IMJUDO Concentrate for solution for infusion Ref.[50776] Active ingredients: Tremelimumab

Pharmacotherapeutic group: Other monoclonal antibodies and antibody drug conjugates
ATC code: L01FX20

Mechanism of action

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 anti-tumour 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 and hepatocellular carcinoma.

Clinical efficacy

HCC – HIMALAYA Study

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:

• Durvalumab 1500 mg every 4 weeks
• IMJUDO 300 mg as a single dose + durvalumab 1500 mg; followed by durvalumab 1500 mg every 4 weeks
• Sorafenib 400 mg twice daily

The primary endpoint was Overall Survival (OS) for the comparison of IMJUDO 300 mg as a single dose in combination with durvalumab vs. sorafenib. 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. Sorafenib:

^a Calculated using the reverse 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. Sorafenib was 0.0398 (Lan◦and◦DeMets 1983).
^c Confirmed complete response.
CI=Confidence Interval

Figure 1. Kaplan-Meier curve of OS:

NSCLC – POSEIDON study

POSEIDON was a study designed to evaluate the efficacy of durvalumab with or without IMJUDO in combination with platinum-based chemotherapy. POSEIDON was a randomised, open-label, multicentre study in 1013 metastatic NSCLC patients with no sensitising epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) genomic tumour aberrations. Patients with histologically or cytologically documented metastatic NSCLC were eligible for enrolment. Patients had no prior chemotherapy or any other systemic therapy for metastatic NSCLC. Prior to randomisation, patients had tumour PD-L1 status confirmed by using the Ventana PD-L1 (SP263) assay. Patients had a World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at enrolment.

The study excluded patients with active or prior documented autoimmune disease; active and/or untreated brain metastases; a history of immunodeficiency; administration of systemic immunosuppression within 14 days before the start of IMJUDO or durvalumab, except physiological dose of systemic corticosteroids; active tuberculosis or hepatitis B or C or HIV infection; or patients receiving live attenuated vaccine within 30 days before or after the start of IMJUDO and/or durvalumab (see section 4.4).

Randomisation was stratified by tumour cells (TC) PD-L1 expression (TC ≥50% vs. TC <50%), disease stage (Stage IVA vs. Stage IVB, per the 8th edition of American Joint Committee on Cancer), and histology (non-squamous vs. squamous).

Patients were randomised 1:1:1 to receive:

• Arm 1: IMJUDO 75 mg with durvalumab 1500 mg and platinum-based chemotherapy every 3 weeks for 4 cycles, followed by durvalumab 1500 mg every 4 weeks as monotherapy. A fifth dose of IMJUDO 75 mg was given at Week 16 alongside durvalumab dose 6.
• Arm 2: Durvalumab 1500 mg and platinum-based chemotherapy every 3 weeks for 4 cycles, followed by durvalumab 1500 mg every 4 weeks as monotherapy.
• Arm 3: Platinum-based chemotherapy every 3 weeks for 4 cycles. Patients could receive 2 additional cycles (a total of 6 cycles post-randomisation), as clinically indicated, at investigator’s discretion.

Patients received one of the following platinum-based chemotherapy regimens:

• Non-squamous NSCLC
  • Pemetrexed 500 mg/m² with carboplatin AUC 5-6 or cisplatin 75 mg/m² every 3 weeks. Unless contraindicated by the investigator, pemetrexed maintenance could be given.
• Squamous NSCLC
  • Gemcitabine 1000 or 1250 mg/m² on Days 1 and 8 with cisplatin 75 mg/m² or carboplatin AUC 5-6 on Day 1 every 3 weeks.
• Non-squamous or squamous NSCLC
  • Nab-paclitaxel 100 mg/m² on Days 1, 8, and 15 with carboplatin AUC 5-6 on Day 1 every 3 weeks.

IMJUDO was given up to a maximum of 5 doses unless there was disease progression or unacceptable toxicity. Durvalumab and histology-based pemetrexed maintenance therapy (when applicable) was continued until disease progression or unacceptable toxicity.

Tumour assessments were conducted at Week 6 and Week 12 from the date of randomisation, and then every 8 weeks until confirmed objective disease progression. Survival assessments were conducted every 2 months following treatment discontinuation.

The dual primary endpoints of the study were progression-free survival (PFS) and overall survival (OS) for durvalumab + platinum-based chemotherapy (Arm 2) vs. platinum-based chemotherapy alone (Arm 3). The key secondary endpoints of the study were PFS and OS for IMJUDO + durvalumab + platinum-based chemotherapy (Arm 1) and platinum-based chemotherapy alone (Arm 3). The secondary endpoints included objective response rate (ORR) and duration of response (DoR). PFS, ORR, and DoR were assessed using Blinded Independent Central Review (BICR) according to RECIST v1.1.

