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

Aged Chemotherapy, Adjuvant / adverse effects Clinical Trials as Topic Drug-Related Side Effects and Adverse Reactions / diagnosis Electronic Health Records Female Humans Immune Checkpoint Inhibitors / adverse effects Lung Neoplasms / drug therapy Male Melanoma / drug therapy Middle Aged Retrospective Studies Risk Assessment Risk Factors Skin Neoplasms / drug therapy Time Factors Treatment Outcome

Immortal time bias Immune-checkpoint inhibitors Immune-related adverse events Late-onset toxicities Long-lasting toxicities

Journal

European journal of cancer (Oxford, England : 1990)

ISSN: 1879-0852

Titre abrégé: Eur J Cancer

Pays: England

ID NLM: 9005373

Informations de publication

Date de publication:
05 2021

Historique:

received: 05 01 2021

revised: 09 03 2021

accepted: 13 03 2021

pubmed: 18 4 2021

medline: 21 10 2021

entrez: 17 4 2021

Statut: ppublish

Résumé

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. 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). 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). 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.

Sections du résumé

BACKGROUND

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.

Identifiants

DOI: 10.1016/j.ejca.2021.03.010 PMID: 33865201

pubmed: 33865201

pii: S0959-8049(21)00169-6

doi: 10.1016/j.ejca.2021.03.010

pii:

doi:

Substances chimiques

Immune Checkpoint Inhibitors 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

153-164

Informations de copyright

Déclaration de conflit d'intérêts

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.