Management of immune checkpoint inhibitor‐related adverse events: A review of case reports

Abstract Immune checkpoint inhibitors represent a major breakthrough in cancer therapy. Immune‐related adverse events (irAEs) may occur during treatment due to their unique mechanism of action. Management of irAEs is based on clinical experience because it is not easy to conduct prospective trials to evaluate the best treatment strategy. Using a combination of search terms in the PubMed and Embase databases, we reviewed all cases in the English language citing toxicities associated with either pembrolizumab, nivolumab, ipilimumab, atezolizumab, tremelimumab, durvalumab, avelumab or any combination of these agents published before 20 May 2019. A total of 128 reports with 239 cases were included in the study. Here, we summarize the spectrum of toxicities, safety in special patients, rechallenging after irAEs and agents used for treatment of irAEs in those reports.


Introduction
Immune checkpoint inhibitors (ICIs) represent a major breakthrough in cancer therapy. Immune-related adverse events (irAEs) may occur during treatment due to their unique mechanism of action. IrAEs are generally manageable but can be fatal in some cases. 1 Management of irAEs is based on clinical experience because it is not easy to conduct prospective trials, although professional groups have developed guidelines of management. Using a combination of research terms in the PubMed and Embase databases, we reviewed all cases in the English language citing toxicities associated with either pembrolizumab, nivolumab, ipilimumab, atezolizumab, tremelimumab, durvalumab, avelumab or any combination of these agents published before 20 May 2019. A total of 128 reports with 239 cases were included in the study. Here, we summarize the spectrum of toxicities, safety in special patients, rechallenging after irAEs and agents used for treatment of irAEs in those cases.

Toxicity profile
IrAEs occur in up to 90% of patients treated with an anti-CTLA-4 antibody and 70% of patients treated with a PD-1/PD-L1 antibody. 2 The profile of irAE was different for PD-1/PD-L1 inhibitors and CTLA-4 inhibitors. Several organ specific AE rates varied among tumor sites. The most frequent AEs of any grade with PD-1/PD-L1 inhibitors and CTLA-4 inhibitors alone were diarrhea (11% and 36%), fatigue (21% and 25%) pruritus (15% and 25%) and rash (10% and 23%). 3 The frequency of colitis ranged from 8% to 22%. It was reported that hypophysitis can affect up to 10% of patients treated with anti-CTLA-4 inhibitors. 2 Hepatitis occurred in 5% to 10% of patients during treatment with ipilimumab, nivolumab and pembrolizumab. 4 Thyroid dysfunction occurred in 5% to 10% patients receiving PD-1/ PD-L1 inhibitors. Pneumonitis occurred in around 1% of patients treated with PD-1/PD-L1 or CTLA-4 inhibitors. 2 IrAEs can mimic autoimmune diseases and affect any organ system. irAEs in the case reports included in the study are summarized in Table 1. Besides common toxicities in different systems, the case reports also describe rare toxicities.
The most frequent skin irAEs reported were rash and pruritus. Vitiligo, depigmented macules resulting from the loss of melanocytes, occurred mostly in melanoma patients treated with ICIs, while it also occurred in lung cancer patients. 5 The PD-L1/PD-1 pathway probably mediates peripheral tolerance of melanosomal proteins, and PD-1 inhibitor may induce vitiligo. 6 Grover's disease, which presents as an intensely pruritic, papulovesicular rash, is a rare dermatologic toxicity. It has occasionally been reported during treatment with ipilimumab. 7 It has been suggested that Th2 cells may play a possible role in its pathogenesis, and systemic corticosteroids may improve pruritus.
Patients presenting with photosensitivity, blurred vision, lacrimation, and diplopia, need an ophthalmology referral, although ophthalmic irAEs, such as uveitis, orbital inflammatory, and ulcerative keratitis, are rare. 21,22 Most patients were treated with topical or systemic corticosteroids.
Two cases of sinusitis, presenting as sinus pressure and nasal congestion after treatment of nivolumab, were reported to have responded to anti-TNF therapy. 23

Safety of ICIs in patients with immune system impairment
Patients with pre-existing diseases, such as autoimmune diseases and human immunodeficiency virus (HIV) infection were excluded from most clinical trials of ICIs. Safety of ICIs in this population is unclear.
It was suggested that patients with autoimmune disease could benefit from immunotherapy and experience tolerable toxicities that are manageable with immunosuppressive regimens. But close clinical monitoring is essential. 24 Calabrese et al. reported a patient with psoriatic arthritis who experienced a psoriasis flare 2.8 weeks after starting nivolumab, while the patient with rheumatoid arthritis remained without disease activity on hydroxychloroquine throughout his course of immunotherapy. 25 Uemura et al. reported a patient with advanced melanoma and refractory Crohn's disease who was treated concurrently with pembrolizumab and tocilizumab, which did not result in Crohn's disease exacerbation. It suggests that targeted immunosuppression combined with checkpoint inhibitors may be a treatment strategy for patients with autoimmune diseases. 26 It was reported that highly active antiretroviral therapy improved the survival of patients with HIV, which increased the incidence of malignancies. 27 Li et al. reported that a patient with HIV infection and non-small cell lung cancer was treated with pembrolizumab and SBRT, and then experienced massive pericardial effusion and interstitial pneumonia. 28 However, this case failed to explain the relationship between HIV infection and AEs. ICIs for the treatment of advanced-stage cancer in patients with HIV infection might be associated with no new safety signals. 29

