Durvalumab (Imfinzi) for Mesothelioma

Durvalumab, marketed as Imfinzi, is a PD-L1 immune checkpoint inhibitor manufactured by AstraZeneca that has been studied extensively in malignant pleural mesothelioma clinical trials. Like atezolizumab, durvalumab works by blocking the PD-L1 protein on tumor cells, preventing them from suppressing the anti-tumor immune response. While not yet FDA-approved for mesothelioma, durvalumab has shown meaningful clinical activity in several mesothelioma trials, both as a single agent and in combination with the CTLA-4 inhibitor tremelimumab.¹

The most significant mesothelioma trial for durvalumab is the PrE0505 study, a single-arm phase II trial that combined durvalumab with standard first-line pemetrexed and cisplatin chemotherapy for up to 6 cycles, followed by durvalumab maintenance. This trial demonstrated a median overall survival of 20.4 months — substantially exceeding the historical benchmark of 12 months with chemotherapy alone — suggesting that adding immunotherapy to standard chemotherapy may significantly improve outcomes.²

Durvalumab has also been studied in combination with tremelimumab, a CTLA-4 inhibitor, as a dual checkpoint blockade strategy. The rationale for combining PD-L1 and CTLA-4 inhibitors mirrors the established approach of nivolumab plus ipilimumab, which received FDA approval for mesothelioma based on the CheckMate 743 trial. The DETERMINE trial evaluated tremelimumab alone and in combination with durvalumab for previously treated mesothelioma.³

The ongoing investigation of durvalumab in mesothelioma represents part of a broader effort to expand immunotherapy options beyond the nivolumab/ipilimumab combination. Different PD-L1 and PD-1 inhibitors may have subtly different activity profiles in mesothelioma, and identifying the optimal immunotherapy strategy — including the best combination partners, sequencing with chemotherapy, and patient selection criteria — remains an active area of clinical research.⁴

Durvalumab has been studied in multiple treatment strategies for mesothelioma:²

First-Line: Durvalumab + Chemotherapy (PrE0505)

The PrE0505 trial combined durvalumab with standard first-line chemotherapy:²

• Induction phase — Durvalumab 1120 mg + pemetrexed 500 mg/m² + cisplatin 75 mg/m² every 3 weeks for up to 6 cycles
• Maintenance phase — Durvalumab 1120 mg every 3 weeks continued until progression
• Median overall survival — 20.4 months, exceeding the pre-specified target of 11 months
• Median progression-free survival — 6.7 months
• 1-year overall survival rate — 70%

Dual Checkpoint Blockade: Durvalumab + Tremelimumab

The combination targets two different immune checkpoints simultaneously:³

• Durvalumab — Blocks PD-L1 on tumor cells, preventing T-cell suppression
• Tremelimumab — Blocks CTLA-4 on T cells, enhancing T-cell activation and proliferation
• DETERMINE trial — Evaluated tremelimumab ± durvalumab in previously treated mesothelioma patients
• Rationale — Dual blockade may overcome resistance mechanisms that limit single-agent immunotherapy

Single-Agent Durvalumab

Durvalumab monotherapy has been evaluated in several early-phase trials for previously treated mesothelioma, demonstrating disease control rates of 47–57% and durable responses in a subset of PD-L1-positive patients.¹

Durvalumab shows encouraging activity in mesothelioma, particularly when combined with chemotherapy:²

• With chemotherapy (PrE0505) — Median OS of 20.4 months with 70% alive at one year, substantially exceeding historical chemotherapy-alone benchmarks
• Single-agent second-line — Disease control rates of 47–57%, with durable responses lasting more than 12 months in selected patients
• Predictive biomarkers — PD-L1 expression and tumor mutational burden are being studied as potential predictors of response, though no validated biomarker has been established for patient selection
• Comparison with nivolumab/ipilimumab — Cross-trial comparisons are unreliable, but the PrE0505 median survival of 20.4 months is noteworthy in the context of the CheckMate 743 result of 18.1 months for nivolumab/ipilimumab

Durvalumab's side effect profile is characteristic of PD-L1 checkpoint inhibitors, driven by immune system activation:¹

• Fatigue — Reported in 30–40% of patients; usually mild to moderate and manageable with rest and activity modification
• Pneumonitis — Immune-related lung inflammation occurs in 3–7% of patients. Particularly important for mesothelioma patients who may already have compromised lung function. Any new or worsening shortness of breath should be reported immediately
• Thyroid dysfunction — Hypothyroidism (10–15%) or hyperthyroidism (5–8%) can develop at any point during treatment. Regular thyroid function tests are required, and thyroid hormone replacement may be needed long-term
• Hepatitis — Immune-mediated liver inflammation occurs in 5–10% of patients. Liver function tests are checked before each infusion cycle
• Rash — Skin reactions affect 15–25% of patients, ranging from mild rash to severe dermatitis. Topical corticosteroids manage most cases
• Combination toxicity — When durvalumab is combined with chemotherapy, patients experience both immune-related side effects and traditional chemotherapy toxicities (nausea, myelosuppression, fatigue), requiring comprehensive supportive care