<p>Risk and incidence of fatal adverse events associated with immune checkpoint inhibitors: a systematic review and meta-analysis</p>

Abstract

Background Given the increasing use of immune checkpoint inhibitors (ICIs), a concomitant rise in adverse events is inevitable. In a recent Phase III trial of ICIs versus placebo, we found the staggering difference of incidence of fatal adverse events (FAEs). Hence, we should determine the risk of FAEs in ICIs. Objective To address the risks of FAEs associated with each ICI regimen, we performed a systematic review and meta-analysis of clinical trials with the Food and Drug Administration-approved ICI regimens in patients with advanced solid tumors. Methods Literature searching was based on PubMed before April 15, 2018. The numbers of FAEs in both study group and placebo group were collected. We assessed the risk of fatal adverse reactions associated with ICIs on Pooled Peto OR and associated 95% CI. Results Twelve trials were identified. OR value of FADs in all ICIs was 2.32 (95% CI: 1.33, 4.05; P =0.003). The incidence of FAE in ICI in all included studies were up to 3.2%. OR value of clinical trials of prostate cancer was 3.71 (95% CI: 1.12, 12.26; P =0.03). Among the ICI cohorts, the common FAEs were gastrointestinal toxicity (n=12, 25%), pulmonary toxicity (n=10, 20%), cardiac toxicity (n=5, 10%), and hepatic toxicity (n=5, 10%). Conclusion The cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) inhibitors have a significantly higher risk of FAE ( P =0.01), whereas programmed cell death protein 1 (PD-1) inhibitors were not. The most common CTLA-4-related FAE was gastrointestinal toxicity, and the most common PD-1-related FAE was pulmonary toxicity. Moreover, we have shown that ipilimumab has significant dose-dependent lethal toxicity.

Classical Examples of the Concept of the ASIA Syndrome

“…This overstimulation of immune system breaks the auto-tolerance and leads to autoimmune reactions [ 104 ]. According to clinical trials irAES develop up to 90% of patients treated with an anti-CTLA-4 antibody and 70% of patients treated with an PD-1/PD-L1 antibody [ 105 , 106 ]. The median onset is 3–6 months after the start of treatment.…”

Nebenwirkungen nach Immuntherapie in der Hämatologie und Onkologie

“…PD-1 angreifende Antikörper weisen weniger Nebenwirkungen auf als eine therapeutische CTLA-4 Blockade: In bis zu 90 % der Patienten, die einen Anti-CTLA-4-Antikörper (Ipilimumab) bekommen, treten Nebenwirkungen auf [16], während Nebenwirkungen nach PD-1/PD-L1 Hemmung in 70 % der Fälle angegeben werden [17]. Die Rate an zum Tod führenden Nebenwirkungen ist jedoch mit 2-3 % als eher gering einzustufen [18].…”

“…Gleichsam steigt das Risiko für jegliche Nebenwirkungen nach CTLA-4 Blockade in einer direkten Beziehung zu steigender verabreichter Dosis an. Dies scheint bei PD-1 Inhibitoren nicht der Fall zu sein [18].…”

Eficacia y seguridad de los inhibidores del punto de control inmune en pacientes con cáncer renal avanzado o metastásico: revisión sistemática

“…Una revisión sistemática mostró que el uso de los IPI aumenta el riesgo de efectos adversos grado 3 o más con el uso de los inhibidores de CTLA-4 frente a los inhibidores PD-1 (44).…”

“…CTLA-4 frena la activación de las células T en una etapa proximal de la respuesta inmune mientras que PD-1 actúa en etapas posteriores a nivel de los tejidos periféricos (45). No obstante, a pesar del riesgo que tienen los IPI, la tasa de eventos adversos sigue siendo mucho menor cuando se compara con otros tipos de fármacos quimioterapéuticos y/o radioterapia (44,46).…”