More than a decade into the remarkable era of cancer immunotherapy, we are facing major challenges with the toxicities of the revolutionary immune checkpoint inhibitor (ICI) therapies. While ICIs have substantially improved survival rates for melanoma and lung cancer among other malignancies, we are in the nascent stage of understanding and management of their adverse events. Imagine an oncologist administering chemotherapy without access to effective antiemetics, myeloid growth factors, blood products, or antibiotics or administering antiangiogenic therapy without the ability to give antihypertensives. Or consider epidermal growth factor receptor inhibitors without antidiarrheal agents. Any of these scenarios represents incomplete care, posing a threat to patient well-being and limiting therapeutic potential. This is the current state of medical care for patients with immune-related adverse events (irAEs).

IrAEs represent an entirely new set of clinical considerations to oncology professionals. Unlike the highly predictable and readily diagnosed toxicities of conventional chemotherapy and molecularly targeted therapies, irAEs may affect almost any organ system and occur at almost any point during—and even occasionally after—treatment.1 Although high-grade toxicities are less frequent with ICI compared with conventional chemotherapy, many higher-grade toxicities from chemotherapy, such as neutropenia or thrombocytopenia, may be asymptomatic and may not require acute intervention. In contrast, high-grade ICI toxicities usually require hospitalization.2 Further, although rates of therapy discontinuation due to toxicity may be lower with ICI compared with chemotherapy, when higher-grade ICI toxicity occurs, the diagnostic uncertainty and management considerations make these cases more challenging. Depending on irAE type and severity, management may entail withholding or permanent discontinuation of checkpoint inhibitors, as well as administration of immunosuppressive agents. However, there is a lack of any formal US Food and Drug Administration (FDA) approvals for irAE treatments in part due to these toxicities representing a new disease state in patients rather than a typical acute oncology adverse event like nausea and vomiting. This is where both patients and clinicians desperately need more information and guidance. Guidelines for irAE management are currently primarily based on retrospective data and expert consensus. This is a similar approach that was initially taken with older treatment-related toxicity like cytopenias, rash, mucositis, and diarrhea.

Corticosteroids, the widely used first-line approach to irAE treatment, convey their own substantial adverse effects, including but not limited to the risk of venous thromboembolism, mental status changes, glucose intolerance, fracture and opportunistic infection, even for short-term use.3 Moreover, the optimal dosing and duration of steroids in this setting is unclear. While multiple steroid-sparing irAE treatments exist for patients, clinical teams may not understand their use, or they may face substantial barriers to accessing these therapies.4

For example, in the case of ICI-colitis, one of the most common irAE that requires hospitalization, monoclonal antibodies such as infliximab (a tumor necrosis factor inhibitor) and vedolizumab (an α4β7 integrin inhibitor) are widely recommended as first-line and second-line treatment.5–7 Nevertheless, clinicians may face numerous hurdles to administering these agents that include the (1) requirement for payor pre-authorization prior to administration; (2) restriction of prescribing authority to a narrowly defined medical specialty; and (3) denial of coverage.

From a clinical perspective, steroid-refractory colitis can present a greater medical urgency than a newly diagnosed or even a progressing malignancy. Requiring a care team to obtain pre-authorization for appropriate medication can result in delays with major medical complications. Similarly, insisting that a gastroenterologist prescribe vedolizumab (as has occurred in our practice) may lead to significant morbidity. The cost of these monoclonal antibodies is prohibitive: several tens of thousands a year, rendering patient self-pay unrealistic.8 Payors generally link coverage decisions to formal regulatory approvals. While infliximab and vedolizumab are FDA-approved for inflammatory bowel disease, there is no specific approval for irAE colitis or any other irAEs. Since irAEs represent a novel syndrome that may last in patients for the rest of their lives, conducting trials maybe even more complicated.

This barrier is exacerbated by the fact that each distinct irAE represents a relatively uncommon occurrence, rendering clinical trials in this setting impractical. In contrast, chemotherapy-associated nausea and vomiting occur commonly and are managed both from preventive and therapeutic angles. As a result, there is a robust clinical trial literature for novel anti-emetics.9 In contrast, therapeutics for irAE are repurposed from existing treatments, and there is no incentive to study these drugs in this setting as financial incentive for pharmaceutical companies is lacking.

Recognizing these ongoing and substantial challenges, we propose a multipronged approach to improving the treatment and outcome of irAE (table 1).

Table 1

Practical barriers to effective irAE treatment and proposed solutions

Pursue clinical trials of irAE diagnosis and treatment

Ongoing examples include, glucocorticoids, vedolizumab, infliximab, and tofacitinib for colitis (NCT04407247, NCT04797325, NCT04768504), infliximab and introavenous immunoglobulin infusions (IVIG) for pneumonitis (NCT04438382), and abatacept for myocarditis (NCT05335928).10 While studies of these agents are difficult to conduct; considering these conditions are rare diseases, small trials might support approvals. As a corollary, translational research efforts to develop biomarkers for irAE prediction, diagnosis, and management also represent crucial research initiatives.

