Immunotherapy for Mesothelioma
Immunotherapy has fundamentally changed the treatment landscape for malignant pleural mesothelioma (MPM). On October 2, 2020, the FDA approved the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) as the first-line treatment for adults with unresectable MPM — the first new systemic therapy approved for mesothelioma in approximately 16 years, since pemetrexed plus cisplatin gained approval in 2004.[1][2]
The approval was based on the CheckMate 743 trial, which demonstrated that the nivolumab-ipilimumab combination significantly improved overall survival compared to standard chemotherapy, with a median overall survival of 18.1 months versus 14.1 months. The benefit was particularly striking in patients with non-epithelioid (sarcomatoid and biphasic) histology, where immunotherapy more than doubled survival compared to chemotherapy.[3][4]
Nivolumab is a PD-1 checkpoint inhibitor and ipilimumab is a CTLA-4 checkpoint inhibitor, both manufactured by Bristol-Myers Squibb. These drugs work by releasing the brakes on the immune system, allowing T cells to recognize and attack mesothelioma tumor cells.[5]
Immunotherapy for mesothelioma at a glance:
- First new treatment in 16 years — nivolumab plus ipilimumab received FDA approval on October 2, 2020 for unresectable malignant pleural mesothelioma[1]
- Median overall survival of 18.1 months — versus 14.1 months for chemotherapy in the CheckMate 743 trial (HR 0.74, 26% reduction in death risk)[3]
- Non-epithelioid survival more than doubled — median OS 18.1 months vs. 8.8 months (HR 0.46) for sarcomatoid and biphasic subtypes[4]
- 3-year overall survival rate of 23% — compared to 15% for chemotherapy, with 14% progression-free survival vs. 1%[6]
- Dual checkpoint inhibitor mechanism — nivolumab blocks PD-1 and ipilimumab blocks CTLA-4, together releasing immune brakes on T cells[5]
- Grade 3-4 adverse events in 30% of patients — immune-mediated side effects (colitis, hepatitis, pneumonitis) differ from chemotherapy toxicities[6]
- DREAM3R phase 3 trial ongoing — testing durvalumab plus chemotherapy in 480 patients after promising phase 2 results showed median OS of 20.4 months[7]
- 5 CAR-T cell therapy trials actively recruiting — representing an emerging frontier in cellular immunotherapy for mesothelioma[8]
- Perioperative immunotherapy shows promise — neoadjuvant nivolumab plus ipilimumab before surgery achieved median OS of 28.6 months in a 2025 phase 2 trial[9]
- BMS patient assistance available — eligible commercially insured patients may pay as little as $0 per infusion through BMS Access Support co-pay programs[10]
Key Facts
| Key Facts: Immunotherapy for Mesothelioma |
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What Is the FDA-Approved Immunotherapy for Mesothelioma?
The FDA-approved immunotherapy regimen for unresectable malignant pleural mesothelioma consists of two immune checkpoint inhibitors given in combination:[1]
Nivolumab (Opdivo): A PD-1 checkpoint inhibitor administered at 3 mg/kg intravenously every 2 weeks. PD-1 is a protein on T cells that normally acts as an "off switch" — when tumor cells express PD-L1 (the ligand for PD-1), they can deactivate attacking T cells. Nivolumab blocks this interaction, allowing T cells to remain active against tumor cells.[3]
Ipilimumab (Yervoy): A CTLA-4 checkpoint inhibitor administered at 1 mg/kg intravenously every 6 weeks. CTLA-4 is another immune checkpoint that normally dampens T cell activation early in the immune response. By blocking CTLA-4, ipilimumab enhances and broadens the T cell response against the tumor.[3]
Treatment continues for up to 24 months or until disease progression or unacceptable toxicity. Prior to this approval, the only FDA-approved first-line systemic therapy was the chemotherapy combination of pemetrexed plus cisplatin, approved in 2004.[2]
What Did the CheckMate 743 Trial Show?
