Elsevier

Cancer Treatment Reviews

Volume 44, March 2016, Pages 51-60
Cancer Treatment Reviews

Complications of Treatment
Management of toxicities of immune checkpoint inhibitors

https://doi.org/10.1016/j.ctrv.2016.02.001Get rights and content

Highlights

  • Role of immune checkpoint inhibition in the management of key malignancies.

  • Description of rates of immune-related adverse events and timing of their onset.

  • Management strategies for immune-related toxicities.

Abstract

Immune checkpoint inhibition with the anti-CTLA-4 antibody ipilimumab and the anti-PD-1 antibodies nivolumab and pembrolizumab has improved survival in metastatic melanoma, lung cancer and renal cancer. Use of these agents holds promise in other malignancies. The augmented immune response enabled by these agents has led to a particular group of side effects called immune-related adverse events (irAEs). The main irAEs include diarrhea, colitis, hepatitis, skin toxicities and endocrinopathies such as hypophysitis and thyroid dysfunction. The anti-PD-1 antibodies have a different toxicity profile to ipilimumab with fewer high grade events. This article identifies the rates of common and uncommon irAEs associated with each immune checkpoint inhibitor (ICPI) and their timing of onset, focusing mainly on the experience in melanoma and lung cancer. An approach to management for each class of irAE is provided.

Introduction

Immune checkpoint inhibitors (ICPIs) have changed the landscape of advanced cancer treatment during the last few years. Blockade with antibodies against cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death-protein 1 (PD-1) or its ligand (PD-L1) augment the immunologic reaction against tumour cells in several cancer types.

CTLA-4 is part of the B7:CD28 immunoglobulin family found on the surface of T-cells and transmits an inhibitory signal to the T-cell. Ipilimumab is a fully human monoclonal antibody against CTLA-4 binding of which leads to deactivation of the inhibitory signal of the T-cell [1]. PD-1 is expressed on T-cells and binds to its ligands PD-L1 and PD-L2 that are expressed on cancer cells and other immune cells. Antibodies against PD-1, such as nivolumab, pembrolizumab and pidilizumab, or PD-L1, such as MEDI4736 and MPDL3280A increase the anti-tumour T-cell response by blocking the interaction of PD1 and PD-L1 to prevent T-cell inactivation [1].

Immune-related adverse events (irAEs) from ICPIs occur as a consequence of impaired self-tolerance from loss of T-cell inhibition. They can potentially involve every organ system but gastrointestinal, dermatologic, hepatic and endocrine toxicities predominate. These side effects are generally manageable but can be fatal in some cases [2], [3], [4], [5]. Their appearance may be subclinical and early diagnosis and management present challenges for the physician.

This article will focus on published toxicity data in phase II and III studies, the majority of which comes from trials in advanced melanoma, and present an approach to management of the main irAEs.

Section snippets

Melanoma

The greatest evidence for the use of ICPIs comes from studies in advanced melanoma. In the metastatic setting, ipilimumab [2], [6], nivolumab [7], [8] and pembrolizumab [5], [9] are all associated with a substantial survival advantage over cytotoxic chemotherapy in both pre-treated and treatment-naïve patients. Pembrolizumab and nivolumab are superior to ipilimumab in the first-line setting with regards to overall and progression-free survival respectively [5], [10]. Combination immunotherapy

General approach to management of irAEs

The disadvantage of an augmented immune response driven by T cell activation is the potential autoimmune-related inflammation of normal tissues. In most circumstances, this may be managed with immune-modulatory medications (IMM). When treating patients with ICPIs it is important to remain open-minded to the possibility of irAEs, both rare and common, and develop a careful approach to their assessment and management. This includes comprehensive education of patients and care-givers on

Diarrhoea and enterocolitis

Diarrhoea is one of the most frequent AEs related to ICPIs. It occurs at any grade in 23–33% of patients treated with ipilimumab, 8–19% of those managed with anti-PD-1 antibodies and 44% with the combination of ipilimumab and nivolumab [5], [7], [8], [10], [19]. Grade 3 and 4 diarrhoea is most prevalent with the combination approach (9%) [10]. The term colitis is used to describe diarrhoea associated with abdominal pain, per rectal bleeding or mucous, or when imaging findings confirm large

Discussion

Immune-checkpoint inhibitors have improved overall survival in a number of malignancies and have an established role in the treatment of advanced melanoma, non-small cell lung cancer and renal cancer. They commonly cause irAEs, some of which are severe, but are usually reversible with early recognition and specialised management. Algorithms for the management of irAEs have been developed and these provide a framework within which individual clinicians may exercise their discretion. Where

Conflict of interest

There are no specific conflicts of interests to declare for any of the authors (L. Spain, S. Diem, J. Larkin).

Disclosures for J.L. include: non-remunerated consultant for Novartis, Pfizer, BMS, MSD and Roche/Genentech and receives institutional research support from Pfizer, BMS, Novartis, MSD.

No funding has been received in relation to this article.

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