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Expert Critique

FROM THE ASCO Reading Room

Amit Reddy, MBBS Postdoctoral Fellow Mitchell Cancer Institute, University of South Alabama

Toxicities related to immune checkpoint inhibitors are rare, but typically arise in the beginning of therapy or from rapid clinical decline. The harmful effects of these drugs may affect any organ, and combination therapies of PD-1 plus CTLA-4 can cause more high-grade side effects (55-60%) compared with just anti-PD-1 therapy (10-20%). As described here, a research group reviewed more than 16 million adverse drug reactions from the WHO database and studied records from several academic centers and found a fatality rate of 0.6%. The study revealed a total of 613 fatal immune checkpoint inhibitor toxicities from 2009 to 2018 in the WHO pharmaco-vigilance database. The major cause of death was colitis (70%) from anti-CTLA-4, whereas those related to PD-L1 were mostly due to pneumonitis (35%). The key prevention of death from these side effects was the timely treatment of corticosteroids with mandatory gastrointestinal prophylaxis. In addition, older patients were more likely to have fatal toxicities due to complications. The grade of disease is the most important factor for treatment of immune-related side effects.

Of note, a multidisciplinary toxicity team has been developed at John Hopkins for treatment of immunotherapy-related adverse effects, and this has been shown to simplify the identification and treatment of immunotherapy adverse effects.

Full Critique

Fatal toxic effects associated with immune checkpoint inhibitors are uncommon, with the incidence approximately the same as with other oncologic interventions. According to the largest evaluation of fatal immune checkpoint inhibitor toxicities published to date, these effects tend to arise early in treatment and often result in rapid clinical deterioration.

Toxic effects associated with checkpoint blockade may affect any organ. Most frequently, immune-related adverse events affect the colon, liver, lungs, pituitary, thyroid, and skin, although uncommon events involving the heart, nervous system, and other organs also occur. Combinations of programmed death-1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) therapies trigger substantially more high-grade adverse events (55%-60%) than anti–PD-1 therapy alone (10%-20%).

"These drugs are quite transformative. The benefits outweigh the risks, but patients and doctors should be aware of the toxicities," said Douglas B. Johnson, MD, of the Vanderbilt-Ingram Cancer Center in Nashville. "These side effects can be quite severe, and they are something that we really need to pay attention to."

Johnson led a team that sorted through in a World Health Organization (WHO) database, searching for those related to immune checkpoint inhibitors; the researchers also reviewed records from seven academic centers and conducted a meta-analysis of published trials for the drugs.

A total of 613 fatal immune checkpoint inhibitor toxicities were found within the WHO pharmacovigilance database (Vigilyze) from 2009 to 2018. Most anti–CTLA-4 deaths were due to colitis (70%), while anti–PD-1/PD-L1–related fatalities were often from pneumonitis (35%), hepatitis (22%), and neurotoxic effects (15%). Combination PD-1/CTLA-4 deaths were frequently from colitis (37%) and myocarditis (25%).

Fatal toxic effects typically occurred early after therapy initiation for combination therapy (median 14.5 days), anti–PD-1 therapy (median 40 days), and ipilimumab monotherapy (median 40 days). Myocarditis had the highest fatality rate (39.7%). Endocrine events and colitis had only 2-5% reported fatalities; 10-17% of other organ-system toxic effects reported had fatal outcomes.

The review of records from the seven academic centers revealed a 0.6% fatality rate. The meta-analysis of data from 112 clinical trials showed a fatality death rate ranging from 0.36% to 1.23%, depending on the specific type of immune checkpoint inhibitor.

To prevent deaths from adverse events, timely treatment with corticosteroids is crucial, Johnson said. "Some of the patients who died had a long delay before they received steroids. 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 study 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 ... We have clinics full of patients now who received these treatments who are alive today because they responded to these treatments."

Management Depends on Disease Grade

Management of immune-related adverse events depends on disease grade. "Grading toxicities will assist in treatment decisions for providers," noted Julie R. Brahmer, MD, of Johns Hopkins Kimmel Cancer Center in Baltimore, speaking at an Education Session at the 2018 ASCO annual meeting.

To manage toxicities, corticosteroids are the mainstay, she said, noting that in general, she suggests holding immunotherapy once adverse events arise, or if they are Grade 3 or 4, permanently stop immunotherapy. "Retreatment with immunotherapy is possible after resolution, depending on the grade of toxicity. Dose reduction does not lessen the occurrence of side effects."

In her talk, titled "General Management of Immune-Related Toxicities Incorporating Guidelines into Practice," she outlined some -- for example:

• For grade 1, provide supportive care and possibly withhold immunotherapy
• For grade 2, withhold immunotherapy and consider redosing if toxicity resolves to grade 1; provide low-dose corticosteroids and, if there is no improvement in 2-3 days, increase the corticosteroid dose to 2 mg per kg daily
• For grade 3 events, hold the drug and provide high-dose corticosteroids; if there is no improvement in 2-3 days, add additional or alternative immune suppressants. Once toxicity resolves to grade 1, consider tapering the corticosteroid dose over 4-6 weeks
• For grade 4 toxicities, discontinue the drug, except for endocrinopathies; continue high-dose corticosteroids and follow the same protocol as for grade 3 events

"When on steroids, patients should receive gastrointestinal prophylaxis," Brahmer said. "Add in Pneumocystis pneumonia prophylactic antibiotics if more than 3 weeks of immunosuppression are expected. During steroid tapering, patients should be evaluated frequently and for an extended period of time."

Multidisciplinary Toxicity Team

She noted that Johns Hopkins has created a . The team of eight oncology and 20 medical subspecialists support multidisciplinary immune-related adverse events diagnosis and management.

In an abstract presented at ASCO18, Jarushka Naidoo, MBBCh, reported that the team received 92 referrals for 80 patients, median age of 65, between January 2017 and March 2018. Patients most commonly had non-small cell lung cancer (35%), melanoma (19%), or gynecologic malignancies (10%), and received immune checkpoint inhibitor monotherapy (56%) or combination immunotherapy (44%).

The researchers confirmed 63 immune-related adverse events (grade 1: 19%; grade 2: 43%; grade 3 or higher: 38%), and 26 patients developed more than one. These events included pneumonitis (22%), arthritis (17%), dermatitis (13%), colitis/diarrhea (13%), idiopathic thrombocytopenia purpura (5%), hepatitis (5%), and thyroid dysfunction (5%). Two patients developed a new immune-related adverse event of bony inflammation. Grade 3 or higher events and colitis/diarrhea were more likely with combination immunotherapy.

"Creation of an immune-related toxicity team facilitated identification and management of complex immune-related adverse events," Naidoo said. "This new model provides a valuable forum to identify educational/service needs, manage multi-system immune-related adverse events, identify new ones, stratify risk, and establish research collaborations."