Mesothelioma can be a difficult cancer to manage, but researchers are looking for new ways to identify and treat this cancer at the molecular level through targeted therapies.
A recent study reviewed the results of several clinical trials testing different targeted therapies for mesothelioma. These treatments focus on genetic mutations and pathways in the body that are involved in the growth and spread of mesothelioma.
The study found that mesothelioma targeted therapies help:
- Stop tumors from growing
- Shrink existing tumors
- Prevent cancer from spreading
- Extend life expectancy
These targeted approaches, which include checkpoint inhibitors and antibody-based treatments, show significant potential in enhancing patient outcomes.
Learn more about the 7 different types of mesothelioma targeted therapies and how they work.
1. Mesothelin Targeted Therapies
Mesothelin is a protein found on the surface of some cells. It’s important in diagnosing mesothelioma because cancer cells usually contain high amounts of mesothelin. Doctors consider mesothelin an indicator (biomarker) of mesothelioma.
Mesothelioma clinical trials show that mesothelin plays a role in the growth of new tumors, leading scientists to target the biomarker as a way of disrupting cancer progression.
Several trials of mesothelin targeted therapies were examined in this study, including:
- Amatuximab. This antibody binds to mesothelin. When combined with the chemotherapy drugs cisplatin and pemetrexed, tumors decreased in 40% of mesothelioma patients, with a 51% stable disease rate (meaning more than half of patients had their cancer stop spreading).
- CAR T-Cell Therapies. Researchers have tested injecting mesothelin-targeted CAR T-cells into the chest cavity after pembrolizumab (Keytruda®). The median overall survival was 23.9 months, with 8 of 18 patients experiencing disease stability for at least 6 months and 2 having all their cancer cells disappear.
- T Cell Receptor Fusion Constructs (TRuC). TRuC fuses to the T-cell receptor, activating T cells to attack tumor cells. TRuC has been effective in cancers with high mesothelin expression.
- Gavocabtagene Autoleucel (Gavo-cel). Gavo-cel is a TRuC infused with a human anti-mesothelin antibody. A recent clinical trial found that patients treated with Gavo-cel had a median progression-free survival of 5.6 months and a median overall survival of 11.2 months. Gavo-cel is being evaluated alone and in combination with immune checkpoint inhibitors.
Mesothelin isn’t usually found in healthy cells and isn’t needed for normal cell functions. This means treatments that target mesothelin can be more effective with fewer side effects on healthy cells.
Our team can connect you with top mesothelioma specialists in your area for the best treatment. Use our Free Doctor Match to get started.
2. BAP1 Mutations
BRCA1-associated protein 1 (BAP1) plays an important role in many cell processes and helps prevent tumors. It’s the most commonly mutated gene in cancer.
Scientists are now studying enzymes that are overly active in mesothelioma patients with BAP1 mutations, like EZH2. By blocking the EZH2 protein, researchers were able to slow down the growth and spread of mesothelioma cells in lab tests.
Researchers are also looking at drugs like olaparib (Lynparza®), rucaparib (Rubraca®), and tazemetostat (Tazverik®) to treat BAP1-related cancers. For example, a 2022 study published in The Lancet Oncology journal found that 50% of pleural mesothelioma patients treated with Tazverik saw their cancer temporarily stabilize at 12 weeks.
3. NF2 Mutations
The mutation of the Neurofibromin 2 (NF2) gene creates a protein called merlin that helps control many cell processes. Researchers have been studying a new drug called VT3989 that helps treat mesothelioma patients with NF2 mutations.
A phase 1 study of VT3989 showed promising results:
- Out of 43 people, 14% (6 people) showed partial improvement
- 57% of patients had a positive response at 8 weeks, meaning their cancer either shrank, disappeared, or stopped growing for at least 6 months after treatment
- 3 patients had a response that lasted at least 21 months after treatment
- VT3989 was safe, well-tolerated, and didn’t have any serious side effects at any dose
Like BAP1 changes, NF2 mutations usually happen after a person is conceived. Around 35-40% of mesothelioma patients have the NF2 gene turned off.
