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Lessons to be Learnt from Real-World Studies on Immune-Related Adverse Events with Checkpoint Inhibitors: A Clinical Perspective from Pharmacovigilance
Open accessAbstract
The advent of immune checkpoint inhibitors (ICIs) caused a paradigm shift both in drug development and clinical practice; however, by virtue of their mechanism of action, the excessively activated immune system results in a multitude of off-target toxicities, the so-called immune-related adverse events (irAEs), requiring new skills for timely diagnosis and a multidisciplinary approach to successfully manage the patients. In the recent past, a plethora of large-scale pharmacovigilance analyses have characterized various irAEs in terms of spectrum and clinical features in the real world. This review aims to summarize and critically appraise the current landscape of pharmacovigilance studies, thus deriving take-home messages for oncologists. A brief primer to study design, conduction, and data interpretation is also offered. As of February 2020, 30 real-world postmarketing studies have characterized multiple irAEs through international spontaneous reporting systems, namely WHO Vigibase and the US FDA Adverse Event Reporting System. The majority of studies investigated a single irAE and provided new epidemiological evidence about class-specific patterns of irAEs (i.e. anti-cytotoxic T-lymphocyte antigen 4 [CTLA-4] versus anti-programmed cell death 1 [PD-1] receptor, and its ligand [PD-L1]), kinetics of appearance, co-occurrences (overlap) among irAEs, and fatality rate. Oncologists should be aware of both strengths and limitations of these pharmacovigilance analyses, especially in terms of data interpretation. Optimal management (including rechallenge), predictivity of irAEs (as potential biomarkers of effectiveness), and comparative safety of ICIs (also in terms of combination regimens) represent key research priorities for next-generation real-world studies.
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“the added value of pharmacovigilance studies has already been demonstrated in various settings (3, 4, 7, 8).”
From The Changing Face of Drug-induced Adrenal Insufficiency in the Food and Drug Administration Adverse Event Reporting System (2022) · cites this paper as [4]
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Cites
Immune-Related Adverse Events Associated with Immune Checkpoint Blockade
Postow, M. A., Sidlow, R., & Hellmann, M. D. (2018) · New England Journal of Medicine · doi:10.1056/nejmra1703481 · Cited by 4,849
Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer
Schmid, P., Adams, S., Rugo, H. S., Schneeweiss, A., Barrios, C. H., Iwata, H., Diéras, V., Hegg, R., Im, S.-A., Shaw Wright, G., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1809615 · Cited by 4,350
Brahmer, J. R., Lacchetti, C., Schneider, B. J., Atkins, M. B., Brassil, K. J., Caterino, J. M., Chau, I., Ernstoff, M. S., Gardner, J. M., Ginex, P., et al. (2018) · Journal of Clinical Oncology · doi:10.1200/jco.2017.77.6385 · Cited by 3,713
First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer
Horn, L., Mansfield, A. S., Szczęsna, A., Havel, L., Krzakowski, M., Hochmair, M. J., Huemer, F., Losonczy, G., Johnson, M. L., Nishio, M., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1809064 · Cited by 3,586
Wang, D. Y., Salem, J.-E., Cohen, J. V., Chandra, S., Menzer, C., Ye, F., Zhao, S., Das, S., Beckermann, K. E., Ha, L., et al. (2018) · JAMA Oncology · doi:10.1001/jamaoncol.2018.3923 · Cited by 2,674
Haanen, J. B. A. G., Carbonnel, F., Robert, C., Kerr, K. M., Peters, S., Larkin, J., & Jordan, K. (2017) · Annals of Oncology · doi:10.1093/annonc/mdx225 · Cited by 2,367
Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance
Martins, F., Sofiya, L., Sykiotis, G. P., Lamine, F., Maillard, M., Fraga, M., Shabafrouz, K., Ribi, C., Cairoli, A., Guex-Crosier, Y., et al. (2019) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-019-0218-0 · Cited by 2,314
on behalf of the Society for Immunotherapy of Cancer Toxicity Management Working Group, Puzanov, I., Diab, A., Abdallah, K., Bingham, C. O., Brogdon, C., Dadu, R., Hamad, L., Kim, S., Lacouture, M. E., et al. (2017) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-017-0300-z · Cited by 1,992
Salem, J.-E., Manouchehri, A., Moey, M., Lebrun-Vignes, B., Bastarache, L., Pariente, A., Gobert, A., Spano, J.-P., Balko, J. M., Bonaca, M. P., et al. (2018) · The Lancet Oncology · doi:10.1016/s1470-2045(18)30608-9 · Cited by 1,271
Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors
Das, S., & Johnson, D. B. (2019) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-019-0805-8 · Cited by 1,145
Cited by
Sorted by citations
Schneider, B. J., Naidoo, J., Santomasso, B., Lacchetti, C., Adkins, S., Anadkat, M. J., Atkins, M. B., Brassil, K. J., Caterino, J. M., Chau, I., et al. (2021) · Journal of Clinical Oncology · doi:10.1200/jco.21.01440 · Cited by 2,536
“In general, patients receiving anti–PD-1 or PD-L1 antibodies have a lower incidence of any-grade irAEs than those treated with anti–CTLA-4 agents, with combinations increasing the incidence, severity, and onset of irAEs.(3) Variable onsets have been described for the different toxicities, from early occurrence within…”
BackgroundClinical cancer immunotherapy: Current progress and prospects
Liu, C., Yang, M., Zhang, D., Chen, M., & Zhu, D. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.961805 · Cited by 261
Conducting and interpreting disproportionality analyses derived from spontaneous reporting systems
Cutroneo, P. M., Sartori, D., Tuccori, M., Crisafulli, S., Battini, V., Carnovale, C., Rafaniello, C., Capuano, A., Poluzzi, E., Moretti, U., et al. (2024) · Frontiers in Drug Safety and Regulation · doi:10.3389/fdsfr.2023.1323057 · Cited by 224
Self-citationAdverse Cardiovascular and Pulmonary Events Associated With Chimeric Antigen Receptor T-Cell Therapy
Goldman, A., Maor, E., Bomze, D., Liu, J. E., Herrmann, J., Fein, J. A., Steingart, R. M., Mahmood, S., Schaffer, W. L., Perales, M., et al. (2021) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2021.08.044 · Cited by 159
Chen, C., Wu, B., Zhang, C., & Xu, T. (2021) · International Immunopharmacology · doi:10.1016/j.intimp.2021.107498 · Cited by 136
Raschi, E., Fusaroli, M., Ardizzoni, A., Poluzzi, E., & Ponti, F. D. (2020) · Breast Cancer Research and Treatment · doi:10.1007/s10549-020-06001-w · Cited by 106
“The study was conceived as an observational, retrospective pharmacovigilance analysis of the FAERS database, which has gained considerable interest in the medical community [10].”
BackgroundMethodInfluentialSelf-citationDaniello, L., Elshiaty, M., Bozorgmehr, F., Kuon, J., Kazdal, D. N., Schindler, H., Shah, R., Volckmar, A., Lusky, F., Diekmann, L., et al. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.703893 · Cited by 70
Raschi, E., Fusaroli, M., Plaça, M. L., Ardizzoni, A., Zamagni, C., Poluzzi, E., & Ponti, F. D. (2021) · American Journal of Clinical Dermatology · doi:10.1007/s40257-021-00645-0 · Cited by 61
Self-citationFusaroli, M., Isgrò, V., Cutroneo, P. M., Ferrajolo, C., Cirillo, V., Bufalo, F. D., Raschi, E., Poluzzi, E., & Trifirò, G. (2022) · Drug Safety · doi:10.1007/s40264-022-01194-z · Cited by 59
“Disproportionality analyses on the FAERS database have already been applied with success to the oncological field, particularly to immunotherapy [20].”
MethodSelf-citationCecco, S., Puligheddu, S., Fusaroli, M., Gerratana, L., Yan, M., Zamagni, C., Ponti, F. D., & Raschi, E. (2024) · Targeted Oncology · doi:10.1007/s11523-024-01058-9 · Cited by 54
“…AEs, individual case safety reports (ICSRs) databases represent a valuable source for post-marketing surveillance and better characterization of AEs occurring in the real-life multifaceted scenario of patients with comorbidities and poly-pharmacotherapy receiving complex anticancer regimens [15].”
Self-citationKhouri, C., Revol, B., Lepelley, M., Mouffak, A., Bernardeau, C., Salvo, F., Pariente, A., Roustit, M., & Cracowski, J. (2021) · Journal of Clinical Epidemiology · doi:10.1016/j.jclinepi.2021.07.014 · Cited by 51
Reynolds, K. L., Arora, S., Elayavilli, R. K., Louv, W. C., Schaller, T. H., Khandelwal, A., Rothenberg, M. L., Khozin, S., Guidon, A. C., Dougan, M. L., et al. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-002896 · Cited by 48
The evolving role of disproportionality analysis in pharmacovigilance
Fusaroli, M., Raschi, E., Poluzzi, E., & Hauben, M. (2024) · Expert Opinion on Drug Safety · doi:10.1080/14740338.2024.2368817 · Cited by 47
“…event), typical of anticancer drugs because of multiple therapeutic regimens, multiple lines of therapy, and frequent confounding and effect modification (e.g. drug – disease interactions) [62], can be only inadequately mitigated restricting to serious outcomes as a proxy of disease severity [43].”