CheckMate 743 (NCT02899299) was the open-label, multicenter, randomized phase 3 trial that led to FDA approval. It was the first immunotherapy trial to demonstrate improved overall survival in first-line mesothelioma treatment.[3][11]
Trial Design
A total of 605 patients were randomized: 303 to nivolumab plus ipilimumab and 302 to standard chemotherapy (pemetrexed plus cisplatin or carboplatin). The study was powered at 90% to detect a hazard ratio of 0.72 with a 5% type-I error. The primary endpoint was overall survival. Lead investigator was Paul Baas of The Netherlands Cancer Institute.[3][12]
Primary Results
| Outcome | Nivolumab + Ipilimumab | Chemotherapy |
|---|---|---|
| Median Overall Survival | 18.1 months (95% CI: 16.8–21.4) | 14.1 months (95% CI: 12.4–16.2) |
| Hazard Ratio | 0.74 (96.6% CI: 0.60–0.91) — 26% reduction in death risk | |
| 2-Year OS Rate | 41% | 27% |
| 3-Year OS Rate | 23% | 15% |
| 3-Year PFS Rate | 14% | 1% |
| Objective Response Rate | 40% | 43% |
At three years, 28% of responders in the immunotherapy arm had an ongoing response, versus 0% in the chemotherapy arm. Patients who discontinued immunotherapy due to adverse events still had a favorable median OS of 25.4 months, and 34% of responders maintained their responses for three or more years after discontinuation.[6][13]
Histology-Specific Results
The most clinically significant finding was the dramatically different benefit by histological subtype:[4][3]
|
Epithelioid subtype: Median OS 18.7 months vs. 16.5 months (modest improvement) Non-epithelioid subtype: Median OS 18.1 months vs. 8.8 months (HR 0.46; 95% CI: 0.31–0.68) — more than doubled survival |
This finding is particularly important because non-epithelioid mesothelioma (sarcomatoid and biphasic subtypes) has historically been poorly responsive to chemotherapy. Immunotherapy demonstrated its greatest relative benefit in this difficult-to-treat population, making it the clear treatment of choice for non-epithelioid disease.[4]
Safety Profile
The safety profile was consistent with known profiles of nivolumab and ipilimumab in other tumor types. Grade 3-4 treatment-related adverse events occurred in approximately 30% of immunotherapy patients versus 32% of chemotherapy patients, though the types differed — immune-mediated events (colitis, hepatitis, pneumonitis) in the immunotherapy arm versus hematological toxicity (neutropenia, anemia) in the chemotherapy arm. Treatment discontinuation due to adverse events was 20% for immunotherapy versus 8% for chemotherapy.[6][13]
A key biomarker finding from the 3-year update: a high score of a 4-gene inflammatory expression signature appeared to correlate with improved survival benefit from immunotherapy, potentially offering a patient selection tool for future clinical practice.[6]
What Other Immunotherapy Trials Have Been Conducted?
CONFIRM Trial (Phase 3, Second-Line)
The CONFIRM trial was a randomized phase 3 study comparing nivolumab versus placebo in patients with relapsed mesothelioma (both pleural and peritoneal) who had received at least one prior line of platinum-based chemotherapy. It was the first randomized trial to demonstrate improved overall survival in relapsed mesothelioma. Both co-primary endpoints (OS and PFS) were met. Notably, PD-L1 was not found to be predictive or prognostic in CONFIRM, suggesting that PD-L1 testing should not be used to select patients for second-line nivolumab.[14][15]
PROMISE-meso Trial (Phase 3, Second-Line)
The PROMISE-meso trial compared pembrolizumab (200 mg fixed dose every 3 weeks) versus single-agent chemotherapy (gemcitabine or vinorelbine) in 144 patients with relapsed MPM. This trial was negative — pembrolizumab did not improve progression-free survival or overall survival compared to chemotherapy in an unselected patient population. The result highlighted that single-agent PD-1 blockade is insufficient as monotherapy in second-line unselected mesothelioma and reinforced the importance of combination approaches or biomarker-driven selection.[16]
DREAM and PrE0505 Trials (Phase 2, First-Line)
The DREAM trial (Australia) and PrE0505 trial (United States) were single-arm phase 2 trials that tested durvalumab (anti-PD-L1) combined with standard chemotherapy (cisplatin plus pemetrexed) as first-line treatment. Both showed promising results — DREAM reported median OS of 18.4 months with a 48% objective response rate, while PrE0505 reported median OS of approximately 20.4 months with a 56.4% partial response rate. These results provided the rationale for DREAM3R, a phase 3 trial of 480 patients comparing durvalumab plus chemotherapy versus chemotherapy alone.[17][18][7]
BEAT-meso Trial (Phase 3)
The BEAT-meso trial was an international randomized phase 3 trial comparing atezolizumab (anti-PD-L1) plus bevacizumab plus chemotherapy versus bevacizumab plus chemotherapy alone in 400 patients. The primary endpoint was not met — median OS was 20.5 months versus 18.1 months (HR 0.84, p=0.14, not significant). However, the addition of atezolizumab did significantly improve progression-free survival (9.2 vs. 7.6 months; HR 0.72, p=0.0021).[19]
What Role Do BAP1, TMB, and Other Biomarkers Play?
