Immune Checkpoint Inhibitor Neuromuscular Complications

A collaborative approach to multidisciplinary care that maximizes shared expertise from multiple subspecialities is critical for diagnosis and management of neuromuscular (NM) immune-related (ir) adverse events (AEs) of immune checkpoint inhibitors (ICIs). In this review, we discuss benefits of multidisciplinary collaboration, including pretreatment risk assessment and counselling, clinical monitoring, early diagnosis of NM and overlapping multisystem immunotoxicities, balancing treatment decisions to optimize NM and oncologic outcomes, and risk-benefit evaluation of potential retreatment with ICIs after a NMirAE.

Overview of ICIs and NMirAEs

Suppression of the intrinsic immune checkpoint system with ICIs increases immune activity with resulting antitumor effects that are therapeutically beneficial,¹ leading to approval for an ever-expanding list of oncologic indications. ICIs are classified by specific targets, including cytotoxic T-lymphocyte antigen 4 (CTLA-4, ipilimumab), programed cell death protein 1 (PD-1, nivolumab, pembrolizumab, cemiplimab, and dostarlimab), and programmed cell death ligand 1 (PD-L1, atezolizumab, avelumab, durvalumab) inhibitors. ICIs are often used in combination and with other treatment modalities (eg, chemotherapy, targeted therapy, or radiation therapy).

Disruption of immune homeostasis, however, commonly results in off-target effects, causing irAEs that can affect any organ or tissue, including the central and peripheral nervous systems (CNS and PNS).¹ Serious irAEs (defined as grade 3 or 4, using the National Cancer Institute’s Common Terminology Criteria for Adverse Events) occur in up to 30% of people treated with CTLA-4 inhibitors, 10% treated with PD-1 inhibitors, and over 50% treated with combination (CTLA-4 and PD-1/PD-L1) therapy.² Serious neurologic irAEs occur in approximately 1% to 2% of those treated,^3,4 and approximately two-thirds of those involve the PNS. Current incidence estimates are based on retrospective data lacking standard disease definitions and mild presentations are not included. With expanding indications for ICIs, NM disorder specialists will see an increasing number of NMirAEs, and an informed, multidisciplinary approach will become even more important.

NirAEs Consensus Definitions

To address variability in neurologic irAE evaluation and classification, consensus definitions (Figure 1) were recently published by a multidisciplinary group that included neurologists, oncologists, and irAE subspecialists. This framework guides diagnostic workup and classification. It also will facilitate clinical and translational research to develop targeted, evidence-based treatment recommendations.⁵ It is anticipated that oncologists will start a basic evaluation, possibly deciphering whether a CNS or PNS etiology is suspected, which the neuro-logists refine to move toward diagnosis and management.

Pretreatment Evaluation & Monitoring

Multidisciplinary collaboration (Figure 2) begins even prior to ICI administration in selected patients. Pretreatment NM consultation is warranted in those with a history of immune-mediated disorders (eg, myasthenia gravis [MG], myositis, and inflammatory neuropathies) or unexplained NM symptoms. Data regarding ICI outcomes for patients with pre-existing neurologic autoimmune disorders is limited. Specific risk of irAEs in this population is not well-understood. Individuals with pre-existing autoimmune disorders were excluded from ICI clinical trials, and so we must extrapolate from those with nonneurologic autoimmune disorders. Retrospective data analysis suggest these individuals are at increased risk of immunotoxicity, either through exacerbation of the baseline autoimmune condition, or development of de novo irAEs. Many irAEs will be mild, and treatable with corticosteroids, and continued ICI treatment will be possible.^6-9

For NM disorders specifically, a literature review identified 13 people with pre-existing MG who received ICI therapy, 8 of whom were maintained on some form of immunosuppression at the time of ICI initiation; 11 of the 13 patients experienced a flare of their MG, and 2 died as a result. Among those who had flares, 4 of 5 who were tested had elevated creatine kinase (CK) suggestive of a possible overlap ICI-related-myositis/MG.⁹

