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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • Immune Checkpoint Inhibitors