BAP1 Mutations
BAP1 (BRCA1-associated protein 1) is the most commonly mutated gene in mesothelioma, found in approximately 45.6% of cases. Other common mutations include CDKN2A (21.7%), TP53 (17.1%), and NF2 (14.3%).[20]
BAP1 deficiency has been found to enrich immune pathways in the tumor microenvironment, increasing interferon-alpha and interferon-gamma signatures, activating dendritic cells, and increasing checkpoint receptor expression. BAP1-deficient mesothelioma tumors may therefore be more responsive to immunotherapy, though this relationship requires further prospective validation.[21]
Tumor Mutational Burden
Mesothelioma has a low tumor mutational burden (TMB) compared to other cancers that respond well to immunotherapy, such as melanoma or non-small cell lung cancer. Despite this low TMB, the CheckMate 743 results demonstrate that combination immunotherapy can still be effective. In the NIBIT-MESO-1 trial, patients with TMB higher than the median of 8.3 mutations per megabase had significantly longer survival (41.3 months vs. 17.4 months; p=0.02), suggesting TMB may help identify patients most likely to benefit.[22]
What Immunotherapy Trials Are Currently Recruiting?
As of January 2026, there are 93 mesothelioma clinical trials actively recruiting patients, of which 32 (34%) are immunotherapy trials and 52 are based in the United States.[8]
Key actively recruiting immunotherapy trials include:
| Trial | NCT Number | Phase | Intervention |
|---|---|---|---|
| Neoadjuvant Durvalumab + Tremelimumab | NCT05932199 | Phase Ib/IIa | Durvalumab + tremelimumab +/- chemo (Baylor) |
| Immunotherapy Before Surgery for Sarcomatoid Meso | NCT05647265 | Phase 2 | Neoadjuvant immunotherapy + surgery |
| Partial Pleurectomy for Unresectable MPM | NCT07126509 | — | Surgery +/- immunotherapy |
| Pembrolizumab + Chemo + Image-Guided Surgery | — | Phase 2 | Pembrolizumab + chemo + surgery |
Additionally, 5 CAR-T cell therapy trials are actively recruiting mesothelioma patients, representing an emerging frontier in cellular immunotherapy for this disease.[8][23]
Perioperative Immunotherapy (2025 Update)
A phase 2 trial published in Nature Medicine (2025) evaluated neoadjuvant immunotherapy before surgery for resectable mesothelioma. Patients receiving nivolumab plus ipilimumab before surgery had a median PFS of 19.8 months and median OS of 28.6 months — substantially better than nivolumab alone (median PFS 9.6 months, median OS 19.3 months). Extended pleurectomy/decortication was performed in 81.8% of patients. These results suggest that perioperative immunotherapy may significantly improve outcomes in surgically resectable disease.[9]
What Does Immunotherapy Cost and How Do Patients Access It?