4. CDKN2A Deletion
The CDKN2A gene is missing in 60-74% of pleural mesothelioma patients, making it the most common genetic change in this cancer. When CDKN2A is absent, enzymes called CDK4 and CDK6, which are linked to worse survival outcomes, are overproduced.
CDK4/6 inhibitors like abemaciclib (Verzenio®) and palbociclib (Ibrance®) have shown promise in early studies by reducing cell growth and causing aging in mesothelioma cells. In mouse studies, palbociclib reduced tumor size and improved survival better than chemotherapy.
The phase 2 MiST2 clinical trial tested abemaciclib in patients who had already received chemotherapy. The results were promising: 14 out of 26 patients had disease control at 12 weeks, with 11 of them having stable disease and 3 showing a partial response (meaning the tumors shrank somewhat).
5. MTAP Deletions
About 66% of pleural mesothelioma patients are missing the MTAP gene, which often happens alongside a missing CDKN2A gene. The MTAP gene is responsible for making an enzyme needed for methionine, a building block for proteins.
When MTAP is missing, a substance called MTA builds up and binds to another protein called PRMT5. Scientists have found PRMT5 inhibitors could be a promising new mesothelioma treatment for patients who are missing the MTAP gene.
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6. AXL Enzyme
The AXL enzyme is linked to poorer survival rates and is overactive in 75% of pleural mesothelioma patients. AXL helps cancer cells survive, grow, spread, and resist immunotherapy by blocking certain signals and natural T-cell activity.
In the MiST3 study, researchers tested a combination of Keytruda and an AXL inhibitor called bemcentinib in pleural mesothelioma patients who had already received treatment.
At 12 weeks:
- 46.2% of patients had stable disease
- 15.4% of patients saw their cancer shrink or disappear
At 24 weeks:
- 38.5% had disease control, with only 7.7% experiencing tumor growth or spread since week 12
Combining an AXL inhibitor with an immunotherapy drug has shown some success in other trials and may be a promising treatment approach.
Contact our team for help accessing immunotherapy and other new treatments for mesothelioma that could help you live longer with fewer symptoms.
7. ASS1 Enzyme
Argininosuccinate synthase 1 (ASS1) helps make arginine, an important amino acid for cell survival and growth.
Researchers found that mesothelioma cells without enough ASS1 die when they can’t get arginine from outside the cell. This discovery led to studies on using arginine depletion as a targeted mesothelioma treatment.
ADAM Trial
In a phase 2 study called ADAM, researchers tested a drug called pegargiminase (ADI-PEG20) on pleural mesothelioma patients who had not received any previous treatment. ADI-PEG20 helps starve mesothelioma cells of arginine, leading to cell death.
The ADAM trial results showed:
- A progression-free period of 3.2 months, compared to 2 months for those receiving the best supportive care
- 52% of patients had stable disease after 4 months, compared to 22% in the supportive care group
- ASS1 deficiency occurs in 48-63% of pleural mesothelioma cases, mostly in the sarcomatoid and biphasic cell types
ATOMIC-Meso Trial
In the combined phase 2/3 ATOMIC-Meso trial, researchers tested ADI-PEG20 combined with chemotherapy vs. chemotherapy alone on 249 patients with non-epithelioid pleural mesothelioma.
The ATOMIC-Meso study results showed:
- The combination group had a median survival of 9.3 months compared to 7.7 months for the chemotherapy-only group
- Median progression-free survival was 6.2 months for the combination group versus 5.6 months for the chemotherapy-only group
- A 13% overall response rate for both groups (percentage of patients who responded to therapy)
With advancements in targeted therapies, doctors hope to one day use predictive biomarkers like ASS1 to determine the most effective treatment strategies for each patient.
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