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. 2021 May:149:153-164.
doi: 10.1016/j.ejca.2021.03.010. Epub 2021 Apr 14.

Late-onset and long-lasting immune-related adverse events from immune checkpoint-inhibitors: An overlooked aspect in immunotherapy

E Ghisoni  1 , A Wicky  2 , H Bouchaab  2 , M Imbimbo  2 , J Delyon  2 , B Gautron Moura  2 , C L Gérard  2 , S Latifyan  2 , B C Özdemir  2 , M Caikovski  2 , S Pradervand  2 , E Tavazzi  3 , R Gatta  2 , L Marandino  4 , G Valabrega  5 , M Aglietta  5 , M Obeid  6 , K Homicsko  1 , N N Mederos Alfonso  2 , S Zimmermann  2 , G Coukos  1 , S Peters  2 , M A Cuendet  7 , M Di Maio  8 , O Michielin  9
Affiliations
Free article

Late-onset and long-lasting immune-related adverse events from immune checkpoint-inhibitors: An overlooked aspect in immunotherapy

E Ghisoni et al. Eur J Cancer. 2021 May.
Free article

Abstract

Background: Immune checkpoint inhibitors (ICIs) have revolutionised cancer therapy but frequently cause immune-related adverse events (irAEs). Description of late-onset and duration of irAEs in the literature is often incomplete.

Methods: To investigate reporting and incidence of late-onset and long-lasting irAEs, we reviewed all registration trials leading to ICI's approval by the US FDA and/or EMA up to December 2019. We analysed real-world data from all lung cancer (LC) and melanoma (Mel) patients treated with approved ICIs at the University Hospital of Lausanne (CHUV) from 2011 to 2019. To account for the immortal time bias, we used a time-dependent analysis to assess the potential association between irAEs and overall survival (OS).

Results: Duration of irAEs and proportion of patients with ongoing toxicities at data cut-off were not specified in 56/62 (90%) publications of ICIs registration trials. In our real-world analysis, including 437 patients (217 LC, 220 Mel), 229 (52.4%) experienced at least one grade ≥2 toxicity, for a total of 318 reported irAEs, of which 112 (35.2%) were long-lasting (≥6 months) and about 40% were ongoing at a median follow-up of 369 days [194-695] or patient death. The cumulative probability of irAE onset from treatment initiation was 42.8%, 51.0% and 57.3% at 6, 12 and 24 months, respectively. The rate of ongoing toxicity from the time of first toxicity onset was 42.8%, 38.4% and 35.7% at 6, 12 and 24 months. Time-dependent analysis showed no significant association between the incidence of irAEs and OS in both cohorts (log Rank p = 0.67 and 0.19 for LC and Mel, respectively).

Conclusions: Late-onset and long-lasting irAEs are underreported but common events during ICIs therapy. Time-dependent survival analysis is advocated to assess their impact on OS. Real-world evidence is warranted to fully capture and characterise late-onset and long-lasting irAEs in order to implement appropriate strategies for patient surveillance and follow-up.

Keywords: Immortal time bias; Immune-checkpoint inhibitors; Immune-related adverse events; Late-onset toxicities; Long-lasting toxicities.

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Conflict of interest statement

Conflict of interest statement EG, AW, MI, BGM, CLG, SL, BCO, MC, SP, ET, RG, LM, MC declare no conflicts of interest. HB received advisory board or consultant fees from MSD, BMS, Astrazeneca, Roche. JD declares research funding from MSD. GV received advisory board or consultant fees from GSK-Tesaro, Amgen, PharmaMar, Roche, Astrazeneca, Clovis. MA received advisory board or consultant fees from Bayer, Novartis, BMS, Merk and institutional research grant from GSK-Tesaro and PharmaMar. MO and HZ declare research support and honoraria from Roche, BMS, MSD, Astra-Zeneca, GSK and Novartis. NNMA declared an advisory role for Astrazeneca. SZ received travel grants from AstraZeneca. GC has received grants, research support and/or is coinvestigator in clinical trials by BMS, Celgene, Boehringer Ingelheim, Roche, Iovance and Kite; has received honoraria for consultations or presentations by Roche, Genentech, BMS, AstraZeneca, Sanofi-Aventis, Nextcure and GeneosTx. SP has received education grants and received honoraria for providing consultations, attending advisory boards, and/or providing lectures for AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, Bioinvent, Blueprint Medicines, Boehringer Ingelheim, Bristol MyersSquibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffmann-LaRoche, Foundation Medicine, Illumina, Incyte, Janssen, Merck Sharp &Dohme, Merck Serono, Merrimack, Novartis, PharmaMar, Pfizer, Regeneron, Sanofi, Seattle Genetics and Takeda. MDM received advisory board or consultant fees from Merck Sharp & Dohme, Bristol Myers Squibb, Eisai, Janssen, Astellas, AstraZeneca, Pfizer, Takeda and an institutional research grant from GSK-Tesaro. OM received advisory board or consultant fees from BMS, Roche, Amgen, MSD, Novartis, GSK, Pierre-Fabre and an institutional research grant from BMS, MSD and Amgen.

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