Management of Steroid-Refractory Immune-Related Adverse Events

Marley L. Watson, PharmD, BCOP

Tyler Beardslee, PharmD, BCOP

Introduction

The development of immune checkpoint inhibitors (ICIs) has led to an instrumental transformation in the treatment of cancer. The only US Food and Drug Administration (FDA)-approved ICIs include cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4)-CD28, programmed death 1 (PD-1), and programmed death ligand 1 (PD-L1) inhibitors. The ever-increasing utilization of these agents including combination regimens (CTLA-4 and PD-1 inhibitors) has presented a novel set of immune-related adverse events (irAEs) that have proven to be extremely challenging to manage in some cases. Based on the mechanism of ICIs, irAEs can affect any organ system in the body at any time during treatment with varying grades of severity. Due to the complexity of these toxicities, an experienced multidisciplinary team is critical to provide optimal treatment recommendations.

Current guidelines have assisted in standardizing the approach to managing irAEs, accentuating the importance of early recognition and preventing delays by initiating immunosuppressive treatment prior to ruling out other potential diagnoses. For more severe irAEs, the guidelines generally recommend initiating corticosteroids (prednisone 1–2 mg/kg/d or equivalent) as first-line treatment. If no improvement is observed after 2 to 3 days, then the irAE may be considered steroid refractory and require increased immunosuppression with other medications. Due to the limited number of clinical trials focusing on steroid-refractory irAEs, most of the data supporting the use of additional immunosuppressive agents are provided by case series, case reports, and expert opinions. This article will focus on three of the most common irAEs seen in clinical practice including immune-related colitis, hepatitis, and pneumonitis.[1–6]

Immune-Related Colitis

Gastrointestinal toxicities are one of the most common irAEs reported in patients receiving ICIs. A systematic review reported the incidence of immune-related colitis among solid tumor patients receiving ICIs and found the overall incidence with CTLA-4 inhibitor ipilimumab was 9.1% for all-grade colitis.[7] Monotherapy PD-1/PD-L1 inhibitors had the lowest incidence at 1.3% for all-grade colitis, while combination CTLA-4/PD-1 inhibition had the highest incidence of all-grade colitis at 13.6%.[7] Symptoms of colitis include watery diarrhea, cramping, urgency, abdominal pain, blood and mucus in the stool, and fever.[1–3,8] The onset of these symptoms more commonly occurs 5 to 10 weeks after ICI initiation. These symptoms, however, can occur or even reoccur months after ICI discontinuation and can sometimes emulate inflammatory bowel disease.[1,3,9]

High-dose corticosteroids are the initial treatment recommendation for high-grade colitis. If no response is seen to corticosteroids after 2 to 3 days, then gastroenterology should be consulted and escalating drug immunosuppression utilizing a tumor necrosis factor inhibitor should be considered. Current guidelines suggest the initiation of infliximab at 5 to 10 mg/kg. The duration of treatment is not well defined, but most patients require only 1 dose [1–3]. If a second dose is required, it should be administered 2 weeks after infliximab initiation. For patients deemed infliximab refractory or who have a contraindication to infliximab (perforation, sepsis, tuberculosis, New York Heart Association class III/IV congestive heart failure), recent case reports have suggested utilizing vedolizumab, an integrin antagonist targeting α4β7 integrin. Due to vedolizumab’s more direct immune suppression to inflamed gastrointestinal mucosa, there is speculation it may not induce systemic immunosuppression, thus potentially improving long-term morbidity and preserving the antitumor immune responses. [2–4,10–12] Mycophenolate mofetil and tacrolimus have also been reported as potential treatment options for steroid-refractory colitis.[4]

Additional Considerations With ICI-Induced irAEs
• ICI-induced irAEs are more common with combination therapy and may occur at any time during treatment including after discontinuation of the ICI.
• Such irAEs require early recognition and initiation of immunosuppressive treatment. Also, irAEs may not respond to corticosteroids and require additional drug immunosuppression.
• Recommended testing prior to infl iximab use includes hepatitis B and C virus, and latent/active tuberculosis. Do not delay infl iximab treatment for severe or refractory irAEs for tuberculosis testing.
• Infliximab is not recommended in the treatment of immune-related hepatitis.