Cost-Effectiveness
A Markov model analysis from a US payer perspective found that the total cost of nivolumab plus ipilimumab treatment was approximately $292,319 compared to $95,715 for chemotherapy — an incremental cost of $196,604 for 0.53 additional quality-adjusted life years (QALYs). At a willingness-to-pay threshold of $207,659 per QALY, the combination was not considered cost-effective unless drug prices were reduced by approximately 34%.[24]
Patient Assistance Programs
BMS Access Support offers benefit investigation, prior authorization assistance, appeal process support, and co-pay assistance programs for eligible commercially insured patients who may pay as little as $0 per infusion, subject to an annual maximum benefit.[10][25]
| "For mesothelioma patients, understanding all available treatment options — including immunotherapy clinical trials — is essential. These advances represent real hope for improved survival, particularly for those with non-epithelioid disease where chemotherapy alone offered limited benefit." |
| — David Foster, Patient Advocate, Danziger & De Llano |
Related Resources
- Mesothelioma Types and Histology
- Pleurectomy and Decortication (P/D)
- Mesothelioma Diagnosis and Staging
- Asbestos Health Effects
- Mesothelioma Settlements
|
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References
- ↑ 1.0 1.1 1.2 FDA Approves Nivolumab and Ipilimumab for Unresectable Malignant Pleural Mesothelioma, U.S. Food and Drug Administration (2020)
- ↑ 2.0 2.1 Tsunami of Immunotherapy Reaches Mesothelioma, World Journal of Clinical Oncology (2022)
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 First-Line Nivolumab Plus Ipilimumab in Unresectable Malignant Pleural Mesothelioma (CheckMate 743), Baas P et al., Lancet 2021;397:375-386
- ↑ 4.0 4.1 4.2 4.3 Full CheckMate 743 Dataset Supporting Nivolumab/Ipilimumab, Cancer Therapy Advisor
- ↑ 5.0 5.1 Nivolumab/Ipilimumab Improves OS in Unresectable Malignant Pleural Mesothelioma, Targeted Oncology
- ↑ 6.0 6.1 6.2 6.3 6.4 First-Line Nivolumab Plus Ipilimumab Versus Chemotherapy: 3-Year Outcomes from CheckMate 743, Baas P et al., Ann Oncol 2022;33(5):488-499
- ↑ 7.0 7.1 Protocol of DREAM3R: Durvalumab with Chemotherapy as First-Line Treatment in Advanced Pleural Mesothelioma, BMJ Open
- ↑ 8.0 8.1 8.2 93 Clinical Trials Are Recruiting People with Mesothelioma (2026), Mesowatch
- ↑ 9.0 9.1 Perioperative Nivolumab or Nivolumab Plus Ipilimumab in Resectable Mesothelioma, Nature Medicine (2025)
- ↑ 10.0 10.1 Patient Programs — OPDIVO (nivolumab), Bristol-Myers Squibb
- ↑ CheckMate 743: Nivolumab Plus Ipilimumab vs. Chemotherapy in Mesothelioma, ClinicalTrials.gov
- ↑ Nivolumab Plus Ipilimumab Improves OS in Malignant Pleural Mesothelioma, Cancer Network
- ↑ 13.0 13.1 Updated Efficacy and Safety Data from CheckMate 743, The ASCO Post (2022)
- ↑ Nivolumab Versus Placebo in Patients with Relapsed Malignant Mesothelioma (CONFIRM), PMC/National Library of Medicine
- ↑ An Update on Emerging Therapeutic Options for Malignant Pleural Mesothelioma, Lung Cancer: Targets and Therapy, Dove Medical Press
- ↑ Immunotherapy Fails to Improve PFS and OS in Relapsed Mesothelioma (PROMISE-meso), ESMO Daily Reporter (2019)
- ↑ DREAM Trial: Durvalumab with First-Line Chemotherapy in Mesothelioma, Lancet Oncology / Elsevier
- ↑ Durvalumab Added to Standard Chemotherapy Improved OS in MPM (PrE0505), The ASCO Post (2020)
- ↑ BEAT-meso: Bevacizumab and Atezolizumab Plus Chemotherapy for Mesothelioma Phase III Results, Journal of Clinical Oncology / ASCO
- ↑ Association of Somatic Mutations and Histologic Subtype/Grade on Prognosis and PD-L1 Expression in Mesothelioma, JCO / ASCO (2023)
- ↑ BAP1 Deficiency Inflames the Tumor Immune Microenvironment, PMC/National Library of Medicine
- ↑ Tremelimumab Plus Durvalumab Retreatment and 4-Year Outcomes in Mesothelioma (NIBIT-MESO-1), PMC/National Library of Medicine
- ↑ Mesothelioma Clinical Trials: Active Recruiting Trials 2026, Mesothelioma Hope
- ↑ Cost-Effectiveness of Nivolumab Plus Ipilimumab as First-Line Treatment for Unresectable MPM, PMC/National Library of Medicine
- ↑ OPDIVO Pricing Information, Bristol-Myers Squibb
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