Increase ability to recognize and diagnose irAE

While physicians, advanced practice providers (APPs), and nurses are learning to recognize and diagnose these toxicities over time, education for healthcare workers remains essential for an understanding of irAE recognition and diagnosis. Furthermore, specific interventions such as modifying clinic nursing intake forms to include potential irAE-related questions, and programs to educate oncology prinicipal investigators (PIs) on the importance of considering irAE recognition and diagnosis in their research programs may be beneficial. These educational initiatives should be a collaborative approach with oncology, emergency departments, APPs, nurses and required subspecialties to ensure cohesive and uniform educational platforms. In addition, many academic oncology centers are establishing dedicated multidisciplinary irAE clinics for the diagnosis and management of complicated cases.

Create an irAE community

Advocacy organizations have improved awareness, education, research, and outcomes of multiple cancers and non-malignant conditions, including autoimmune diseases. Standing Together to Optimize Research, Interventions, and Educations in irAEs (STORIES) serves as a community for patients and caregivers. The Alliance for the Support and Prevention of Immune-Related Events (ASPIRE) is a research consortium dedicated to all irAE research. Together, these two groups represent an emerging grass roots effort recently encapsulated at the inaugural meeting of ASPIRE and STORIES.11 This event, held at the Cleveland Clinic in March 2024, brought together patients, clinicians, and researchers from multiple backgrounds with the goals of creating a national research consortium and an advocacy non-profit organization. The irAE Consortium is currently working on amending the irAE International Classification of Diseases, 10th Revision (ICD10) codes to have an immunotherapy modifier. This proposal has been approved and is expected to be available in the fall of 2024. Thus, rather than creating new ICD 9/10 codes for every irAE, a modifier of an existing code will support more rapid identification of and better algorithms for irAE in the electronic health record. For example, if the patient has ICI-induced pneumonitis, the physician would code for pneumonitis and add the “irAE” modifier. This modifier will be live in October 2024. Ultimately, the irAE Consortium envisions the integration of ASPIRE and STORIES into existing clinical and research societies to advance irAE treatment and investigation. Next year’s irAE Consortium meeting, planned for March 2025 at Duke University, welcomes interested individuals from across specialties to come together and move the field forward.

Promote an accepted source of treatment recommendations

For coverage of cancer treatments, public and private payors recognize National Comprehensive Cancer Network (NCCN) compendia as authoritative references. Similar adoption of the NCCN compendium derived from the Management of Immune Checkpoint Inhibitor-Related Toxicities Guidelines would provide a consistent approach to coverage. In routine oncology practice, some cancer therapies can be given emergently without prior approval if the pharmacy or supportive staff are able to predict if the therapy will be approved based on expert guidelines. A similar approach could be taken to allow urgent access to potentially lifesaving irAE treatments. While the NCCN does have irAE guidelines, American Society of Clinical Oncology (ASCO) and Society for Immunothrapy of Cancer (SITC) also have irAE guidelines, and these guidelines are all slightly different, and all important. However, as more subspecialists who are not oncologists are needed to help manage these patients, it is confusing to know which guidelines should be followed. Also, the payors can take advantage of the discrepancies to continue to make drug access difficult for patients. The goal of the ASPIRE consortium will be to highlight the differences and bring these guidelines together.

Develop assistance programs

Multiple pharmaceutical companies support patient assistance programs that provide access to cancer treatments that would otherwise not be available due to lack of insurance approval or high co-pays.12 Comparable programs for irAE treatments would provide similar access to potentially life-saving medications.

Consider the big picture

While the measures suggested above may eventually enhance irAE management, they will take time. In the interim, payors need to recognize the clinical, ethical, and economic reasons to provide access to effective irAE treatments. Covering irAE treatments may ultimately be cost-saving, as delaying or denying access could result in or lengthen hospitalization. Compared with chronically administered checkpoint inhibitors, even highly costly irAE therapies are likely to convey a relatively small, additional expense.

As the use of immunotherapy extends to earlier-stage cancers and indications for combination immunotherapy regimens expand, the incidence and clinical significance of irAE will only increase. It is essential that clinicians managing irAE and patients experiencing these events have access to the full range of effective treatments. Achieving this requires creative and nimble approaches, as prospective large randomized clinical trials and formal FDA approval for the spectrum of irAE treatments are not practical or realistic expectations for most irAEs. The involvement of key stakeholders including professional societies, patient advocacy groups, regulators, and pharmaceutical companies is necessary to address persistent barriers to optimal irAE management.

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