Findings from a retrospective cohort study suggest that immune checkpoint inhibitors (ICIs) can be considered for patients with preexisting neurologic autoimmune disorders (NAIDs) at risk of disease-related exacerbationswhen oncologically indicated, although use in patients with myasthenia gravis warrants particular caution due to a higher risk of clinically severe exacerbations, according to Shailee S. Shah, MD.
Shah and colleagues conducted a retrospective study to assess the safety and clinical outcomes of ICI therapy in patients with NAIDs (n = 135). These included multiple sclerosis (n = 45), myasthenia gravis (n = 18), Guillain-Barré syndrome (n = 10), and Parkinson’s disease (n = 57), which served as the control cohort.
Data published in JAMA Network Open demonstrated that NAID exacerbations were most frequently observed in patients with myasthenia gravis (67%) and were often severe, with 50% requiring hospitalization and 17% resulting in death. In contrast, patients with multiple sclerosis experienced a lower rate of exacerbation (18%). There were no significant differences in response rate, progression-free survival (PFS), or overall survival (OS) across NAID subgroups.
“This tells us that although the risk [of NAID exacerbation] is somewhat heterogeneous across different neurologic disease types, these patients are going to require monitoring from both oncologists and neurologists even prior to ICI initiation” said Shah, a clinical assistant professor of Neurology (MS/Neuroimmunology) at Northwestern University Feinberg School of Medicine in Chicago, Illinois.
In an interview with OncLive®, Shah explained the rationale for conducting this study; discussed variations in ICI outcomes and the frequency and severity of NAID exacerbation by underlying condition; and emphasized the importance of multidisciplinary collaboration and individualized risk-benefit assessments to manage these patients effectively.
Shah: As we know, ICIs are being increasingly used in a number of different cancer types. The number of indications continues to grow, and these agents are highly efficacious in patients who typically have metastatic cancers. They work by blocking negative regulatory checkpoints that prevent T-cell activation. By unleashing those T cells, we induce cytotoxic cancer cell death.
Generally speaking, that is how these drugs work, and their on-target effects are as desired. However, it is when they have off-target effects or adverse effects [AEs]—specifically immune-related AEs [irAEs] affecting different organs of the body, and in our case, the neurologic system—that patients run into issues.
We know that these complications can occur, are immune-mediated in nature, and can occur de novo. What we did not know was whether patients who already have immune system dysregulation, or disorders in which they already have autoimmunity, whether in the past or as an ongoing issue, would worsen or be at risk of worsening if given these treatments. That was the rationale.
Some smaller studies have looked at some of these disease states individually, such as myasthenia gravis or multiple sclerosis, but we wanted to compile additional disease states and include a larger group of patients to better understand their outcomes upon receiving immune checkpoint inhibitors.
This was a multicenter retrospective cohort study. We included patients who had cancer or who were being actively treated for cancer with an ICI between 2013 and 2023. These were patients with cancer being treated with ICIs who had a known preexisting neurologic disease.
Specifically, we were interested in looking at multiple sclerosis, myasthenia gravis, and Guillain-Barré syndrome, as well as Parkinson's disease as a neurologic disease control that is not immune-mediated, unlike the others mentioned.
Not only were we looking at neurologic outcomes, but we were also assessing any other irAEs in other systems. Additionally, we evaluated patients’ OS and outcomes in terms of their cancers.
We identified a total of 135 patients, with a [median] age of 72. Sixty-two percent of these patients were male. There were several different cancers associated with these patients with neurologic diseases. [These included] melanoma, non–small cell lung cancer, urothelial cancer, and others. The vast majority of these patients had stage IV disease. Another important piece of information is that most of them received monotherapy with the ICI.
In terms of baseline characteristics, these patients were quite heterogeneous. Many of the patients with Parkinson’s disease and multiple sclerosis, as expected, had more baseline disability compared with those with myasthenia gravis. The likelihood of being on an immunosuppressive treatment varied.
This [analysis comprised] a total of 25 patients from all of the immune-mediated disease cohorts. Thirty-two percent of these patients were receiving or had recently received some sort of immunosuppressive or disease-modifying treatment within 3 months of actually getting their ICI. Most often, this was in patients with multiple sclerosis or myasthenia gravis, and more commonly in myasthenia gravis. We looked at the safety of these ICIs in these patients and the development of any exacerbations in their underlying diseases.
The main takeaway was that 8 of the 45 patients developed symptoms that were related to their [underlying condition]. However, of those 8, only 2 had known active inflammatory disease that developed after receiving an ICI. The other 6 patients were thought to have developed pseudo-relapse, or the recurrence of symptoms they previously had. When this happens in a disease like multiple sclerosis, it is usually in the context of a toxic-metabolic derangement, changes in medications, new medical issues, or active infections.