International consensus guidelines for MG¹¹ include discussing increased risk of serious irAEs in underlying MG with those who have MG and their oncologists before treatment. Well-controlled MG is not considered an absolute contraindication to ICI therapy. Considering the increased risk of severe irAEs with combination therapy, monotherapy may be preferred depending on oncologic context. People with MG should be medically optimized to a “minimal manifestations” status before starting ICIs, if possible. For those using immunosuppressive therapy (IST), continuation or substitution with an alternate treatment is preferred while taking ICIs. People with MG who are asymptomatic and not currently using IST may consider concurrent treatment, particularly if their MG has previously been severe, understanding the potential risk of undermining the antitumor effect of the ICI. After starting ICI therapy, those with MG should be closely monitored for development of new weakness, with particular attention to bulbar and respiratory function. A similar approach applies to other immune-mediated NM disorders.

At present, nonselective screening of all persons considering ICI therapy for antibodies to the acetylcholine receptor (antiAChR) or other autoantibodies is not recommended. Notably, people with antiAChR⁺ vs antiAChR^– thymoma without clinical signs or symptoms of MG appear to have increased risk of ir-myositis but not ir-MG.¹³ Therefore, in our practice, we recommend screening for relevant antibodies in people with cancers associated with high rates of paraneoplastic NM disorders (eg, antiAChR⁺ thymoma or antibodies to P/Q type voltage gated calcium channels antibodies in small cell lung cancer) before ICI treatment, even if there are no NM symptoms. These individuals may be at heightened risk of any irAE, although this remains an area of investigation.

Diagnosis of Neurologic irAE

Neurologic irAEs can be difficult to recognize and diagnose. Typically, those with severe NMirAEs first present to their oncology team members or the emergency department. Symptoms (eg, dyspnea, fatigue, trouble walking, and generalized weakness) are vague and nonspecific. A high degree of suspicion for and familiarity with NMirAEs is needed to distinguish nonspecific symptoms from other treatment effects or the underlying cancer. Some “textbook” features of classic NM syndromes may be lacking; clinical presentations of NMirAEs differ significantly from their idiopathic counterparts. For example, ir-myositis frequently involves ocular and bulbar muscles, which is rare in other inflammatory myositis, and creatine kinase (CK) or electrodiagnostic studies can be normal in some cases. The incidence of antiAChR⁺ is lower than in idiopathic generalized MG.¹² Fluctuating, fatigable weakness characteristic of NM junction dysfunction is also often absent in ir-MG,¹² particularly when ir-MG and ir-myosytis are overlapping. In a systematic review, diagnostic inaccuracies were noted in 22% of reported NMirAEs.¹² Patients with elevated CK may also have elevated liver enzymes (ie, aspartate transaminase and alanine transaminase). If CK and gamma-glutamyl transferase are not tested, ir-hepatitis may be erroneously diagnosed, which can lead to NMirAE diagnostic delay. Similarly, for those with elevated troponin, CK should be checked and ir-myocarditis considered in addition to coronary artery disease and other causes of elevated troponin.

NMirAEs frequently overlap with nonneurologic irAEs, underscoring the need for a collaborative multidisciplinary approach. In a case series, the most common reasons for hospitalization with irAEs were colitis, pneumonitis, and hepatitis, and 25% of patients had more than 1 irAE at admission. In another series, 50% of patients had additional organ system irAEs, and in a systematic review, half the fatalities from severe irAEs were neurologic and/or cardiac, with frequent overlap of those systems.¹³ Myocardial involvement is reported in 30% of ir-MG, ir-myositis, and overlapping ir-MG/ir-myositis cases.¹⁴ In cases with overlapping, fatal ir-myositis and ir-MG, autopsy results show T-cell inflammatory infiltrate involving striated muscle (ie, cardiac and skeletal) and primary tumor, with clonal high-frequency expression of shared T-cell receptors at these sites.¹⁵ Expression of muscle-specific antigens (eg, desmin and troponin) is high in tumor tissue, suggesting this severe toxicity may be mediated by T-cell targeting of an antigen in both striated muscle and tumor.¹⁶

