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Study Details Long-Term Side Effects of Immune Checkpoint Inhibitors

, by Nadia Jaber

A factoid that reads "43% of people with melanoma had a chronic side effect from treatment with an immune checkpoint inhibitor. 96% were mild side effects. 4% were more severe."
Credit: National Cancer Institute

Immune checkpoint inhibitors are a type of immunotherapy used to treat many kinds of cancer. In some patients, these drugs can lead to long-lasting remissions. While doctors are familiar with the short-term side effects of these drugs, less is known about the possibility of long-term, or chronic, side effects. According to a new study, immune checkpoint inhibitors can cause a range of long-term side effects, most of them mild.

Immune checkpoint inhibitors like nivolumab (Opdivo) and pembrolizumab (Keytruda) take the brakes off of cancer-killing immune cells. But these activated immune cells can also harm healthy tissues, leading to side effects.

Most side effects of immune checkpoint inhibitors are short-lived (acute) and can be treated with steroid drugs. Until now, less was known about the frequency, timing, and spectrum of long-term side effects of these treatments.

The new study looked at real-world data on people with melanoma who were recently treated with an immune checkpoint inhibitor. The researchers focused on side effects that were caused by the immune system.

More than 40% of the patients developed a long-term immune-related side effect, the researchers reported March 25 in JAMA Oncology. Most of these side effects did not go away during the nearly 1.5 years that patients were tracked.

“These therapies are providing the opportunity for long-term survival for many patients,” said the study’s leader, Douglas Johnson, M.D., of Vanderbilt University Medical Center. But with longer survival comes the possibility of long-term side effects, he explained.

Better understanding the long-term effects of immune checkpoint inhibitors is increasingly important because these drugs are being used to treat more kinds of cancer and in more treatment combinations, Dr. Johnson added.

The bottom line is that doctors should talk with their patients about the possibility of chronic side effects, he said, so they can weigh the potential benefits and harms.

Short-Term, or Acute, Side Effects

The researchers looked at the medical records of 387 people with advanced melanoma who were treated at eight hospitals in the United States or Australia.

These patients had received standard therapy: surgery to remove their tumors completely, followed by treatment with an immune checkpoint inhibitor (either nivolumab or pembrolizumab). For most patients, the cancer didn’t come back and almost all were still alive after a median of 18 months.

The majority of patients (267, or 69%) experienced a short-term immune-related side effect—meaning, a problem that arose during treatment. The most common short-term effects were skin rash or itchy skin, inflammation of the thyroid (thyroiditis) or low thyroid hormones (hypothyroidism), and joint pain.

Short-Term Side Effects Percentage
Mild 87%
Severe to deadly 13%

Two patients died from short-term side effects, one from inflammation of the heart muscle (myocarditis) and another from an autoimmune condition resembling Guillain-Barré syndrome.

The frequency and severity of short-term side effects are in line with what has been observed in other studies, Dr. Johnson said.

Long-Term, or Chronic, Side Effects

Overall, 167 patients (43%) had an immune-related side effect that lasted for at least 3 months after the patient finished taking the immune checkpoint inhibitor—what the researchers labeled a chronic, or long-term, side effect.

That frequency was “higher than what I would have thought based on studies of [patients with] metastatic disease,” said James Gulley, M.D., Ph.D., who has led a number of immunotherapy clinical trials for NCI’s Center for Cancer Research but was not involved in this study.

Long-Term Side Effects Percentage
Mild 96%
Severe to deadly 4%
Persisted during study 86%
Went away during study 14%

The vast majority of these long-term side effects were mild, meaning they interfered somewhat with the patient’s daily activities and may have required treatment. The most common chronic effects were skin rash, hypothyroidism, and joint pain.

Most of the long-term side effects didn’t go away during the study. Certain side effects were more likely than others to persist, namely:

“We don’t know how long some of these chronic side effects will last. That’s certainly an area we need to study further,” Dr. Johnson said. Data recorded in medical charts are not collected as systematically as they are in clinical trials, he added, so more rigorous data collection on long-term side effects may be warranted.

Research on the best way to treat or control these chronic conditions is also needed, Dr. Gulley noted. While some long-term side effects can be easily treated with steroids or other drugs, other issues like dry mouth and brain-related effects (such as Guillain-Barré syndrome), are not.

Stopping Treatment Early

A quarter of the patients in the study stopped taking the checkpoint inhibitor because of an acute side effect.

“That’s definitely higher than what’s being reported in clinical trials [of immune checkpoint inhibitors]. But it’s actually about what I would expect from the real-world setting,” Dr. Johnson said.

People with melanoma are recommended to take an immune checkpoint inhibitor for 12 months, he explained. But in clinical practice, some patients and their doctors decide to stop the therapy a few months earlier if the patient is in remission and has a mild, but bothersome side effect.

That calls into question the necessary length of treatment, Dr. Gulley said. It’s possible that shortening the duration of therapy might be just as effective but less toxic, he explained.

Weighing the Pros and Cons of Checkpoint Inhibitors

This study focused on immune checkpoint inhibitors as adjuvant therapy, meaning therapy given after surgery to reduce the chances of the cancer coming back. For some people, melanoma can be cured with surgery alone, and the adjuvant therapy is just extra protection. So, the long-term harms of adjuvant treatment are particularly important for this group, Dr. Johnson explained.

That’s a different scenario than someone with actively growing metastatic cancer, who is not likely to be cured with treatment, Dr. Gulley said.

Patients and their doctors should weigh the potential harms and benefits of adjuvant therapy with an immune checkpoint inhibitor, the researchers noted. But for an individual, the chances of experiencing those benefits and harms is not so clear cut.

Doctors use certain features, like the extent of cancer in the body (the disease stage), to estimate the general risk of a person’s cancer returning and the potential benefit from adjuvant treatment. But there’s currently no way to precisely determine an individual’s risk.

And while this new study provides a better idea of the range of side effects, it’s impossible to know whether someone will develop a chronic side effect and how severe it will be. That’s something Dr. Johnson’s team hopes to change by studying ways to predict who might develop severe or chronic side effects.

The impact of chronic side effects on people’s quality of life is also not well known, Dr. Gulley said. Some may be easily managed, while others may have a major impact on a person’s day-to-day life, he added.

And the fundamental question, Dr. Gulley said, is “where is that tipping point” at which the benefits outweigh the harms?

This study will hopefully open the door to more research that delves further into these unanswered questions, Dr. Johnson said.