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Study Discerns Rare Risks of Fatal Side Effects From Cancer Immunotherapy


Researchers determined the incidence and timing of rare, fatal side effects from immune checkpoint inhibitors, and said the number is still extremely low.

ICIs target cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death 1/ligand-1 (PD-1/PD-L1). In a study published in JAMA Oncology, researchers examined exposure to anti—CTLA-4 (ipilimumab or tremelimumab), anti–PD-1 (nivolumab, pembrolizumab), or anti–PD-L1 (atezolizumab, avelumab, durvalumab).

The most widely prescribed class of immunotherapies, known as immune checkpoint inhibitors (ICIs), have transformed care for patients with cancer, even as the therapies are known to carry a range of toxic effects. Researchers led by Vanderbilt-Ingram Cancer Center said they’ve determined the incidence and timing of rare but sometimes fatal adverse events to these treatments.

Read coverage of the risks and benefits of immune checkpoint inhibitors.

In the largest study to date on the topic of immune-related adverse events (irAEs), the researchers used 3 sources. They retrospectively queried a World Health Organization (WHO) pharmacovigilance database (Vigilyze) made up of more 16 million adverse drug reactions; reviewed records from 7 academic centers; and conducted a meta-analysis of 112 trials.

The WHO/Vigilyze results

From the World Health Organization database, the team found 613 fatal ICI toxicities from 2009 to 2018. Myocarditis had the highest fatality rate, at 40%. Of 613 deaths, 193 received ipilimumabmonotherapy, 333 received anti—PD-1/PD-L1, and 87 received the combination of anti–PD-1/PD-L1 plus anti–CTLA-4 (combination).

Patients treated with anti—CTLA-4 (all with ipilimumab) largely had melanoma (136 [96%] for monotherapy and 49 [66%] for combination). Most patients treated with anti–PD-1/PD-L1 had lung cancer (152 [54%]), melanoma (50 [18%]), or genitourinary cancers (10%).

Most patients had a single toxic effect causing death, although combination therapy had multiple concurrent irAEs present more often than either monotherapy (27% for combination vs 14% for ipilimumab and 15% for anti-PD-1/PD-L1; P = .01)

The type of fatal event differed between regimens, the study found. Ipilimumab monotherapy was highly dominated by colitis/diarrhea, followed to a lesser extent by hepatitis and pneumonitis. Anti—PD-1/PD-L1 monotherapy had a wide range of toxic effects.

Academic center analysis

The review of records from the 7 academic centers found 21 deaths out of 3545 patients (0.59%). Most of the patients who died were age 65 or older with melanoma or another skin cancer. Deaths occurred in 7 patients treated with ipilimumab, 9 treated with anti—PD-1, and 5 treated with combined PD-1/CTLA-4 blockade.

Fatal toxic effects included myocarditis, neurologic toxic effects, colitis/enteritis, and hepatitis.

Clinical trial review

The meta-analysis of data from 112 clinical trials and 19,217 patients showed a fatality death rate ranging from 0.36% to 1.23%, depending upon the specific type of immune checkpoint inhibitor.

Researchers examined all published clinical trials of anti—PD-1 (nivolumab, pembrolizumab), anti–PD-L1 (atezolizumab, avelumab, durvalumab), anti–CTLA-4 (ipilimumab, tremelimumab) therapies, and combinations (PD-1/PD-L1/ plus CTLA-4 inhibition).

There were 122 deaths, in 0.36% (PD-1), 0.38% (PD-L1), 1.08% (CTLA-4), and 1.23% (PD-1/PD-L1 plus CTLA-4) of patients.

PD-1/PD-L1 inhibitors were associated with lower fatal toxic effects rates compared with either CTLA-4 monotherapy or combination (χ2 = 58.8; P <.001). There was no difference in fatal toxic effects incidence between PD-1 and PD-L1 inhibitors (χ2 = 0.021; P = .88) or between anti—CTLA-4 monotherapy and combination therapy (χ2 = 0.23; P = .62). A formal meta-analysis revealed similar patterns, although with slightly higher estimates of fatality rates (0.8%-1.7%)

Despite the number of fatal events reported, the risk of fatal irAEs remains very low for individual patients with advanced cancer, and should not keep patients from using these therapies, of which 13 are on the market. The risks are “within or well below” fatality rates for more common cancer treatments, including chemotherapy, stem cell transplants and complex cancer surgeries, researchers said.

“These drugs are quite transformative,” Douglas Johnson, MD, MSCI, senior author, said in a statement. “The benefits outweigh the risks, but patients and doctors should be aware of their toxicities. These side effects can be quite severe, and they are something that we really need to pay attention to.”

Fatal reactions tended to happen early after starting treatment, on average 15 to 40 days, depending upon the type of ICI.

Checkpoint inhibitors spur the immune system to attack cancer, but they may also attack the heart, lungs, liver and colon. Steroids can relieve the resulting inflammation, but timely treatment is crucial, Johnson said.

“Some of the patients who died had a long delay before they received steroids,” Johnson said. “In some cases, the patient didn’t call in to report their symptoms or experienced a very unusual presentation that was difficult to diagnose.”

The data also showed that older patients were more prone to experience fatal toxicities, although the occurrence was still rare.

“We don’t necessarily think that older patients have more side effects, but when they do have toxicities, they can potentially have more complications,” Johnson said.


Wang DY, Salem JE, Cohen JV, et al. Fatal toxic effects associated with immune checkpoint inhibitors a systematic review and meta-analysis. [published online September 13, 2013]. JAMA Oncol. doi:10.1001/jamaoncol.2018.3923.

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