A new worldwide clinical trial for mesothelioma is now open for enrollment

• Maja Belamaric
• Featured News

The “handshake” between the tumor and T cell prevents a T cell immune attack against mesothelioma. Disrupting the “handshake” holds the key to an immune response against this cancer. This Phase 3 immunotherapy clinical trial for mesothelioma tests a drug made to do exactly that and is now available to patients in the United States and across the world.

A new phase 3 clinical trial testing the efficacy of dual checkpoint inhibitor immunotherapy in combination with chemotherapy is now available to patients in the United States as well as around the world. The official name for the study is MEDI5752 in Combination With Carboplatin Plus Pemetrexed in Unresectable Pleural Mesothelioma and the shortened name is eVOLVE-Meso.

This AstraZeneca study tests a single immunotherapy agent called volrustomig in combination with standard chemotherapy against either standard of care chemotherapy alone or immunotherapy alone.  The study builds on the recent FDA-approval of immunotherapy for mesothelioma which saw two agents, nivolumab (Opdivo) and ipilimumab (Yervoy), activate the immune system against cancer cells by binding to two receptors located on the T cell: the PD-1 and the CTLA-4. Single agent volrustomig targets the same two proteins, but the study also adds standard chemotherapy to its protocol.

How to inquire about enrollment?

The clinical trial is widely available at centers across the United States. A patient should contact their treating physician to discuss enrollment. Locations where the Evolve-Meso clinical trial is available are listed here: https://clinicaltrials.gov/study/NCT06097728#contacts-and-locations.

How does immunotherapy work to kill mesothelioma cells?

To understand how immunotherapy treatment works, we must first understand why the immune system tends to stay inactive against mesothelioma cells. Both the T cell and other cells, including tumors, express proteins. When certain proteins on the T cell bind to their counterparts on a healthy cell, this communicates to the T cell to not attack the healthy cell. This is an important preservation mechanism that prevents autoimmune reactions. So when the tumor’s proteins bind to the ones on the T cell, they tell the immune system not to attack which allows the cancer to proliferate. Immunotherapy medications act as a decoy binding protein that binds to either the T cell or the tumor cell, disrupting their ability to bind with one another.

In the top part of this image, the T cell and the tumor cell connect causing no immune response against the tumor. In the bottom part of the image, the immunotherapy drugs connect to the expressed proteins on either the T cell or tumor thus inhibiting the connection between the two which in turn creates an immune reaction against the tumor. This is the basis of checkpoint inhibitor immunotherapy.

Immunotherapy + Chemotherapy: what is the rationale?

A common and valid question about combining chemotherapy with immunotherapy is: are we just throwing the kitchen sink at mesothelioma to see what sticks?

The answer is no.

There are, in fact, scientific reasons that would suggest that combining these two methods would lead to better results than administering them one at a time. Reason number one can be found in the answer to the question “why does the immune system not recognize mesothelioma as a foreign entity worth attacking from the beginning?” The answer is that mesothelioma cells’ receptors mimic those on the surface of healthy cells and they use the brakes built into the immune system to their advantage. But when chemotherapy is used to kill the cancer, the by-product of those dead cancer cells is seen as a foreign body by the immune system. So, adding chemotherapy to an immunotherapy regimen is one way to maximize the anti-tumor activity of both agents.

Timeline of FDA-approvals for mesothelioma

2004: Chemotherapy (Alimta/cisplatin)

2022: Immunotherapy (nivolumab / ipilimumab)

2024: Immunotherapy + chemotherapy for advanced mesothelioma (pembrolizumab also known by the brand name Keytruda, which is an anti-PD-1 agent, plus standard chemotherapy)

What is the difference between volrustomig and other immunotherapy agents used against mesothelioma

The volrustomig study is different from the 2024 immunotherapy (Keytruda) plus chemotherapy combination approval because volrustomig singularly binds to both the PD-1 and CTLA-4 receptors. Immunotherapy drugs targeting only the PD-1 or PDL1 receptors have shown to not be as effective as those also targeting the CTLA-4 receptor.

These two proteins, also known as checkpoint inhibitors, are located on the T cell. There, they play a crucial role in signaling to the immune system whether to attack the cancer cells or not. Without immunotherapy treatment, the tumor receptors (PD-L1 and CD80) bind to the reciprocal T cell receptors, signaling to the immune system not to attack the tumor. With immunotherapy that binds to them instead, the “handshake” between the tumor and the T cell is disrupted letting the immune system to attack the tumor.

Why should a patient consider participation in this study?

Mesothelioma patients have limited options for treatment available to them while the cancer is aggressive and moves fast. This study is an opportunity to try the combination of chemotherapy plus immunotherapy to potentially reap the most benefits.

What are the risks?

As with any study and/or treatment, one risk is that the treatment won’t work. With mesothelioma, this is a significant risk because the disease is quick and aggressive. However, over time, survival for mesothelioma patients has increased at least in part due to advancements in treatment options, and this study is one such option. Being a Phase 3 clinical trial, the drugs it uses have already been extensively studied for safety, but it is important to note that undergoing any type of immunotherapy can cause unintended immune reactions some of which can be life threatening. Speaking with the treating physician about potential risks and benefits is an important part of enrolling into a clinical trial.

What other treatments are in the works for mesothelioma?

Two other significant studies have been released in the last two years, both holding promise with regards to further treatment approvals. Both studies showed an improvement in survival in the most aggressive type of mesothelioma called the sarcomatoid subtype.

One of these studies combined Alimta/cisplatin (chemotherapy) with atezolizumab (immunotherapy) and also with bevacizumab (a VEGF inhibitor agent that limits vascular development leading to the tumor).

The other study, called ATOMIC, was successful in improving survival in the sarcomatoid and biphasic mesothelioma subtypes (most aggressive) by depriving the cancer cells of arginine, which is generally widely present in the most aggressive mesotheliomas.

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