Opdivo (nivolumab) and Yervoy (ipilimumab) are immunotherapy drugs approved to treat pleural mesothelioma. The National Comprehensive Cancer Network (NCCN) recommends that physicians use a combination of both agents for treating mesothelioma that has progressed through an initial first-line treatment.[1]
What Is Nivolumab and Ipilimumab Combination Mesothelioma Treatment?
In 2020, the U.S. Food and Drug Administration (FDA) approved the combination of nivolumab and ipilimumab for treating pleural mesothelioma. This was the first new treatment approved for mesothelioma in 16 years.
About Opdivo/Nivolumab
Made by Bristol-Myers Squibb and approved by the FDA in 2011, nivolumab is an immunotherapy drug sold under the brand name Opdivo®. The drug works by binding to a signaling receptor on T-cells in the immune system.
This receptor, PD-1, interacts with proteins on cancer cells, which tell the immune system that the cancer cells are normal and not to attack.
Nivolumab interferes with this interaction, allowing the immune system to recognize the cancer cells as abnormal. It has been extensively tested in clinical trials and is FDA-approved for treating many types of cancer:[2]
- Pleural mesothelioma
- Melanoma
- Non-small cell and small cell lung cancer
- Renal cell carcinoma
- Hodgkin’s lymphoma
- Head and neck cancer
- Urothelial cancer
- Colorectal cancer
- Hepatocellular carcinoma
About Yervoy/Ipilimumab
Made by Bristol-Myers Squibb and approved by the FDA in 2014, ipilimumab is another immunotherapy drug sold under the brand name Yervoy®. Like nivolumab, ipilimumab works upon receptors within the immune system to help the body identify and remove cancer cells.
Ipilimumab targets the protein CTLA-4 on T-cells in our immune system. This protein acts as an off-switch for the immune cells. The drug blocks it and encourages the T-cells to activate to attack and kill cancer cells.
Ipilimumab is not approved to treat as many cancers as nivolumab. While some cancers can be treated with ipilimumab as initially approved by the FDA, subsequent studies have found this agent is much more effective when combined with nivolumab. The medication has the most supporting evidence for use in metastatic melanoma and renal cell carcinoma.
Is This the Best Immunotherapy for Mesothelioma?
Immunotherapy is still a new type of treatment for mesothelioma. Only two lines of immunotherapy are currently FDA-approved for mesothelioma patients. Each type of immunotherapy treatment is best for different situations:
- Opdivo and Yervoy are usually best for mesothelioma patients who are newly diagnosed and not good candidates for surgery.
- Keytruda (pembrolizumab) may be helpful for mesothelioma patients who have already gone through first-line treatment and are experiencing a recurrence of cancer.
How Nivolumab and Ipilumab Work
The body naturally identifies abnormal aspects of cancer cells, and T-cells are recruited to perform the work of destroying these cancer cells. However, cancer cells can develop resistance mechanisms to this natural process, helping these cells to evade discovery by the immune system. Ipilimumab and nivolumab work together to override it:
- One of the resistance mechanisms is that cancer begins to over-express PD-L1 as a signal on the outside of the cell. As the T-cells arrive to attack cancer, the PD-1 receptor on the T-cells interacts with PD-L1 on the cancer cell, and the T-cell is then inactivated.
- This mirrors the body’s natural mechanism for helping the immune system to recognize our healthy organs.
- Nivolumab works upon the PD-1 receptors of the T-cells to lower their ability to recognize this signal and thus continue performing their assigned task of attacking the cell.
- The CTLA-4 receptor on the T-cell functions in a similarly inhibitory manner. CTLA-4 binding suppresses the T-cell activation before the cells are ever sent out to attack the cancer.
- It appears that this receptor’s natural function is to keep the immune system from being constantly activated, though this mechanism isn’t well understood.
- Ipilimumab blocks this CTLA-4 receptor, leading to a greater number of activated T-cells patrolling the body for problem cells.
Why Are Ipilimumab and Nivolumab Used Together?
When combined, nivolumab increases the likelihood that T-cells will find and attack the cancer, and ipilimumab helps increase the number of T-cells that have been recruited to the task.
Because these agents use the body’s own immune system, the number of cancers that can be treated is very high. If the body can successfully begin to identify cancer, then ongoing treatment success is possible, in some cases for years.
Black Box Warnings – Risks Associated with Opdivoy and Yervoy
Ipilimumab comes with significant risks. These risks led the FDA to include a black box warning, its most serious, for more severe side effects. This warning is for immune-mediated adverse reactions.
Because of the unique mechanism these agents employ, they have often been accused of “taking the brakes off” the immune system. This means the more notable side effects occur when the immune system begins attacking a part of the body that isn’t cancerous.
The most common organ that is attacked is the thyroid, leading to hypothyroidism.[3] This is similar to Hashimoto’s thyroiditis and is treated by supplementing the body with thyroid hormone. The more serious organs that are attacked include the intestines and the lungs.
While rare, report symptoms of greatly increased diarrhea or blood in the stool to your oncologist; likewise, a suspicious cough should be reported to and evaluated by a medical professional.
There are also risks for liver damage, severe skin reactions, and neuropathy (loss or disruption of the sense of feeling). While these are life-threatening conditions, providers can treat these issues if addressed quickly. All physicians should be informed at each visit that immunotherapy is being used to treat this cancer.
