Chronic and late-onset toxicities from immune checkpoints inhibitors (ICIs): Analysis of the publications leading to ICIs approval between 2011 and 2019

Abstract

Abstract Background Immune checkpoints inhibitors (ICIs) are receiving approval for a growing number of indications. Even if generally well-tolerated, ICIs can cause rare but severe immune-related adverse events (irAEs) with late onset and long-term impact. Aim of this analysis was to evaluate the completeness of irAEs description, with particular attention to irAEs duration and occurrence of late toxicities, in ICIs pivotal trials. Methods We analysed the publications corresponding to the studies leading to ICIs approval by US Food and Drug Administration (FDA) and/or European Medicines Agency from March 2011 up to August 2019. We searched for duration of follow-up, proportion of patients still on treatment at data cut-off, duration of irAEs and proportion of patients with unresolved toxicities at data cut-off. Results Overall, we found 58 publications, corresponding to 49 trials (table). Among all studies, median follow-up was 13,5 months (interquartile range [IQR] 5,8–14,9), and it was 10,2 months (IQR 5 -11,9) for the ones which led to ICIs approval with FDA fast-track procedure versus 15,2 months (IQR 12-16,2) for those leading to ICIs approval through regular procedure (p\u2009 Table . 52P Publications n (%) Studies with patients ongoing at data cut-off n (%) Median follow-up months Studies reporting duration of irAEs n (%) Whole series 58 40 (81) 13.5 6 (10.3) Year of publication 2010 1 (1.7) n.a. 27.8 1 (100) 2015 11 (18.9) 3 (27.2) 13.1 3 (27.2) 2016 5 (8.6) 5 (100) 10.4 0 2017 21 (36.2) 17 (80.9) 14 1 (4.7) 2018 15 (25.8) 13 (86.6) 12.9 1 (7.6) 2019 5 (8.6) 3 (60) 11.1 0 Drug Pembrolizumab 29 (50) 18 (62) 10.6 0 Nivolumab 12 (20.6) 9 (75) 9.5 3 (20) Atezolizumab 7 (12) 6 (85.7) 14.5 0 Avelumab 3 (5.2) 3 (100) 13.4 0 Durvalumab 2 (3.5) 2 (100) 10.1 0 Ipilimumab 2 (3.5) n.a. 30.3 2 (100) Nivolumab + Ipilimumab 3 (5.2) 3 (100) 18.7 1 (33.3) Studies leading to FDA fast-track approval 24 (41.4) 23 (95,8) 10.2 2 (6) n.a.: not available data Conclusion Description of toxicity in publications of clinical trials of ICIs is often suboptimal especially in terms of duration and long-term sequelae. Future efforts should focus on capturing the real impact of irAEs on patients’ QoL to better define treatments value. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure G. Valabrega: Honoraria (self): Roche; Honoraria (self): Amgen; Honoraria (self): AstraZeneca; Honoraria (self): PharmaMar; Honoraria (self): Tesaro. M. Aglietta: Honoraria (self): Tesaro; Honoraria (self): Roche; Honoraria (institution): AstraZeneca. M. Di Maio: Honoraria (institution): Tesaro; Honoraria (self): Bristol Meyers Squibb; Honoraria (self): Roche; Honoraria (self): AstraZeneca; Honoraria (self): Takeda; Honoraria (self): Janssen. All other authors have declared no conflicts of interest.