien Fleming type boundary and the actual number of events observed, the boundary for declaring statistical significance for IMJUDO 300 mg + durvalumab vs. S was 0.0398 (Lan and DeMets 1983).
c Confirmed complete response.
NR=Not Reached, CI=Confidence Interval
Figure 1. Kaplan-Meier curve of OS:
The European Medicines Agency has deferred the obligation to submit the results of studies with tremelimumab in all subsets of the paediatric population in the treatment of malignant neoplasms (except central nervous system tumours, haematopoietic and lymphoid tissue neoplasms). See section 4.2 for information on paediatric use.
The pharmacokinetics (PK) of tremelimumab was assessed for tremelimumab as monotherapy and in combination with durvalumab.
The PK of tremelimumab was studied in patients with doses ranging from 75 mg to 750 mg or 10 mg/kg administered intravenously once every 4 or 12 weeks as monotherapy, or at a single dose of 300 mg. PK exposure increased dose proportionally (linear PK) at doses ≥75 mg. Steady state was achieved at approximately 12 weeks. Based on population PK analysis that included patients who received tremelimumab monotherapy or in combination with other medicinal products in the dose range of ≥75 mg (or 1 mg/kg) every 3 or 4 weeks, the estimated tremelimumab clearance (CL) and volume of distribution (Vd) were 0.309 l/day and 6.33 l, respectively. The terminal half-life was approximately 14.2 days.
Age (18–87 years), body weight (34-149 kg), gender, positive anti-drug antibody (ADA) status, albumin levels, LDH levels, creatinine levels, tumour type, race or ECOG/WHO status had no clinically significant effect on the PK of tremelimumab.
Mild (creatinine clearance (CrCL) 60 to 89 ml/min) and moderate renal impairment (creatinine clearance (CrCL) 30 to 59 ml/min) had no clinically significant effect on the PK of tremelimumab. The effect of severe renal impairment (CrCL 15 to 29 ml/min) on the PK of tremelimumab is unknown.
Mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin >1.0 to 1.5 × ULN and any AST) and moderate hepatic impairment (bilirubin >1.5 to 3 x ULN and any AST) had no clinically significant effect on the PK of tremelimumab. The effect of severe hepatic impairment (bilirubin >3.0 x ULN and any AST) on the PK of tremelimumab is unknown; however, as IgG monoclonal antibodies are not primarily cleared via hepatic pathways, a change in hepatic function is not expected to influence tremelimumab exposure.
In the chronic 6-month study in cynomolgus monkeys, treatment with tremelimumab was associated with dose-related incidence in persistent diarrhoea and skin rash, scabs and open sores, which were dose-limiting. These clinical signs were also associated with decreased appetite and body weight and swollen peripheral lymph nodes. Histopathological findings correlating with the observed clinical signs included reversible chronic inflammation in the cecum and colon, mononuclear cell infiltration in the skin and hyperplasia in lymphoid tissues.
A dose-dependent increase in the incidence and severity of mononuclear cell infiltration with or without mononuclear cell inflammation was observed in the salivary gland, pancreas (acinar), thyroid, parathyroid, adrenal, heart, esophagus, tongue, periportal liver area, skeletal muscle, prostate, uterus, pituitary, eye (conjunctiva, extra ocular muscles), and choroid plexus of the brain. No NOAEL was found in this study with animals treated with the lowest dose of 5 mg/kg/week, however the intermediate dose of 15 mg/kg week was considered the highest non-severely toxic dose (HNSTD). This dose provided an exposure-based safety margin of 1.77 to clinical relevant exposure.
The carcinogenic and genotoxic potential of tremelimumab has not been evaluated.
Animal fertility studies have not been conducted with tremelimumab. Mononuclear cell infiltration in prostate and uterus was observed in repeat dose toxicity studies. Since animal fertility studies have not been conducted with tremelimumab, the clinical relevance of these findings for fertility is unknown. In reproduction studies, administration of tremelimumab to pregnant cynomolgus monkeys during the period of organogenesis was not associated with maternal toxicity or effects pregnancy losses, foetal weights, or external, visceral, skeletal abnormalities or weights of selected foetal organs.
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