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Original Investigation
April 16, 2020

Immune Checkpoint Inhibitor Rechallenge After Immune-Related Adverse Events in Patients With Cancer

Author Affiliations
  • 1Normandie University, University of Caen Normandy, Centre Hospitalier Universitaire (CHU) de Caen Normandie, PICARO Cardio-oncology Program, Department of Pharmacology, EA 4650, Signalisation, Électrophysiologie et Imagerie des Lésions d'Ischémie-Reperfusion Myocardique, Caen, France
  • 2Hôpitaux Universitaires Paris-Est, Assistance Publique-Hôpitaux de Paris, Hôpital Saint Antoine, Service de Cardiologie, Unico, Unité de Cardio-Oncologie APHP.6, GRC Groupe de Recherche Clinique en Cardio Oncologie, Inserm 856, Université Pierre et Marie Curie, Paris, France
  • 3CHU de Caen Normandie, Department of Pharmacology, Caen, France
  • 4Aix-Marseille Mediterranean University, Assistance Publique-Hôpitaux de Marseille, Marseille, France
  • 5Cardio-Oncology Center, Unit of Heart Failure and Valvular Heart Diseases, Department of Cardiology, Hôpital Nord, Marseille, France
  • 6Centre de Recherche Cardiovasculaire et Nutrition, Inserm 1263, Inra, Marseille, France
  • 7Groupe Méditerranéen de Cardio-Oncologie, Marseille, France
  • 8Oncosafety Network of the Early Phases Cancer Trials Center, Marseille, France
  • 9Centre Francois Baclesse Centre de Lutte Contre le Cancer (Cancer Centre), Caen, France
  • 10CHU de Caen Normandie, PICARO Cardio-oncology Program, Department of Cardiology, Caen, France
  • 11Normandie University, UNICAEN, CHU de Caen Normandie, PICARO Cardio-oncology Program, Department of Cardiology, EA 4650, Signalisation, Électrophysiologie et Imagerie des Lésions d'Ischémie-Reperfusion Myocardique, Caen, France
JAMA Oncol. Published online April 16, 2020. doi:10.1001/jamaoncol.2020.0726
Key Points

Question  What is the recurrence rate of an immune-related adverse event after the resumption of immune checkpoint inhibitors (ICIs) in patients with cancer?

Findings  In this cohort study of 24 079 immune-related adverse events associated with at least 1 ICI, the recurrence rate of the same immune-related adverse event that prompted discontinuation of ICI therapy was 28.8% after patients received a rechallenge with the same ICI. In a rechallenge, colitis, hepatitis, and pneumonitis had higher recurrence rates compared with other immune-related adverse events.

Meaning  Findings of this study suggest that resumption of ICI therapy could be considered for select patients, with appropriate monitoring and use of standard treatment algorithms to identify and treat toxic effects.

Abstract

Importance  Limited information is available on the safety of a rechallenge with an immune checkpoint inhibitor (ICI) after an immune-related adverse event (irAE).

Objective  To identify the recurrence rate of the same irAE that prompted discontinuation of ICI therapy after an ICI rechallenge in patients with cancer and to identify the clinical features associated with such recurrences.

Design, Setting, and Participants  This observational, cross-sectional, pharmacovigilance cohort study examined individual case safety reports from the World Health Organization database VigiBase, which contains case reports from more than 130 countries. Case reports were extracted from database inception (1967) to September 1, 2019. All consecutive ICI cases with at least 1 associated irAE were included.

Main Outcomes and Measures  The primary outcome was the rate of recurrence of the initial irAE after an ICI rechallenge. Secondary outcomes included the factors associated with the recurrence after a rechallenge among informative rechallenges, the recurrence rate according to the ICI regimen (anti–programmed cell death 1 or anti–programmed cell death ligand 1 monotherapy, anti–cytotoxic T-lymphocyte antigen-4 monotherapy, or combination therapy), and the rate of occurrence of a different irAE after a rechallenge.

