Mesothelioma Experts Explain Opdivo and Yervoy Side Effects

The immunotherapy combination of nivolumab and ipilimumab, known by the brand names Opdivo and Yervoy, became the first new drug therapy for mesothelioma in 16 years when the U.S. Food and Drug Administration approved it in 2020.

This new therapy is available to pleural mesothelioma patients ineligible for surgery who haven’t undergone any prior treatment.

Because it is one of the most recent mesothelioma treatments, patients understandably have questions about the new regimen. They often ask how it works and how the combination differs from more traditional drugs such as chemotherapy. Many have questions about how mesothelioma immunotherapy affects their bodies and how they can manage its side effects.

Immunotherapy Side Effects vs. Chemotherapy

There are differences between chemotherapy for mesothelioma and immunotherapy. Chemotherapy drugs typically target cells that grow and divide rapidly, such as cancer cells that quickly form tumors. However, many healthy cells in the body also grow swiftly, such as hair follicles and nails. Mesothelioma chemotherapy side effects often include hair loss, nail bed pain or weakness, mouth sores and digestive tract issues.

Immunotherapy works much differently. Opdivo, for example, removes immune system checkpoints that prevent immune cells, such as T cells, from “seeing” mesothelioma cancer. Yervoy assists in activating more T cells that seek out cancer and create an immune response.

An activated immune response feels similar to when you’re sick with a cold or flu virus. You may experience fever, headache, fatigue, nausea or gastrointestinal distress.

“The most common side effects of the ipilimumab and nivolumab combination include fatigue, itching, diarrhea, rash, pain in muscles and joints, decreased thyroid hormone and, rarely, inflammation of the lungs, known as pneumonitis,” said Dr. Estelamari Rodriguez, a thoracic oncologist at the University of Miami Health System.

Pleural mesothelioma survivor Emily Ward began treatment with the Opdivo and Yervoy immunotherapy combination in January.

“They all said it would get worse before it gets better, but I’m tolerating it fine,” she said when she started the regimen.

Joint Pain, Pneumonitis Are Common

“I have seen a lot of toxicity with it and side effects, so it is not a benign treatment,” Dr. Jeffrey Velotta, a thoracic surgeon at Oakland Medical Center in California, told The Mesothelioma Center at Asbestos.com.

Immune reactions can cause inflammation throughout the body, making side effects more unpredictable than chemotherapy.

“The main side effect that affects the patients that I see are immune-mediated pneumonitis,” said Velotta. “[Pneumonitis] severely affects the patient, and they often have to stop one or both [immunotherapy drugs] and reduce the dose. In addition, they will need to go on prednisone and immunosuppression.”

Another common side effect of Opdivo and Yervoy is joint pain or stiffness. Doctors often prescribe strong anti-inflammatory medications called corticosteroids for severe joint pain. Prednisone is one drug that can help reduce joint inflammation when taken daily.

As evidenced by a 2018 research study at Memorial Sloan Kettering Cancer Center in New York and Gustave Roussy cancer center in France, corticosteroids given after the start of treatment do not significantly impact immunotherapy effectiveness.

However, continued corticosteroid use could lead to changes in blood sugar, vision changes and a higher risk of infection.

“We ask patients to avoid unnecessary steroids that may decrease immune response,” said Rodriguez.

If joint pain persists after oral corticosteroids, patients may want to consider a joint injection that involves corticosteroid and anesthetic injected directly into the affected joints. Patients may need a referral for pain management for this procedure, but pain relief can last several months.

Mild Side Effects Could Lead to Severe Reactions

Immune checkpoint inhibitors such as Opdivo and Yervoy are the most common form of immunotherapy, and about 75% of patients receiving this medication experience side effects.

Dr. Alan Bryce, an oncologist at Mayo Clinic in Phoenix, discussed immunotherapy at a 2018 conference hosted by CancerCare.

“Immunotherapy dials things up to 11. With severe side effects, we dial it back down to five or six, usually with an immunosuppressant drug,” he said. “The last thing we want is a patient needing oxygen or being hospitalized.”

Many immunotherapy side effects, such as rash, changes in bowels or weight changes, may start as minor symptoms. In most cases, immunotherapy side effects are reversible with a short course of medication.

Rodriguez advises her patients to stay in close contact while on Opdivo and Yervoy.

“We counsel our patients to communicate any symptoms early, especially diarrhea,” she said. “The drugs may not be tolerated in patients with autoimmune diseases, rheumatoid arthritis, psoriasis, ulcerative colitis or lupus.”

If patients don’t report early side effects to their doctor and go without treatment, the immunotherapy reactions can eventually cause permanent damage. For example, constant diarrhea can lead to bowel inflammation, known as colitis, as well as severe dehydration.

Unfortunately, unlike diarrhea, fatigue or rash, some immunotherapy side effects are irreversible. Immunotherapies such as Opdivo and Yervoy may cause hormone irregularities called endocrinopathies that can be permanent and require lifelong therapy to maintain hormonal balance.

These permanent changes occur in hormone glands, such as the pituitary, adrenals or thyroid. Symptoms may initially appear as changes in weight, fevers, fatigue or muscle and joint pain.

Communicating any changes in your health is vital for preventing any long-term adverse effects from immunotherapy.

“I strongly emphasize the need to be in close, almost daily contact with your physicians,” Bryce recommended.

If you notice any new or worsening symptoms while on Opdivo and Yervoy, let your doctor know right away. A mesothelioma specialist can help make the correct adjustments to your treatment and reverse inflammation damage that could lead to permanent damage.

Opdivo/Yervoy Combination Improves Mesothelioma Survival

In the recent CheckMate 743 mesothelioma clinical trial, which compared the drug combination to standard chemotherapy, Opdivo and Yervoy improved median overall survival by four months.

“At two years, 41% of patients in the immunotherapy arm were alive compared to 27% in the chemo arm,” said Rodriguez.  “Improvement in survival was most notable in sarcomatoid histology in this trial.”

For mesothelioma patients with sarcomatoid or biphasic mesothelioma cell type, median survival was almost 10 months longer than with chemotherapy alone.

“I personally feel that immunotherapy is going to be better in the adjuvant setting,” said Velotta.

Adjuvant therapy increases the benefit of other treatments and helps prevent cancer recurrence.