Neurologic Adverse Events With Checkpoint Inhibitors in Cancer

Nancy A. Melville

October 30, 2018

ATLANTA — Immune checkpoint inhibitor therapies, which are generating high interest because of encouraging, prolonged survival in the treatment of advanced malignancies, pose the risk for rare but serious neurologic adverse events that begin early in the course of treatment and can have complex clinical presentations, a review of cases shows.

"Neurologists are probably going to encounter more of these cases of neurological complications from checkpoint inhibitors in the future, and it will be important to recognize them immediately and start appropriate management to reduce disability and morbidity," first author Sophie L. Duong, Department of Neurology, Yale School of Medicine, New Haven, Connecticut, told Medscape Medical News.

The findings were presented here at the ANA 2018: 143rd Annual Meeting of the American Neurological Association.

Checkpoint inhibitors have been transforming cancer treatment. The US Food and Drug Administration has recently approved treatments for various advanced malignancies, including melanoma, non—small cell lung cancer, and renal cell carcinoma. With promising results, research is moving full speed ahead on various other malignancies.

But in revving up the immune system, the drugs are also linked to autoimmune-like side effects. Serious neurologic effects have been reported in about 2% of patients receiving checkpoint inhibitors. It is anticipated that the use of these drugs will increase, so a better understanding of the nature of these complications is essential, Duong said.

"The larger clinical trials haven't really reported on neurological complications because, as opposed to other complications that affect the skin or the muscle or rheumatologic system, these neurological events are considered relatively rare," she explained.

In an effort to document and characterize the clinical manifestations and outcomes, Duong and colleagues identified 18 patients at the Neuromuscular and Neuro-Oncology Clinic at Yale New Haven Hospital between 2014 and 2018 who developed neurologic adverse events after treatment with immune checkpoint inhibitors.

The patients (median age, 64 years) were treated with atezolizumab (Tecentriq, Genentech) (n = 1), pembrolizumab (Keytruda, Merck Sharp & Dohme) (n = 4), ipilimumab (Yervoy, Bristol-Myers Squibb) (n = 3), nivolumab (Opdivo, Bristol-Myers Squibb) (n = 3) or a combination of ipilimumab and nivolumab (n = 7).

They all had advanced-stage malignancies at the time of their checkpoint inhibitor therapy. Melanoma was the most common underlying malignancy (n = 10), followed by small cell lung cancer (n = 4), non—small cell lung cancer (n = 3), and Merkel cell carcinoma (n = 1).

The neurologic adverse events occurred after a median of 32 days (range, 4 to 503 days) after checkpoint inhibitor treatment. The central nervous system was more frequently affected (67%) than the peripheral nervous system (33%).

The most common neurologic events were central demyelinating disorders, which occurred in seven patients (28%). The severity of these events ranged from grade 2 (moderate) to grade 4 (life threatening).

The other neurologic immune-related adverse events included myasthenic syndrome (22%), encephalitis (17%), hypophysitis (17%), neuropathy (11%), and aseptic meningitis (6%).

Rates of neurologic adverse events were higher in patients treated with combination checkpoint inhibitor therapies.

Most patients (n = 15) also experienced concomitant nonneurologic, immune-related adverse events, including dermatologic, gastrointestinal, hepatic, endocrine, pancreatic, ophthalmologic, rheumatologic, and musculoskeletal events, as well as fatigue and fever.

Most, Not All Respond Well to Treatment

Patients were treated for the adverse events after a median of 7.5 days from the onset of neurotoxic symptoms. The checkpoint inhibitor therapy was discontinued in all cases. The treatment consisted of high-dose corticosteroids. Most patients (16, 89%) responded well to the treatment. Nine patients required treatment with intravenous immune globulin.

"With the high-dose corticosteroid therapy, patients usually responded very quickly — immediately after treatment was started," Duong said.

Five patients experienced a complete resolution of symptoms, 11 had some residual neurologic complications, and two did not respond, she said.

"The two nonresponders had sensorimotor mixed axonal-demyelinating neuropathy, which tends to respond later, so that wasn't entirely surprising," Duong noted.

For patients who do recover from the complications, it is unclear whether it is safe to resume checkpoint inhibitor therapy. Some studies recommend that therapy not be resumed for patients who experience neurologic toxicities of grade 3 or 4.

Duong noted that two patients in the Yale cohort were able to restart the therapy successfully.

"The two patients have been restarted and actually tolerated them quite well," she said. "The literature suggests that restarting patients does not lead to a more severe phenotype, but of course they are prone to develop those complications again," she said.

Neurologists Likely to See More Cases

Justin McArthur, MBBS, MPH, president-elect of the ANA and director of the Department of Neurology, Johns Hopkins Medicine, Baltimore, Maryland, agreed that neurotoxicities related to immune checkpoint inhibitor therapies represent a concern that neurologists are going to increasingly have to keep on their radar.

"This is a new neurological syndrome, and we're probably going to see a lot more of it, because these checkpoint inhibitors are being very widely used," he told Medscape Medical News.

"It's an interesting phenomenon because these compounds have the effect of accelerating the immune system, potentially creating some of these abnormal neurological problems," he explained.

"Even if only 5% of patients develop these complications, it's a significant limitation for this therapy, which could otherwise be really meaningful for some patients, particularly those with melanoma and lung cancer," he said.

Larger studies on the neurologic adverse events are lacking, but a recent systematic review, presented this year at the annual meeting of the American Academy of Neurology and reported by Medscape Medical News, described 73 cases of wide-ranging neurologic adverse events associated with treatment with ipilimumab, nivolumab, or pembrolizumab. The cases were reported through May 2017.

In that review, the most common adverse event was neuropathy, occurring in 29% of patients, followed by myositis in 25% and myasthenia gravis in 19%.

Although immunotherapy was used in 95% of patients, only 32% of patients fully recovered, and approximately 1 in 5 patients died, the authors reported.

The investigators and Dr McArthur have disclosed no relevant financial relationships.

ANA 2018: 143rd Annual Meeting of the American Neurological Association. Abstract M103, presented October 21, 2018.

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