Results  A total of 24 079 irAE cases associated with at least 1 ICI were identified. Among the irAEs, 452 of 6123 irAEs associated with ICI rechallenges (7.4%) were informative rechallenges. One hundred thirty recurrences (28.8%; 95% CI, 24.8-33.1) of the initial irAE were observed. In a rechallenge, colitis (reporting odds ratio [OR], 1.77; 95% CI, 1.14-2.75; P = .01), hepatitis (reporting OR, 3.38; 95% CI, 1.31-8.74; P = .01), and pneumonitis (reporting OR, 2.26; 95% CI, 1.18-4.32; P = .01) were associated with a higher recurrence rate, whereas adrenal events were associated with a lower recurrence rate (reporting OR, 0.33; 95% CI, 0.13-0.86; P = .03) compared with other irAEs.

Conclusions and Relevance  This cohort study found a 28.8% recurrence rate of the same irAE associated with the discontinuation of ICI therapy after a rechallenge with the same ICI. Resuming ICI therapy could be considered for select patients, with appropriate monitoring and use of standard treatment algorithms to identify and treat toxic effects.

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    1 Comment for this article
    EXPAND ALL
    RE: Immune checkpoint inhibitor rechallenge after immune-related adverse events in patients with cancer
    Tomoyuki Kawada, MD & PhD | Nippon Medical School
    Dolladille et al. reported a 28.8% recurrence rate of the same immune-related adverse event (irAE) that prompted discontinuation of immune checkpoint inhibitor (ICI) therapy after an ICI rechallenge in patients with cancer (1). Odds ratios (ORs) (95% confidence intervals [CIs]) of colitis, hepatitis and pneumonitis against other irAEs were 1.77 (1.14-2.75), 3.38 (1.31-8.74) and 2.26 (1.18-4.32), respectively. In contrast, OR (95% CI) of adrenal events against other irAEs was 0.33 (0.13-0.86). I have a query about their study.

    The authors presented three significant increases of ORs and one significant decrease of OR. AS they set other irAEs as control
    to calculate OR of irAE in the target organ, OR of each irAE varies around 1. Total of 28.8% recurrence rate is a risk in prognosis, but selection of effective treatment might be limited. I suppose that physician planned ICI rechallenge by estimating treatment benefits, and if so, magnitude of irAE and treatment benefits should be simultaneously evaluated.

    Regarding the first query, Zhou et al. conducted a meta-analysis of cohort studies to investigate the association of irAEs and efficacy of ICIs in patients with cancer (2). Hazard ratio (HR) (95% CI) of patients with cancer who developed irAEs for mortality was 0.54 (0.45-0.65), and HRs (95% CIs) of patients with irAEs by programmed cell death-1 inhibitors and by ICI monotherapy were 0.51 (0.42-0.62) and 0.53 (0.43-0.65), respectively. A better ICI efficacy was observed in endocrine, dermatological, and low-grade irAEs. Maillet et al. also evaluate the association between irAEs and ICI efficacy (3). HR (95% CI) of patients with cancer who developed irAEs for mortality was 0.57 (0.43-0.74), and HR of patients with irAEs by programmed cell death-1 inhibitors and patients with lung cancer significantly decreased. As irAEs are closely related to a better efficacy in cancer patients with ICI treatment, disease progression and mortality study in patients with ICI rechallenge should also be evaluated.

    References
    1. Dolladille C, Ederhy S, Sassier M, et al. Immune checkpoint inhibitor rechallenge after immune-related adverse events in patients with cancer. JAMA Oncol. 2020 Apr 16. doi: 10.1001/jamaoncol.2020.0726
    2. Zhou X, Yao Z, Yang H, et al. Are immune-related adverse events associated with the efficacy of immune checkpoint inhibitors in patients with cancer? A systematic review and meta-analysis. BMC Med. 2020;18(1):87. doi: 10.1186/s12916-020-01549-2
    3. Maillet D, Corbaux P, Stelmes JJ, et al. Association between immune-related adverse events and long-term survival outcomes in patients treated with immune checkpoint inhibitors. Eur J Cancer. 2020;132:61-70. doi: 10.1016/j.ejca.2020.03.017
    CONFLICT OF INTEREST: None Reported
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