Complications of TreatmentManagement of toxicities of immune checkpoint inhibitors
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.
References (91)
- et al.
Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial
Lancet Oncol
(2014) - et al.
Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial
Lancet Oncol
(2015) - et al.
Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial
Lancet Oncol
(2015) - et al.
Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial
Lancet Oncol
(2015) - et al.
Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study
Lancet Oncol
(2010) - et al.
Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial
Lancet
(2014) - et al.
Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial
Lancet Oncol
(2015) - et al.
Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial
Lancet Oncol
(2013) - et al.
Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: an open-label, single-arm, phase 2 study
Lancet Respir Med
(2015) - et al.
Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial
Lancet Oncol
(2014)