Management of Immune-Related Adverse Events and Kinetics of Response With Ipilimumab

Abstract

Monoclonal antibodies directed against the immune checkpoint protein cytotoxic T-lymphocyte antigen-4 (CTLA-4; CD152)-ipilimumab and tremelimumab-have been investigated in metastatic melanoma and other cancers and have shown promising results. Recently, ipilimumab was approved by the US Food and Drug Administration for the treatment of metastatic melanoma. We review the literature on managing the adverse effects and kinetics of tumor regression with ipilimumab and provide guidelines on their management. During treatment with these antibodies, a unique set of adverse effects may occur, called immune-related adverse events (irAEs). These include rashes, which may rarely progress to life-threatening toxic epidermal necrolysis, and colitis, characterized by a mild to moderate, but occasionally also severe and persistent diarrhea. Hypophysitis, hepatitis, pancreatitis, iridocyclitis, lymphadenopathy, neuropathies, and nephritis have also been reported with ipilimumab. Early recognition of irAEs and initiation of treatment are critical to reduce the risk of sequelae. Interestingly, irAEs correlated with treatment response in some studies. Unique kinetics of response have been observed with CTLA-4 blockade with at least four patterns: (1) response in baseline lesions by week 12, with no new lesions seen; (2) stable disease, followed by a slow, steady decline in total tumor burden; (3) regression of tumor after initial increase in total tumor burden; and (4) reduction in total tumor burden during or after the appearance of new lesion(s) after week 12. We provide a detailed description of irAEs and recommendations for practicing oncologists who are managing them, along with the unusual kinetics of response associated with ipilimumab therapy.

Immune Checkpoint Blockade: The New Frontier in Cancer Treatment

“…By enhancing immune system function, ICBs can lead to adverse events (AEs) distinct from chemotherapy [144,145], which include a range of dermatologic, gastrointestinal (GI), endocrine, and hepatic toxicities, as well as other less common inflammatory events [146]. Though imAE onset is variable, most occur during the initial months of therapy [11][12][13][14][15][16].…”

“…Guidelines for the management of imAEs have been proposed in expert reviews [144,145,151,152] but are also available within the prescribing information for each agent and in brochures that can be downloaded from the manufacturers' websites [11][12][13][14][15][16][153][154][155][156][157]. Most moderate and severe immune-mediated toxicities can be managed effectively with corticosteroids and can be resolved within 6 to 12 weeks [146].…”

The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma

“…Special attention to the development of autoimmune-like symptoms is particu larly important and these have been reported with interferon-α2b, 32,55 IL-2 57,60 and ipilimumab. 10 The panel recommends all patients be routinely assessed with thyroid function studies, complete blood counts, liver function and metabolic panels, and serum LDH tests. The majority opinion is that baseline laboratory data should be obtained on all patients treated with any immuno therapy and then weekly during induction and monthly for patients on standard high-dose interferon-α2b therapy.…”

“…Although therapeutic benefits can be durable, only a subset of patients respond. 7,8 In addition, unique adverse effects of immunotherapy, many of which relate to the induction of autoimmunity and pro-inflammatory-like states, 10 might limit eligibility or become challenges in clinical management. Recent studies suggest immunotherapy, particularly with ipilimu mab and related agents, might result in tumour regression over a prolonged time, based on the kinetics of establishing an effective host anti tumour immune response.…”

“…Recent studies suggest immunotherapy, particularly with ipilimu mab and related agents, might result in tumour regression over a prolonged time, based on the kinetics of establishing an effective host anti tumour immune response. 10,11 This finding has led to the develop ment of immune-related response criteria to better monitor patients treated with immuno therapy and to determine appropriate clinical end points. 12 Availability of non-immunotherapy strategies has also resulted in the opportunity to develop combination treatment regimens for clinical evaluation and the need to better define optimal sequencing of therapy for patients with advanced-stage melanoma.…”