Myocardial involvement, in addition to a high frequency of respiratory skeletal muscle involvement, likely explains the high mortality rate from NMirAEs reported,¹³ estimated at 20% with ir-MG.^9,14 Initial presentation of potentially fatal myocardial involvement, however, can be as seemingly benign as pure ocular symptoms (eg, ptosis, diplopia),¹⁷ or myalgias.¹³ Early recognition of subclinical myocarditis with early initiation of IST may prevent subsequent significant cardiac events, including arrythmia. Diagnostic delays and delayed initiation of IST are risk factors for death from irAEs.¹⁸ Close collaboration among neurologists and cardiologists familiar with NMirAEs is essential. Approximately 20% of NMirAEs will have additional, noncardiac irAEs (eg, thyroiditis, hepatitis, hypophysitis, or colitis),requiring collaboration with other medical subspecialists to determine the optimal treatment strategy.

Alternate etiologies must be rigorously evaluated in this medically complex patient population. Symptoms caused by metastatic disease, opportunistic infections, or other treatment modalities may be misattributed to neurologic irAEs. A study evaluating referrals to a dedicated immunotoxicity service for suspected neurologic irAEs found only 30% were ultimately felt to have confirmed irAEs compared with 87% of suspected gastroenterology irAEs and 64% of suspected pulmonary irAEs. Alternative diagnoses were identified in many cases,¹³ further emphasizing the importance of interdisciplinary collaboration between specialists with expertise in the field of irAEs.

Treatment of NMirAEs

NMirAE management is guided by consensus statements from major oncologic associations,^19-21 that recommend holding the ICI and possibly initiating corticosteroids and/or other immunomodulatory agents, depending on the severity of the irAE. For NMirAEs, mild toxicity may be managed by holding or discontinuing the ICI. More typically, however, an oral prednisone taper over several weeks is required. For more severe toxicities, we combine this taper with pulse methylprednisolone initially. Corticosteroids combined with intravenous immunoglobulins (IVIG) or therapeutic plasma exchange (TPE) are used for life-threatening NMirAE (eg, ir-MG with or wihout myositis or grade III-IV neuropathy). Additional IST in the form of steroid-sparing agents (eg mycophenolate mofetil or rituximab) or more targeted IST may also be indicated, with drug selection based on the underlying immunopathology.²² The choice of steroid-sparing agent is based on anecdotal evidence at this time. Intensity, duration, and selectivity of IST depends on the clinical syndrome, presence of other organ system involvement, and the underlying malignancy. Selection and clinical monitoring relies on close communication between the primary oncologist and treating subspecialists. Oncology providers typically see patients before each ICI treatment cycle. Communication with these providers can provide insights to a patient’s status between NM visits.

Treatment intensity is typically dictated by the most severe irAE (eg, control of concurrent ir-myocarditis frequently determines the rate of corticosteroid taper in ir-myositis). Therapies such as IVIG, TPE, or mycophenolate mofetil may be considered to treat all elements of an irAE. Abatacept is a promising CTLA-4 agonist under investigation for the treatment of refractory ir-myocarditis, with its impact on concurrent NMirAEs also yet to be determined.²² Ensuring that therapeutic interventions align with the patient’s goals of care requires thoughtful discussion between patients, families, oncologists, and other subspecialists.

Effect of NMirAEs and IST on Oncologic Outcomes

ISTs may negatively impact the intended antitumor effect of ICIs and require individualized risk-benefit assessment. In some cases, irAEs are a surrogate marker of treatment efficacy; dermatologic, gastrointestinal, and endocrine irAEs correlate with improved tumor response rates in a variety of solid malignancies.²⁵ Excessive suppression of the immune response with IST, particularly before initiating ICIs, may negate the desired effect. Tumor response rates are significantly lower in patients on IST at the time of ICI initiation.⁷ People with melanoma who had ir-hypophysitis treated with relatively higher vs lower steroid doses had worse overall survival rates.²⁵ Using the lowest effective IST dose for the shortest possible duration is a reasonable guiding strategy. In persons without paraneoplastic antibodies or a defined autoimmune disease, corticosteroid taper can typically be done more rapidly than in idiopathic disease. We attempt taper to discontinuation in 4 to 8 weeks.