Self-citationCardiovascular Toxicity of Immune Checkpoint Inhibitors: A Guide for Clinicians
Raschi, E., Rossi, S., Giglio, A. D., Fusaroli, M., Burgazzi, F., Rinaldi, R., & Potena, L. (2023) · Drug Safety · doi:10.1007/s40264-023-01320-5 · Cited by 48
“, endocrinopathies after > 6 months, even after ICI interruption) [11], with a median onset of 40 days [12].”
BackgroundSelf-citationFilippini, D. M., Gatti, M., Martino, V. D., Cavalieri, S., Fusaroli, M., Ardizzoni, A., Raschi, E., & Licitra, L. F. (2021) · International Journal of Cancer · doi:10.1002/ijc.33592 · Cited by 45
“These postmarketing studies are particularly suited to early detect rare, unexpected and delayed adverse events (AEs), which cannot be fully appreciated in pivotal trials (where only irAEs occurring in at least 5% of patients were reported), and are recommended for real-time safety assessment of recently marketed drug…”
BackgroundSelf-citationRaschi, E., Fusaroli, M., Ardizzoni, A., Poluzzi, E., & Ponti, F. D. (2021) · Cancers · doi:10.3390/cancers13081758 · Cited by 46
Self-citationBrower, B., McCoy, A. S., Ahmad, H., Eitman, C., Bowman, I. A., Rembisz, J., & Milowsky, M. I. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1326715 · Cited by 44
“Although irAEs can occur early in treatment, onset may be delayed and duration is prolonged (31, 32, 37, 38).”
BackgroundGatti, M., Turrini, E., Raschi, E., Sestili, P., & Fimognari, C. (2021) · Pharmaceuticals · doi:10.3390/ph14080738 · Cited by 45
“In particular, spontaneous reporting databases, such as the FDA Adverse Event Reporting System (FAERS) and WHOVigibase, have been successfully exploited to characterize the safety profile of drugs, thus informing clinical practice for proactive monitoring [45,46].”
BackgroundSelf-citationChen, C., Zhang, C., Jin, Z., Wu, B., & Xu, T. (2022) · International Journal of Clinical Pharmacy · doi:10.1007/s11096-022-01395-7 · Cited by 37
“, ICIs were classified by targets, which reduces channeling bias and confounding by disease-specific factors [12].”
BackgroundImmune Checkpoint Inhibitors and Pregnancy: Analysis of the VigiBase® Spontaneous Reporting System
Noseda, R., Müller, L., Bedussi, F., Fusaroli, M., Raschi, E., & Ceschi, A. (2022) · Cancers · doi:10.3390/cancers15010173 · Cited by 37
“We used three reference groups as comparators: (i) the entire database, (ii) only safety reports suspecting antineoplastic agents different from ICIs (using the anatomical, therapeutic and chemical, ATC, code L01) to control confounding by indication [33], and (iii) only safety reports suspecting antineoplastic agents…”
MethodSelf-citationMa, R., Wang, Q., Meng, D., Li, K., & Zhang, Y. (2021) · BMC Cancer · doi:10.1186/s12885-020-07741-0 · Cited by 38
“Secondly, although ROR, PRR, and IC are called quanti cation signal detection approaches, they are only simple indicators of potential safety issues and cannot quantitatively calculate the incidence (occurrence rates) and the risk of ADRs[4, 13].”
BackgroundInfluentialHyperglycaemic disorders associated with PCSK9 inhibitors: a real-world, pharmacovigilance study
Goldman, A., Raschi, E., Cukierman‐Yaffe, T., Dankner, R. S., Shouval, R., Shechter, M., Ben‐Zvi, I., Gerstein, H. C., & Maor, E. (2021) · European Journal of Preventive Cardiology · doi:10.1093/eurjpc/zwab209 · Cited by 38
Self-citationBenesova, K., Kraus, F. V., Carvalho, R. A., Lorenz, H., Hoerth, C. H., Günther, J., Klika, K. D., Graf, J., Diekmann, L., Schank, T. E., et al. (2022) · Annals of the Rheumatic Diseases · doi:10.1136/ard-2022-222451 · Cited by 39
“…severe irAEs in any organ in the ICI-CNT and the fact that patients exposed to anti- CTLA-4 or the combination treatment generally show a higher incidence, increased severity and faster onset of irAEs 23 24 and, therefore, are less likely to remain irAE free over a longer period of ICI treatment.”