ICI = immune checkpoint inhibitor; irAEs = immune-related adverse events. Source: Ref 1–4,7,19

Immune-Related Hepatitis

Hepatic toxicity related to immune therapy is slightly less common than immune-related colitis and is often less severe.[13] The incidence of immune-related hepatitis is highest in combination therapy with dual CTLA-4/PD-1 inhibition. With combination therapy, 29% of patients experienced all-grade hepatitis and 17% experienced severe hepatitis. Ipilimumab monotherapy results in immune-related hepatotoxicity in 3% to 9% of patients, and immune-related hepatotoxicity is less prevalent in PD-1/PD-L1 monotherapy with just 0.7% to 1.8% of patients experiencing all-grade hepatitis.[2] The typical case of immune-related hepatitis occurs 5 to 6 weeks after initiation of ICIs, but immune-related hepatitis can occur at any time during ICI therapy. Other medications that have the potential to cause hepatotoxicity should be stopped in a patient experiencing hepatitis on ICIs. Histologic features are different in autoimmune hepatitis and drug-induced hepatitis, however, and imaging may also help distinguish this difference.[2,14]

As with other irAEs, high-dose corticosteroids are indicated in patients with immune-related hepatitis of grade 2 or greater. Early initiation of corticosteroids is key, and consultation with a gastroenterology specialist may be indicated for patients with irAEs that worsen or do not demonstrate improvement within 2 to 3 days of high-dose corticosteroid initiation. Infliximab should be avoided in this setting due to concern about liver toxicity. Mycophenolate mofetil dosed at 0.5 to 1 g every 12 hours is the recommended drug of choice in steroid-refractory immune-related hepatitis. Case reports and small studies have shown that calcineurin inhibitors may also be used in steroid-refractory immune-related hepatitis.[15,16]

Immune-Related Pneumonitis

Pneumonitis related to ICI therapy is relatively rare compared to immune-related hepatitis or immune-mediated colitis, but it carries a higher risk of fatality. Unlike with most other irAEs, the incidence of immune-related pneumonitis is less common with ipilimumab monotherapy than with PD-1/PD-L1 inhibitors, with 1% or fewer of patients experiencing immune-related pneumonitis with ipilimumab.[17] All-grade immune-related pneumonitis occurs in 5% or fewer of patients, and only 1% of patients experience severe immune-related pneumonitis with PD-1/PD-L1 inhibitors.[18] Up to 10% of patients receiving combination therapy may experience immune-related pneumonitis. It is important to rule out an infection or start antibiotics along with corticosteroids if an infection cannot be ruled out when diagnosing immune-related pneumonitis. Imaging with chest CT scans can be useful in diagnosing immune-related pneumonitis and monitoring response to treatment. Once immune-related pneumonitis is diagnosed, prednisone 1 to 2 mg/kg or equivalent should be initiated. If there is no improvement in pulmonary function within 2 to 3 days, then additional immunosuppression with infliximab 5 mg/kg, intravenous immunoglobulin 2 g/kg, or mycophenolate mofetil 1 to 1.5 g twice daily should be considered.[2]

Conclusion

Treatment options for irAEs are limited and still not well defined. Other potential immunosuppressive agents may become useful in the future based on immunopathologic patterns.[5] More clinical trials focusing on steroid-refractory irAEs, however, are critical to develop additional treatment options for these life-threatening and sometimes fatal toxicities.

Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

PERSPECTIVE

Immunosuppressive Drugs for the Management of irAEs: A Double-Edged Sword?

Ninh M. La-Beck, PharmD

The rapidly expanding repertoire of immune checkpoint inhibitors approved for the treatment of various cancers now include ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, and cemiplimab. In addition to activating antitumor immune responses, immune checkpoint inhibition can lead to activation of autoreactive T-cells resulting in unique immune-related adverse events (irAEs). Corticosteroids are the mainstay for treating irAEs, although a portion of patients are refractory to corticosteroids, and Drs. Watson and Beardslee summarize the immunosuppressive drugs that can be used in this scenario. As they have pointed out, there have been no prospective randomized trials comparing the efficacy of immunosuppressive therapies in mitigating irAEs and the current approach is largely based on case reports and expert opinions. One imperative question that is not addressed is whether corticosteroids and other immunosuppressive drugs can oppose the immunostimulatory activity of immune checkpoint inhibitors. A retrospective study in 604 non-small cell lung cancer patients treated with PD-1 or PD-L1 inhibitors found that progression-free survival and overall survival were significantly lower in those with baseline corticosteroid use > 10 mg, even after adjusting for smoking history, performance status, and history of brain metastases. While these results should be confirmed prospectively and in a larger cohort of patients, they support a potential pharmacodynamic drug interaction that may adversely impact clinical outcomes. Perhaps it is time to reassess when and how we use immunosuppressive drugs in the setting of concurrent immunotherapy aimed at stimulating antitumor immunity.

Financial Disclosure:Dr. La-Beck has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

Reference:
Arbour, K.C., et al., Impact of Baseline Steroids on Efficacy of Programmed Cell Death-1 and Programmed Death-Ligand 1 Blockade in Patients With Non-Small-Cell Lung Cancer. J Clin Oncol, 2018. 36(28): p. 2872-2878.

Disclosures:

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