What is Imfinzi (durvalumab) therapy?

What is Imfinzi (Durvalumab) Therapy?

Imfinzi (durvalumab) is a fully human IgG1 monoclonal antibody that blocks PD-L1 (programmed death-ligand 1), functioning as an immune checkpoint inhibitor to restore anti-cancer immune activity by preventing PD-L1 from binding to PD-1 on T cells. 1, 2

Mechanism of Action

• Durvalumab binds to PD-L1 expressed on tumor cells and antigen-presenting cells, blocking its interaction with PD-1 receptors on T cells 3, 4
• This blockade prevents the tumor from suppressing the immune system, allowing T cells to recognize and attack cancer cells 1, 5
• Unlike anti-PD-1 antibodies, durvalumab specifically targets the ligand (PD-L1) rather than the receptor 3

FDA-Approved Indications

Non-Small Cell Lung Cancer (NSCLC):

• Unresectable Stage III NSCLC: Durvalumab is standard of care as consolidation therapy after concurrent chemoradiotherapy (CCRT) in patients without disease progression, administered at 1,500 mg every 4 weeks for up to 12 months 1, 2, 3
• Resectable NSCLC: Used in combination with platinum-based chemotherapy before surgery and as monotherapy after surgery for tumors without EGFR or ALK mutations 2
• Extensive-Stage Small Cell Lung Cancer (ES-SCLC): Combined with etoposide and carboplatin/cisplatin as first-line treatment 2, 6

Hepatocellular Carcinoma (HCC):

• Unresectable HCC: Durvalumab combined with tremelimumab (anti-CTLA-4 antibody) received full FDA approval in 2022 for first-line treatment 1
• The HIMALAYA trial demonstrated superior overall survival (16.43 months vs 13.77 months with sorafenib; HR 0.78, P=0.0035) 1
• Durvalumab monotherapy (1,500 mg every 4 weeks) showed non-inferior survival to sorafenib (16.56 vs 13.77 months) 1

Urothelial Carcinoma:

• Approved for advanced disease 2, 4

Administration and Dosing

• Standard dose: 1,500 mg intravenously every 4 weeks 1
• Duration: Varies by indication—12 months for stage III NSCLC consolidation 1, until disease progression for advanced HCC 1
• Combination regimen with tremelimumab: Tremelimumab 300 mg as a single dose plus durvalumab 1,500 mg every 4 weeks 1

Safety Profile and Adverse Events

Common Adverse Events:

• Dermatologic: Pruritus (10.9-32.4%) and rash (6.9-32.4%), more frequent when combined with tremelimumab 1
• Fatigue, hypothyroidism, and pneumonitis 1
• Grade 3/4 treatment-related adverse events: 8.2% with durvalumab monotherapy, 17.5% with durvalumab plus tremelimumab 1

Immune-Related Adverse Events (irAEs):

• Can affect any organ system including lungs (pneumonitis), liver (hepatitis), intestines (colitis), endocrine glands, kidneys, and skin 2
• These problems can become severe or life-threatening and may occur during treatment or after discontinuation 2
• Require immediate medical attention and may necessitate corticosteroid treatment or permanent discontinuation 2

Infusion Reactions:

• Can range from mild (chills, rash, flushing) to severe (shortness of breath, hypotension, back/neck pain) 2

Pulmonary Toxicity:

• Slight increase in pneumonitis after radiotherapy in stage III NSCLC, though most cases are mild 5

Clinical Efficacy Data

Stage III NSCLC (PACIFIC Trial):

• Significant improvement in both progression-free and overall survival compared to placebo after CCRT 1, 3
• Established durvalumab as standard of care in this setting 1, 3

Hepatocellular Carcinoma:

• Objective response rate: 20.1% with durvalumab plus tremelimumab vs 5.1% with sorafenib 1
• Disease control rate: 60.1% with combination therapy 1
• Durvalumab monotherapy showed 17.0% objective response rate 1

ES-SCLC (CASPIAN Trial):

• Significantly longer overall survival when added to chemotherapy compared to chemotherapy alone 6
• Higher objective response rates with durvalumab combination 6

Important Clinical Considerations

Predictive Biomarkers:

• Higher PD-L1 expression may correlate with better response, though this relationship is imperfect 1, 4
• PD-L1 expression thresholds remain controversial and vary by assay 1, 4

Contraindications and Precautions:

• Patients with active autoimmune disease require careful evaluation 2
• History of allogeneic stem cell transplant carries risk of graft-versus-host disease 2
• Pregnancy and breastfeeding are contraindicated 2

Monitoring Requirements:

• Regular assessment for immune-related adverse events affecting multiple organ systems 2
• Liver function tests, thyroid function, and pulmonary symptoms should be monitored 2
• Immediate evaluation needed for new or worsening symptoms 2

Combination Strategies

• With tremelimumab (anti-CTLA-4): Approved combination for HCC with demonstrated survival benefit 1
• With chemotherapy: Standard approach in ES-SCLC and resectable NSCLC 2, 6
• After radiotherapy: Consolidation approach in stage III NSCLC 1, 3
• Combination therapies generally increase both efficacy and toxicity compared to monotherapy 5