Rechallenging With ICIs After a Neurologic irAE

Data guiding ICI rechallenge are sparse and retrospective. The decision to rechallenge with an ICI after an irAE depends on many factors, including the severity of the initial irAE, tumor response to the ICI, and the availability of alternative treatment options.²⁶ Retrospective studies have examined risk of new or worsening irAEs after rechallenge with ICI (typically a different class, often switching from antiCTLA-4 to anti-PD1/PDL1 therapy) among those who had significant irAEs with initial ICI treatment.^7,8,26-29 Risk of a new or recurrent irAE appears to increase by 30% to 50% after a prior irAE. The majority of those irAEs were mild and treated effectively with steroids and, in many cases, did not lead to permanent discontinuation of ICI therapy. The most common cause of death in these individuals remains cancer progression. Severe and fatal irAEs, however, have been reported in the context of ICI retreatment.^7,26,27

Retreatment data are more limited for NMirAEs considering there is more caution for rechallenge in these potentially fatal cases. In 7 cases of fully resolved ir-neuropathy without IST at the time of ICI rechallenge, 4 had relapses with or without new irAEs.^30,31 In 6 reported cases of ir-MG with subsequent ICI rechallenge, there were no reported relapses, but all patients had maintenance steroid treatment with or without IVIG at the time of rechallenge.⁹ Several small retrospective case series have described safely rechallenging with ICI after severe irAEs alongside infliximab (in ir-enterocolitis)³² or tocilizumab (in cases of ir-arthritis).³³ Primary and secondary prevention of NMirAEs with more selective IST is an area of active research.

In certain cases, rechallenge with an ICI may be relatively safe but not pursued because of limited anticipated anticancer benefit. This requires thoughtful oncologic expertise. In a study of people with melanoma treated with ipilimumab/nivolumab combination therapy, progression-free survival and overall survival were similar in those who discontinued therapy during the induction phase due to adverse events vs those who continued treatment.³⁴ These data suggest that irAEs, as a surrogate marker of vigorous antitumor immunity, may be predictive of an enduring benefit from ICIs without the need for retreatment in select cases.

In summary, limited data regarding the risks and potential benefits of rechallenge with ICI therapy mean that this difficult decision is necessarily made in conversation with the patient, their oncologist, and multiple other specialists, as indicated. The threshold for rechallenge with ICIs after NMirAEs is much higher than for other forms of immunotoxicity, considering the high burden of morbidity and mortality associated with these specific irAE subtypes.

Multidisciplinary Care Improves Care

Academic medical centers increasingly have developed structured multidisciplinary “immunotoxicity” teams over the past 5 years. Typically, team members include oncology, neurology, cardiology, gastroenterology, pulmonology, dermatology, nephrology, endocrinology, and rheumatology. Teams collaborate on both acute inpatient irAEs and outpatient cases.^35,36 Real-time case discussion aimed at providing multidisciplinary recommendations within 24 hours of referral has been facilitated with a password-protected electronic messaging forum.³⁷ At our institution, templated urgent referral requests and clinical documentation in the electronic health record are standardized. We have a dedicated inpatient severe immunotherapy complications service with improved outcomes and reduced utilization of healthcare resources.³⁶

Conclusion

NMirAEs are a unique clinical challenge requiring a collaborative, multidisciplinary approach to prevention, identification, management, and subsequent risk stratification. Immunotoxicity teams have been created to meet this challenge and advance research efforts. Considering the increasing numbers of cancer patients eligible for ICI treatment, a growing need exists for this service. Optimal strategies for orch-estration of care at the health system and regional levels, however, remains unknown. Additionally, collaboration between various stakeholders including academic researchers, industry, and regulatory authorities will be needed to facilitate the open sharing and understanding of irAE data, with the goal of advancing understanding of the underlying mechanisms, risk factors, biomarkers, and evidence-based treatment.