The demographics and baseline disease characteristics were well-balanced between study arms. Baseline demographics of the overall study population were as follows: male (76.0%), age ≥65 years (47.1%), age ≥75 years (11.3%) median age 64 years (range: 27 to 87 years), White (55.9%), Asian (34.6%), Black or African American (2.0%), other (7.6%), non-Hispanic or Latino (84.2%), current smoker or past-smoker (78.0%), WHO/ECOG PS 0 (33.4%) and WHO/ECOG PS 1 (66.5%). Disease characteristics were as follows: Stage IVA (50.0%), Stage IVB (49.6%), histological sub-groups of squamous (36.9%), non-squamous (62.9%), brain metastases (10.5%), PD-L1 expression TC ≥50% (28.8%) and PD-L1 expression TC <50% (71.1%).

The study showed a statistically significant improvement in OS with IMJUDO + durvalumab + platinum-based chemotherapy (Arm 1) vs. platinum-based chemotherapy alone (Arm 3). IMJUDO + durvalumab + platinum-based chemotherapy showed a statistically significant improvement in PFS vs. platinum-based chemotherapy alone. The results are summarised below.

Table 5. Efficacy results for the POSEIDON study:

^a Analysis of PFS at data cut off 24 July 2019 (median follow up 10.15 months). Analysis of OS at data cut off 12 March 2021 (median follow up 34.86 months). The boundaries for declaring efficacy (Arm 1 vs. Arm 3: PFS 0.00735, OS 0.00797; 2-sided) were determined by a Lan-DeMets alpha spending function that approximates an O’Brien Fleming approach. PFS was assessed by BICR according to RECIST v1.1.
^b HR are derived using a Cox pH model stratified by PD-L1, histology and disease stage.
^c 2-sided p-value based on a log-rank test stratified by PD-L1, histology and disease stage.
^d Confirmed Objective Response.
^e Post-hoc analysis.
NR=Not Reached, CI=Confidence Interval

Figure 2. Kaplan-Meier curve of OS:

Figure 3. Kaplan-Meier curve of PFS:

Figure 4 summarises efficacy results of OS by tumour PD-L1 expression in prespecified subgroup analyses.

Figure 4. Forest plot of OS by PD-L1 expression for IMJUDO + durvalumab + platinum-based chemotherapy vs. platinum-based chemotherapy:

Elderly population

A total of 75 patients aged ≥75 years were enrolled in the IMJUDO in combination with durvalumab and platinum-based chemotherapy (n=35) and platinum-based chemotherapy only (n=40) arms of the POSEIDON study. An exploratory HR of 1.05 (95% CI: 0.64, 1.71) for OS was observed for IMJUDO in combination with durvalumab and platinum-based chemotherapy vs. platinum-based chemotherapy within this study subgroup. Due to the exploratory nature of this subgroup analysis no definitive conclusions can be drawn, but caution is suggested when considering this regimen for elderly patients.

Paediatric population

The safety and efficacy of IMJUDO in combination with durvalumab in children and adolescents aged less than 18 years has not been established. Study D419EC00001 was a multi centre, open-label dose finding and dose expansion study to evaluate the safety, preliminary efficacy and pharmacokinetics of IMJUDO in combination with durvalumab followed by durvalumab monotherapy in paediatric patients with advanced malignant solid tumours (except primary central nervous system tumours) who had disease progression and for whom no standard of care treatment exists. The study enrolled 50 paediatric patients with an age range from 1 to 17 years with primary tumour categories: neuroblastoma, solid tumour and sarcoma. Patients received IMJUDO 1 mg/kg either in combination with durvalumab 20 mg/kg or durvalumab 30 mg/kg every 4 weeks for 4 cycles, followed by durvalumab as monotherapy every 4 weeks. In the dose finding phase, IMJUDO and durvalumab combination therapy was preceded by a single cycle of durvalumab; 8 patients in this phase however discontinued treatment prior to receiving IMJUDO. Thus, of the 50 patients enrolled in the study, 42 received IMJUDO in combination with durvalumab and 8 received durvalumab only. In the doseexpansion phase, an ORR of 5.0% (1/20 patients) was reported in the evaluable for response analysis set. No new safety signals were observed relative to the known safety profiles of IMJUDO and durvalumab in adults. See section 4.2 for information on paediatric use.