Management of side effects of immune checkpoint blockade by anti‐CTLA‐4 and anti‐PD‐1 antibodies in metastatic melanoma

Abstract

SummaryCTLA-4 and PD-1 are potential targets for tumor-induced downregulation of lymphocytic immune responses. Immune checkpoint-modifying monoclonal antibodies oppose these effects, inducing T cell-mediated immune responses to various tumors including melanoma. Both anti-CTLA-4 and anti-PD-1 antibodies modify the interaction between tumor, antigen-presenting cells, and T lymphocytes. With respect to overall survival, clinical studies have shown a major benefit for the anti-CTLA-4 antibody ipilimumab as well as the two anti-PD-1 antibodies nivolumab and pembrolizumab. Following approval of ipilimumab in 2011, the latter two achieved market authorization in the summer of 2015. Immune responses thus induced and enhanced inevitably entail autoimmune phenomena, affecting various organs to varying degrees. Knowledge of these side effects is crucial with regard to prevention and management by treating physicians. Typically occurring early on and presenting with pronounced and persistent diarrhea, colitis represents a major and severe side effect. Other immune-mediated disorders include dermatitis, hypophysitis, thyroiditis, hepatitis, iridocyclitis as well as other less common autoimmune phenomena. Early recognition and initiation of treatment can reduce risks and sequelae for patients. This review describes the mechanisms of action of immune checkpoint blockade as well as its clinical effects in metastatic melanoma, with a detailed focus on the spectrum of adverse events and their therapeutic management.

Investigation of clinical factors associated with longer overall survival in advanced melanoma patients treated with sequential ipilimumab

“…The frequency of mild irAE was also higher with ipilimumab than with nivolumab (37% [anti‐PD‐1 antibody] vs 60% [ipilimumab]). Colitis was reported to be particularly common in patients receiving ipilimumab treatment . However, hepatitis was a more common severe irAE than colitis in our study (23%, n = 7/30).…”

“…In past reports, the objective response rates were 3.6–16% in advanced melanoma patients given an anti‐PD‐1 antibody followed by ipilimumab . However, ipilimumab therapy is reportedly used more frequently and produces more severe immune‐related adverse events (irAE) than nivolumab . Additionally, ipilimumab is very expensive, as are other immune checkpoint inhibitors (nivolumab and pembrolizumab), increasing state‐sponsored health‐care expenditures.…”

Management of Gastrointestinal Toxicity from Immune Checkpoint Inhibitor

“…Management of patients with non-severe diarrhoea is mainly supportive, with antidiarrhoeals, fluid, and electrolyte supplementation. Persistence of grade 2 diarrhoea (defined as four to six stools per day for more than 3 days), should prompt initiation of 0.5 to 1 mg/kg/day of oral corticosteroids and ICPIs should be withheld [2, 3, 5, 13, 19, 21, 22]. The use of budesonide seems attractive since it might avoid the systemic effects of corticosteroids, though its effect in this context seems limited.…”

Severe bullous skin eruptions on checkpoint inhibitor therapy – in most cases severe bullous lichenoid drug eruptions

“…In this context, severe epidermolytic skin reactions are rare. Grade 3/4 skin toxicities (without specification as to the exact dermatological condition) have been observed in less than 1 % of patients on anti-PD-1 and anti-PD-L1 antibodies and in 5.8 % of cases treated with a combination of nivolumab and ipilimumab [3,4]. Such adverse events include bullous lichenoid drug eruptions, drug-induced bullous pemphigoid as well as severe cutaneous reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).…”