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. 2025 Jun 4;30(6):oyaf120.
doi: 10.1093/oncolo/oyaf120.

Safety and efficacy of retreatment with immune checkpoint inhibitors after severe immune-related adverse events

Kazuyuki Mizuno  1   2 , Takanori Ito  2 , Tsunaki Sawada  2 , Tomoko Kobayashi  3 , Shintaro Iwama  3 , Shoichiro Mori  4 , Tetsunari Hase  5 , Yuki Fukami  6 , Kenji Furusawa  7 , Yoshimitsu Yura  7 , Ryota Morimoto  7 , Ai Fujita Sajiki  8 , Hiroaki Ushida  8 , Noritoshi Kato  9 , Shoichi Maruyama  9 , Toyoaki Murohara  7 , Masahisa Katsuno  6   10 , Makoto Ishii  5 , Masashi Akiyama  4 , Hiroshi Arima  3 , Hiroki Kawashima  2 , Yuichi Ando  1
Affiliations

Safety and efficacy of retreatment with immune checkpoint inhibitors after severe immune-related adverse events

Kazuyuki Mizuno et al. Oncologist. .

Abstract

Background: While immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, they can trigger severe immune-related adverse events (irAEs). The safety and efficacy of ICI retreatment after severe irAEs remain poorly understood.

Methods: We conducted a retrospective analysis of 1271 patients with malignancies treated with ICIs at a university hospital in Japan between September 2014 and June 2023. We evaluated the incidence and characteristics of severe irAEs, defined as grade ≥3, and the safety and efficacy of ICI retreatment.

Results: Severe irAEs occurred in 222 patients (17.5%). Patients with single endocrinopathies were excluded, and 46 (28.4%) of the remaining 162 patients underwent ICI retreatment. Upon retreatment, 14 patients (30.4%) experienced recurrent or new grade ≥2 irAEs. One patient who experienced hepatotoxicity (grade 3) at initial ICI treatment developed a recurrence (grade 4). Regarding antitumor response, the objective response rate to retreatment was 28.3% (13/46), with 10.9% achieving complete and 17.4% partial response. The median duration of ICI administration after retreatment was 218 days (95% confidence interval [CI]: 84-399). At 1 year after retreatment, 15.4% (95% CI: 6.8-27.4) of patients discontinued due to irAEs, 44.4% (95% CI: 29.7-58.1) due to disease progression, 6.6% (95% CI: 1.7-16.3) completed planned treatment, and 33.4% (95% CI: 20.3-47.2) continued treatment.

Conclusions: ICI retreatment after severe irAEs demonstrated a manageable safety profile and promising efficacy, even in patients with grade ≥3 irAEs. ICI retreatment may be a viable option for patients with limited alternatives, particularly those showing favorable antitumor responses at initial treatment.

Keywords: efficacy; immune checkpoint inhibitors; immune-related adverse events; retreatment; safety.

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Conflict of interest statement

S.I. received personal fees from Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., MSD K.K., AstraZeneca Co., Ltd., and Merck Biopharma Co., Ltd. outside of the submitted work. T.H. received personal fees from AstraZeneca K.K., Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb Co., Ltd., Taiho Pharmaceutical Co., Ltd., MSD K.K., Merck Biopharma Co., Ltd., Pfizer Inc., and Eli Lilly Japan K.K., and grants from Novartis Pharma K.K., AstraZeneca K.K., BeiGene Inc., AbbVie Inc., Amgen Co., Ltd., and Chugai Pharmaceutical Co., Ltd., outside of the submitted work. T.M. received personal fees from AstraZeneca K.K. outside of the submitted work. M.I. received research funding from Nippon Boehringer Ingelheim Co., Ltd. and lecture fees from AstraZeneca K.K. and Shionogi Co., Ltd. outside of the submitted work. H.A. received grants from Ono Pharmaceutical Co., Ltd., MSD K.K., and Chugai Pharmaceutical Co., Ltd., and personal fees from Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb Co., Ltd., and MSD K.K. outside of the submitted work. Y.A. received grants and personal fees from Chugai Pharmaceutical Co., Ltd., and personal fees from Ono Pharmaceutical Co., Ltd., MSD K.K., and AstraZeneca K.K., outside of the submitted work. Y.A. is an Editorial Board member of Cancer Science.

Figures

Graphical Abstract
Graphical Abstract
Figure 1.
Figure 1.
Flowchart of the patient selection process. ICI, Immune checkpoint inhibitor; irAE, Immune-related adverse event.
Figure 2.
Figure 2.
Median time to onset of grade 3/4 immune-related adverse events following immune checkpoint inhibitor therapy. IQR, Interquartile range.
Figure 3.
Figure 3.
Outcomes of immune checkpoint inhibitor retreatment after initial immune-related adverse events. (A) Frequency of recurrent or new irAEs after ICI retreatment. (B) Comparison of best antitumor response before initial irAE and after ICI retreatment. (C) Duration of ICI administration after initiation of retreatment. (D) Competing risk analysis of causes for ICI discontinuation after retreatment. Abbreviations: CR, Complete response; CI, Confidence interval; ICI, Immune checkpoint inhibitor; irAEs, Immune-related adverse events; PR, Partial response; PD, Progressive disease; SD, Stable disease.
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