Prevalence of immune-related adverse events and anti-tumor efficacy following immune checkpoint inhibitor therapy in Japanese patients with various solid tumors
Yuki Yoshikawa,
Michio Imamura,
Masami Yamauchi,
C. Nelson Hayes,
Hiroshi Aikata,
Wataru Okamoto,
Yoshihiro Miyata,
Morihito Okada,
Noboru Hattori,
Kazuhiko Sugiyama,
Yukio Yoshioka,
Shigeaki Toratani,
Masaaki Takechi,
Tatsuo Ichinohe,
Tsutomu Ueda,
Sachio Takeno,
Tsuyoshi Kobayashi,
Hideki Ohdan,
Jun Teishima,
Michihiro Hide,
Yasushi Nagata,
Yoshiki Kudo,
Koji Iida,
Kazuaki Chayama
Affiliations
Yuki Yoshikawa
Department of Gastroenterology, Graduate School of Biomedical and Health Science, Hiroshima University
Michio Imamura
Department of Gastroenterology, Graduate School of Biomedical and Health Science, Hiroshima University
Masami Yamauchi
Department of Gastroenterology, Graduate School of Biomedical and Health Science, Hiroshima University
C. Nelson Hayes
Department of Gastroenterology, Graduate School of Biomedical and Health Science, Hiroshima University
Hiroshi Aikata
Department of Gastroenterology, Graduate School of Biomedical and Health Science, Hiroshima University
Wataru Okamoto
Cancer Treatment Center, Hiroshima University Hospital
Yoshihiro Miyata
Department of Surgical Oncology, Hiroshima University
Morihito Okada
Department of Surgical Oncology, Hiroshima University
Noboru Hattori
Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University
Kazuhiko Sugiyama
Department of Clinical Oncology, Hiroshima University Hospital
Yukio Yoshioka
Department of Molecular Oral Medicine and Maxillofacial Surgery, Graduate School of Biomedical and Health Science, Hiroshima University
Shigeaki Toratani
Department of Molecular Oral Medicine and Maxillofacial Surgery, Graduate School of Biomedical and Health Science, Hiroshima University
Masaaki Takechi
Department of Oral and Maxillofacial Surgery, Program of Dentistry, Graduate School of Biomedical and Health Sciences, Hiroshima University
Tatsuo Ichinohe
Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University
Tsutomu Ueda
Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University
Sachio Takeno
Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University
Tsuyoshi Kobayashi
Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Science, Hiroshima University
Hideki Ohdan
Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Science, Hiroshima University
Jun Teishima
Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University
Michihiro Hide
Department of Dermatology, Graduate School of Biomedical and Sciences, Hiroshima University
Yasushi Nagata
Department of Radiation Oncology, Hiroshima University Hospital
Yoshiki Kudo
Department of Obstetrics and Gynecology, Graduate School of Biomedical Sciences, Hiroshima University
Koji Iida
Department of Neurosurgery, Graduate School of Biomedical and Health Sciences, Hiroshima University
Kazuaki Chayama
Department of Gastroenterology, Graduate School of Biomedical and Health Science, Hiroshima University
Abstract Background While immune checkpoint inhibitors (ICIs) occasionally cause immune-related adverse events (irAEs) in various organs, the prevalence of irAEs and potential risk factors have not been clarified. We identified irAE predictive factors and examined the relationship between the effect of ICIs and irAEs for patients with malignancies. Methods A total of 533 cases treated with ICIs, including programmed death 1 (PD-1), PD-ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4), for various malignancies were included retrospectively. We recorded irAEs from medical records and graded them using the Common Terminology Criteria for Adverse Events version 5. Prevalence and predictive factors associated with immune-related liver injury and the relationship between irAE and treatment response were analyzed. Results During a median of 10 (1–103) cycles with a median follow-up after several ICI initiations of 384 (21–1715) days, irAEs with all grades and with grade ≥ 3 developed in 144 (27.0%) and 57 (10.7%) cases. Cumulative irAE development rates were 21.9, 33.5, and 43.0% in all grades and 8.8, 14.9, and 20.7% in grade ≥ 3 at 5, 10, and 20 cycles, respectively. Patients who received anti-CTLA4 therapy were more likely to develop irAEs compared to those who received anti-PD-1 or anti-PD-L1 monotherapy. Liver injury was the most common irAE. Multivariate analysis identified the combination of PD-1 and anti-CTL-4 antibodies (hazard ratio [HR], 17.04; P < 0.0001) and baseline eosinophil count ≥130/μL (HR, 3.01 for < 130; P = 0.012) as independent risk factors for the incidence of immune-related liver injury with grade ≥ 2. Patients who developed irAEs had a higher disease control rate (P < 0.0001) and an increased overall survival rate compared to those without irAEs (P < 0.0001). Conclusion Combination therapy with anti-PD-1 and anti-CTL-4 antibodies resulted in higher a frequency of irAEs. Baseline absolute eosinophil count was found to be a predictive factor for immune-related liver injury. Occurrence of irAEs may be associated with higher efficacy of ICI treatment and longer survival among patients who receive ICI therapy.
