Dose dependence of treatment-related adverse events for immune checkpoint inhibitor therapies: a model-based meta-analysis

Abstract

Programmed cell death-1 (PD-1) and/or cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) immune checkpoint inhibitor (ICI) treatments are associated with adverse events (AEs), which may be dependent on ICI dose. Applying a model-based meta-analysis to evaluate safety data from published clinical trials from 2005 to 2018, we analyzed the dose/exposure dependence of ICI treatment-related AE (trAE) and immune-mediated AE (imAE) rates. Unlike with PD-1 inhibitor monotherapy, CTLA-4 inhibitor monotherapy exhibited a dose/exposure dependence on most AE types evaluated. Furthermore, combination therapy with PD-1 inhibitor significantly strengthened the dependence of trAE and imAE rates on CTLA-4 inhibitor dose/exposure.

Alopecia areata as an immune‐related adverse event of immune checkpoint inhibitors: A review

“…There is a dose-dependent increase in the frequency of irAEs secondary to ipilimumab and combination immunotherapy in particular. 14,27 With approval of ipilimumab at higher doses by the US Food and Drug Administration, the frequency of ICI-induced AA could increase. 14 Alternatively, ICI therapy may reveal or amplify pathology preferentially in those patients with pre-existing compromise of the hair follicle immune privilege.…”

“…Additionally, the ICI dosage used may be too low to induce collapse of the immune privilege at the hair follicle. There is a dose‐dependent increase in the frequency of irAEs secondary to ipilimumab and combination immunotherapy in particular 14,27 . With approval of ipilimumab at higher doses by the US Food and Drug Administration, the frequency of ICI‐induced AA could increase 14…”

Advanced Nanotechnology for Enhancing Immune Checkpoint Blockade Therapy

“…Although anti-CTLA4 treatment allowed to the overall survival of melanoma to be reached, with even cure of metastatic disease, for about 20% of the patients [ 46 , 47 , 50 , 51 ], nevertheless clinical application is limited because of its AIEs [ 52 , 53 ]. It is likely that CTLA-4 blockade can promote recruitment of peripheral T cells, thus enhancing the probability of autoimmune reaction [ 54 ]. A correlation between dose and both efficacy and toxicity has been highlighted.…”

Beidseitige Nivolumab-assoziierte Vogt-Koyanagi-Harada-artige Uveitis bei einem Patienten mit metastasiertem Nierenzellkarzinom

“…Hingegen könnte bei einer Uveitis anterior (Grad-2-Nebenwirkung) die Therapie mit dem Checkpoint-Inhibitor fortgeführt werden [9]. Bei der Therapie mit PD1-Inhibitoren konnte ein Zusammenhang der Nebenwirkungen mit der verabreichten Medikamentendosis nicht nachgewiesen werden, sodass eine Dosisreduktion beim Auftreten von Nebenwirkungen vorerst keine Alternative darstellt [10]. Insgesamt zeigen sich die meisten in der Literatur beschriebenen Uveitiden, welche durch die Therapie mit Checkpoint-Inhibitoren ausgelöst werden, unter der Therapie mit topischen, periokulären oder systemischen Steroiden rückläufig [1,4].…”