An area of interest is the occurrence of these AEs in patients with multiple sclerosis who are younger. Most of the patients in our multiple sclerosis cohort were older. Typically, as patients [with multiple sclerosis] age, the likelihood of [developing] active inflammatory disease or ongoing development of new plaques decreases, particularly after the age of 65. For these purposes, we looked at whether patients younger than 50 were more likely to have new or enhancing lesions. There were 3 patients [younger than] age 50, and only 1 of those patients developed new symptoms. Even that patient, who did develop a new demyelinating lesion, was able to continue on their ICI therapy and was treated with steroids at the same time.
Of the 18 patients who had myasthenia gravis, 12 experienced a relapse. It seemed like patients actively on immunosuppressive treatment were a bit less likely to have exacerbations than those who were not, but these were small cohorts of patients, and there was no statistically significant difference.
The type of AEs that occurred varied, but 50% of these patients did have more severe exacerbations, were hospitalized, and required the use of immunosuppressive treatment. Of those, 56% discontinued their ICI afterward. One patient was rechallenged after starting an immunosuppressive treatment and seemed to do well subsequently. Unfortunately, 2 patients died as a result of, in part, myasthenia gravis and the worsening that occurred.
The takeaway is that although ICIs can be used safely [in this patient population], we still don't yet know [for] whom that is going to be the case. Overall, the likelihood of a relapse or severe worsening is relatively high [for patients with myasthenia gravis]. We have to be very careful when considering ICIs for these patients.
It is worth noting that the vast majority of those who continued their ICIs did achieve a good response in terms of their cancer, with durable responses [spanning] several years. Weighing those 2 things will be important when talking to patients with myasthenia gravis and deciding whether or not an ICI is an appropriate drug for them when treating their cancer.
[One of] the other disease states that was looked at was Guillain-Barré syndrome. In general, the thought is that these patients are not at increased risk of developing the same syndrome again. There was no exacerbation of known prior neurologic disease [with ICIs] for these patients, and that was in line with what we expected. Interestingly, in these patients and several others, there were [several] other immune-mediated AEs that occurred, both neurologically and non-neurologically. This does bring into question whether or not there's an underlying predisposition toward autoimmunity in these patients as a whole.
We also evaluated patients with Parkinson's disease. Although we would not necessarily expect them to have any exacerbations with ICIs, this is something that comes up in the oncology world with the administration of chemotherapeutics or immunotherapies. We found that although patients did seem to have worsening of their Parkinson's disease, there were no serious AEs. [For] many of these patients, [their Parkinson’s disease] was managed medically. There were mild symptoms related to their known Parkinson’s symptoms that could get slightly worse, but were [primarily] unaffected by ICIs.
Lastly, the clinical outcomes in terms of patients' cancers were no different between the different [underlying disease cohorts]. Many of them did have OS, and the OS and PFS were no different between the groups, regardless of whether they had a neurologic iRAE or not, in terms of their cancer.
Although this was one of the largest studies looking at patients with preexisting autoimmune neurologic diseases and the use of ICIs, it is still a relatively small patient population. Following these patients across multiple institutions for a longer period…and trying to understand specific risk factors for exacerbations and then optimizing those prior to cancer treatment is going to be important moving forward.
Patients who have more active inflammatory disease that is uncontrolled are potentially at higher risk for developing an iRAE, but we will need to investigate that further in prospective trials. To some extent, there are some reassuring data here that not every NAID necessarily exposes patients to exacerbation. Guillain-Barré syndrome, in particular, is useful for oncologists to be aware of, as we are not necessarily worried that it is going to worsen.
In the future, [an improved] understanding of patients with multiple sclerosis and their risk of relapse [after ICI therapy] is going to be important. The biggest [subset we’re] actively looking at is in patients younger than 50 years of age, who may have more active inflammatory disease.
Ultimately, identifying patients with neurologic diseases who are at risk of having disease-related exacerbations when using ICIs is going to be the main focus of future research. Developing risk stratification criteria or scoring systems may be useful for these patients. This will require neurologists and oncologists to work together closely in multidisciplinary clinics to prospectively follow these patients.
The 2 main limitations are that this [was a] retrospective [study] and that each individual neurologic disease cohort was still relatively small. [We] collected data from multiple centers with patients who've been taken care of by different providers. One other main limitation would be that some of these centers do not have access to neurologic expertise. That may limit the evaluation that has been done and can be done for these patients. What this study emphasizes, though, is that [neurologic expertise] will be increasingly needed for these sorts of patients.
[For a] patient with a new cancer and a known neurologic disease, engaging their neurologist early on is going to be important, [as will] making sure that [disease management] is optimized from that perspective, and then having a discussion [about] the risks and benefits and potential outcomes between all these different groups. [It is necessary to] help inform the patient and their providers about what the next steps would be best.
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