Rechallenging with ICIs after irAEs
Whether patients who experienced irAEs should be rechallenged with immunotherapy is a question for clinicians. When a good response (complete or partial) is observed prior to the onset of irAEs that require a treatment delay, it may be better to suspend retreatment with ICIs. A total of 15 patients were rechallenged with ICIs after experiencing irAEs details of which are provided in Table 2. Recurrence of irAEs is possible during rechallenging. Guidelines recommend permanent discontinuation of ICIs following a CTCAE grade 4 toxicity except endocrine toxicities which can be treated with hormone replacement.
Utsunomiya et al. reported a patient retreated with nivolumab after grade 4 erythema multiforme major. 30 However, they did not recommend retreatment after grade 4 dermatologic toxicities according to NCCN and ESMO guidelines. For cases of interstitial pneumonitis consistent with a diffuse alveolar damage (DAD) pattern, it is suggested that the corticosteroid dose should be gradually reduced over time, and ICIs should be discontinued. 31 A retrospective study showed the risk-reward ratio for an anti-PD-1 or anti-PD-L1 rechallenge appeared to be acceptable, although these patients require close monitoring. 40 Agents used for treatment of irAEs Most irAEs are steroid-sensitive and resolve within six to 12 weeks. If irAEs show insufficient improvement despite the use of adequate corticosteroids, immunomodulatory agents should be considered after exclusion of other causes.
Intravenous immunoglobulin (IVIg) has been used with corticosteroid in patients with immunotherapy-related erythema multiforme major, 30 myasthenia gravis, 41 Guillain-Barré syndrome, 42 encephalopathy, 43 peripheral neuropathy, 44 scleroderma, 45 ocular myositis, 46 pancytopenia, 39,47 and neutropenia. 48 Most irAEs showed improvement, while myasthenia gravis, Guillain-Barré syndrome, and necrotizing encephalopathy worsened in some patients. Infliximab is a chimeric monoclonal antibody binding to tumor necrosis factor-α. Infliximab was used in patients with immunotherapy-related polymyalgia rheumatic, 25 peripheral neuropathy, 44 necrotic myelopathy, 43 Guillain-Barré syndrome, 49 hemorrhagic gastritis, 50 and organizing pneumonia. 51 Infliximab is recommended to be used in patients with severe immunotherapy-related toxicities whose symptoms cannot be controlled by corticosteroids within 48 to 72 hours according to the National Comprehensive Cancer Network (NCCN) guidelines. 52 However, Abu-Sbeih et al. reported that infliximab should be introduced early in the disease course of immunotherapyrelated colitis instead of waiting until failure of corticosteroid therapy or corticosteroid taper. 53 Adalimumab is a recombinant human monoclonal antibody that binds specifically to tumor necrosis factor-α, blocking interaction with its cell surface receptors and thereby reducing the impact of inflammation. Adalimumab was used in two cases of sinusitis induced by ICIs. 23 Tocilizumab is a recombinant humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody. Tocilizumab was used in patients with immunotherapyrelated pneumonitis 54 and arthritis. 55 Rituximab is a chimeric monoclonal antibody binding to CD20 proteins. Rituximab was used in patients with autoimmune encephalitis associated with nivolumab and ipilimumab. 56 Martins et al. proposed a so-called shut-off strategy aimed at inhibiting key inflammatory components involved in the pathophysiological processes of irAEs, and limited potential adverse effects of drug immunosuppression on tumor response. 57 The biological immunosuppressive agents are important to manage refractory irAEs.

Limitations of review
The limitations of this review are potential selection bias and publication bias based on case reports. Authors and editors usually choose rare and successfully managed cases to publish. Our study is limited by information available in the original reports. This review did not include cases of immunotherapies combined with chemotherapy, which may cause a higher incidence and severity of irAEs.
In conclusion, as immune-related toxicity can affect any organ system, clinicians should keep this in mind as a possible cause of any symptom or abnormality during treatment of ICIs. Rechallenging with ICIs after irAEs requires close monitoring. The biological immunosuppressive agents will be important to manage refractory irAEs. Further research establishing optimal guidelines on how to manage irAEs is necessary. Recurrence †Non-small cell lung cancer. ‡Intravenous immunoglobulin.