Neurologic Effects of 'Revolutionary' Cancer Drugs May Be Severe, Fatal

Damian McNamara

May 01, 2018

LOS ANGELES — Checkpoint inhibitors, a novel class of agents promising in the treatment of a wide range of cancers, have been tied to serious neurologic, immune-related adverse events, new research shows.

Checkpoint inhibitors are used to treat melanoma, non-small cell lung cancer, kidney cancer, bladder cancer, and head and neck cancers, among others. Their neurotoxic effects can be severe, even fatal, warranting increased vigilance and rapid treatment when they are administered, researchers caution.

"I'm a neuromuscular specialist but I have a niche in cancer and chemotherapy. Over the last year and a half I've had eight cases with really rapidly progressive neurotoxicity," study investigator Kelsey Juster-Switlyk, MD, assistant professor in the Division of Neuromuscular Medicine, Department of Neurology, University of Utah Medical Center in Salt Lake City, told Medscape Medical News.

"The neurologic immune-related adverse events are a lot more severe, refractory, and prolonged compared to the non-neurologic," she added during a poster presentation here at the American Academy of Neurology (AAN) 2018 Annual Meeting.

20% Mortality Rate

One patient treated with the checkpoint inhibitor pembrolizumab (Keytruda, Merck) developed autoimmune myositis and myasthenia gravis. Electromyography and muscle biopsy confirmed the diagnoses. In this case, the patient died despite treatment with high-dose corticosteroids, Juster-Switlyk noted.

"The key case I wrote up, the fatal case of myositis, was tragic," she said.

Juster-Switlyk noted that the literature does not offer any consensus on how to reverse these adverse events.

"There are no prospective studies on how to treat these cases. There are only case reports. I have a patient right now. She's 25 and she has lymphoma. She's been on nivolumab [Opdivo, Bristol-Myers Squibb] for about a year, and it's the only thing that has kept her cancer at bay. I think it's causing a really aggressive, immune-related neuropathy, a Guillain-Barré–like neuropathy. It's really hard to tell her, 'Maybe we need to stop this for good.'"

With little more than case reports to go by, Juster-Switlyk and colleague Nicholas Johnson, MD, performed a systematic review of the literature. They identified 65 studies with 73 patients reported in PubMed through May 2017.

They found a wide range of neurologic immune-related adverse events associated ipilimumab (Yervoy, Bristol-Myers Squibb), nivolumab, or pembrolizumab. The most common of these adverse effects were neuropathy in 29% of patients, myositis in 25%, and myasthenia gravis in 19%.

Despite use of immunotherapy in 95% of patients, only 32% of patients made a full recovery and approximately 1 in 5 patients died.

"Interestingly, there has been more interest at the AAN and several courses I've been to recently on checkpoint inhibitors, but still not a ton of answers," Juster-Switlyk said.

"My big question, which this [report] does not answer, is can you ever re-expose patients to checkpoint inhibitors?"

In addition, she said, there is a need for prospective studies to understand whether concurrent intravenous immunoglobulin (IVIG) added to corticosteroids improves treatment of these adverse effects and/or whether IVIG and rituximab work better than prednisone alone.

Juster-Switlyk also wants to increase awareness of the adverse effects of these agents so oncologists know how to recognize these neurotoxicities.

"They have patients who have a lot of muscle pain, maybe a CK [creatine kinase] elevation or muscle cramping, and they don't always think it's immune-mediated."

Revolutionizing Cancer Treatment

Commenting on the study for Medscape Medical News, Avi Fellner, MD, professor in the Department of Neurology at Rabin Medical Center in Petah Tikva, Israel, noted that the field of immunotherapy in cancer is rapidly evolving and immune checkpoint inhibitors have "revolutionized" cancer treatment in recent years.

Nevertheless, he said, the growing use of these agents is associated with an increasing number of reports on neurologic immune-related adverse effects, the diagnosis of which may at times can be "very challenging."

"This study emphasizes the need to keep in mind the possibility of immune checkpoint inhibitors–related neurological adverse effects and the importance of early recognition and aggressive treatment in these cases," said Fellner, lead author of a similar study that reported nine cases of neurologic complications associated with use of checkpoint inhibitors.

His report includes patients who developed meningoencephalitis, limbic encephalitis, polyradiculitis, cranial polyneuropathy, and myasthenic syndrome (J Neurooncol. 2018;137:601-609).

Fellner and colleagues also pointed to the heterogeneity and seriousness of the presentations, two of which proved fatal.

Other specialties outside of neurology are also reporting conditions associated with use of checkpoint inhibitors, including new-onset connective tissue diseases and inflammatory arthritis. The American Society of Oncology and the National Comprehensive Cancer Network, recognizing the adverse events associated with these agents, released joint guidelines for treating checkpoint inhibitor toxicities in February 2018.

Juster-Switlyk and Fellner have disclosed no relevant financial relationships.

American Academy of Neurology (AAN) 2018 Annual Meeting. Abstract P4.161. Presented April 25, 2018.

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