What Are Other Potential Side Effects of Opdivo/Yervoy Immunotherapy?
Clinical trials determine the effectiveness of new therapies, what side effects they cause, and if they are worth the benefits of the treatment.
The more common side effects reported included:[3]
- Low sodium
- Rashes
- Itchiness
- Fatigue
- Liver damage
- Difficulty breathing
- Pain
- Cough
- Nausea
- Anemia
- Constipation
- Vomiting
- Diarrhea
How Effective Are Nivolumab and Ipilimumab for Mesothelioma?
The FDA approved Opdivo and Yervoy after successful clinical trials showed that the combination could be effective and well-tolerated by mesothelioma patients. Studies continue to investigate this type of immunotherapy and others.
Phase II Clinical Trial Results
The first study monitored twelve-week disease control and watched how many patients responded to the treatment. Researchers tested nivolumab compared to the combination of nivolumab plus ipilimumab on 125 patients.
They found that while nivolumab alone was helpful for 40% of patients, the combination treatment held cancer stable or better in 52% of the patients. Despite the benefits, the combination treatment came with an increase in side effects, including liver damage.[4]
The other key phase II trial was smaller but confirmed the results of the earlier study. The researchers recruited thirty-six patients who all received the combination of nivolumab plus ipilimumab. These patients had already received a first-line treatment with pemetrexed and a platinum drug.
The study found that the combination held cancer stable or better in 68% of patients; however, serious side effects were noted in 34% of patients.[5]
Phase III Clinical Trial Results
Researchers researched long-awaited results from a large phase III trial in 2021. The trial evaluated nivolumab plus ipilimumab as a first-line treatment compared to pemetrexed plus a platinum drug like cisplatin or carboplatin.
The nivolumab/ipilimumab combination produced better results than standard treatment. This included a survival time of 18 months compared to 14 months with standard chemotherapy. The combination also improved two-year survival rates.[6]
Other Nivolumab/Ipilimumab Mesothelioma Studies
Researchers continue to study this immunotherapy combination for safety and effectiveness in mesothelioma patients:
A study published in 2024 showed the first results from real-world, non-clinical trial uses of the immunotherapy in mesothelioma patients. Researchers found similar results in terms of overall survival. However, many patients experienced treatment-related adverse events, which led to 25% discontinuing treatment.[7]
Another real-world study of nivolumab/ipilimumab from Australia found that the toxic effects of the treatment are more significant than what was seen in clinical trials. Colitis was the most common adverse event. Three patients died due to treatment-related events.[]
Can Nivolumab and Ipilimumab Treat Peritoneal Mesothelioma?
Opdivo and Yervoy are currently only approved by the FDA to treat pleural mesothelioma. Researchers continue to investigate the use of this immunotherapy combination for peritoneal mesothelioma.
Clinical trials using Opdivo and Yervoy and currently recruiting patients with peritoneal mesothelioma include:
- A Study of Immunotherapy Drugs Nivolumab and Ipilimumab in Patients w/Resectable Malignant Peritoneal Mesothelioma. This study is specific to peritoneal mesothelioma patients. It is using the immunotherapy combination either before or after surgery to remove tumors.[9]
- Nivolumab and Ipilimumab in Treating Patients With Rare Tumors. While this study is recruiting patients with many types of cancer, peritoneal mesothelioma patients are included if they qualify.[10]
- Phase 1/2 Trial of Gavo-cel (TC-210) in Patients With Advanced Mesothelin-Expressing Cancer. Patients with the biomarker mesothelin may qualify for this trial using a new immunotherapy medication along with nivolumab and ipilimumab.[11]
Talk to your medical team about clinical trials and whether you qualify. They can be a good way to access new treatments that are not yet generally available.
Treatment centers with mesothelioma experts on staff might offer Opdivo and Yervoy as an off-label treatment for peritoneal mesothelioma. MD Anderson Cancer Center in Texas recently published the results of a brief study conducted there using this combination with peritoneal patients.
Because of the success of nivolumab and ipilimumab with pleural mesothelioma patients, the MD Anderson specialists wanted to give their peritoneal patients the option to benefit from the combination. Their results were limited but promising.[10]
How Much Longer Can Patients Live with Opdivo and Yervoy?
Nivolumab and ipilimumab represent a new treatment possibility shaping the options available to treat difficult diseases like mesothelioma. When they convince the immune system to work against cancer, the positive effects can last much longer than traditional chemotherapies.
Overall Survival Time
Every patient is different and will get different results, but this combination does help most live longer. With the most recent results showing a survival time of 18 months, patients get more time with this type of immunotherapy.
Overall Survival for Non-Epithelioid Mesothelioma
Survival times vary by patient based on multiple factors, including cell type. Patients with sarcomatoid mesothelioma have shorter survival times. Sarcomatoid mesothelioma is more aggressive and less responsive to treatment.
The nivolumab ipilimumab combination extended survival time for non-epithelioid mesothelioma patients by about nine months. This is as compared to using chemotherapy alone. Survival is still lower for this group but improved by the new immunotherapy combination.[11]
Ongoing research will help to further strengthen an understanding of what role Opdivo and Yervoy should play in the order of treatment, but having a successful and effective option as a second-line treatment has been a significant development within just the past few years.