A real-world pharmacovigilance study investigating the toxicities of histone deacetylase inhibitors
Li, W., Fu, Y., & Wang, W. (2024) · Annals of Hematology · doi:10.1007/s00277-024-05691-2 · Cited by 35
Goldman, A., Galper, B.-E. L., Druyan, A., Grossman, C., Sharif, Κ., Shechtman, L., Moshkovits, Y., Lahat, A., & Ben‐Zvi, I. (2024) · Seminars in Arthritis and Rheumatism · doi:10.1016/j.semarthrit.2024.152461 · Cited by 34
Goldman, A., Bomze, D., Dankner, R. S., Fourey, D., Boursi, B., Arad, M., & Maor, E. (2021) · Targeted Oncology · doi:10.1007/s11523-021-00817-2 · Cited by 33
Le, T. K., Brown, I. D., Goldberg, R., Taylor, M. T., Deng, J., Parthasarathy, V., Bordeaux, Z. A., Alphonse, M. P., Kwatra, M. M., Naranbhai, V., et al. (2022) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2022.04.020 · Cited by 32
Noseda, R., Bedussi, F., Gobbi, C., Ceschi, A., & Zecca, C. (2023) · Cephalalgia · doi:10.1177/03331024231158083 · Cited by 31
“Accordingly, the ROR is not a measure of risk and does not inform about the incidence of an adverse event of interest, rather, as signal of disproportionate reporting, it indicates that a statistically significant disproportionality exists in the reporting frequency of that adverse event (48).”
BackgroundNoseda, R., Ruinelli, L., van der Gaag, L. C., & Ceschi, A. (2020) · Cancers · doi:10.3390/cancers12113480 · Cited by 34
“Lastly, instead of querying VigiBase to generate hypotheses, as has been widely done in pharmacovigilance studies on ICIs through disproportionality analysis [38], we used VigiBase to test a hypothesis.”
MethodJiang, T., Su, H., Xu, J., Li, C., Zhang, N., Li, Y., Wu, Y., Ni, R., Ming, Y., Li, Z., et al. (2024) · Therapeutic Advances in Drug Safety · doi:10.1177/20420986231224227 · Cited by 30
“8,9 Recently, some studies have evaluated drug-specific lung injury through the FAERS database.”
BackgroundXia, S., Gong, H., Wang, Y., Liu, L., Zhao, Y., Guo, L., Zhang, B., Sarangdhar, M., Noguchi, Y., & Yan, M. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1129730 · Cited by 28
“The analysis of spontaneous reporting databases, such as the FDA Adverse Even Reporting System (FAERS) and WHO Vigibase, allows a broader perspective by collecting unpublished reports of adverse events submitted all over the world occurring in real-world unselected subjects with comorbidities, poly-pharmacotherapy and…”
BackgroundRong, Y., Bentley, J. P., Bhattacharya, K., Yang, Y., Chang, Y., Earl, S. R., & Ramachandran, S. (2024) · Cancer Medicine · doi:10.1002/cam4.6879 · Cited by 29
Checkpoint Inhibitor-Induced Colitis: An Update
Losurdo, G., Angelillo, D., Favia, N., Sergi, M. C., Leo, A. D., Triggiano, G., & Tucci, M. (2023) · Biomedicines · doi:10.3390/biomedicines11051496 · Cited by 28
“Immune-related adverse events (IrAEs) generally arise within weeks to months after treatment initiation (a median onset of approximately 40 days) and may be defined as “acute” if they develop during treatment, “delayed” if they appear following ICI completion, and “chronic” if they persist beyond 12 weeks after discon…”
BackgroundSun, J.-Y., Qu, Q., Lou, Y.-X., Yang, H., Sun, G.-Z., Sun, W., & Kong, X. (2021) · International Journal of Cardiology · doi:10.1016/j.ijcard.2021.09.041 · Cited by 27
Emerging Ocular Side Effects of Immune Checkpoint Inhibitors: A Comprehensive Review
Wu, K. Y., Yakobi, Y., Gueorguieva, D. D., & Mazerolle, É. (2024) · Biomedicines · doi:10.3390/biomedicines12112547 · Cited by 28
“It would be interesting to examine whether such a trend exists in the eye, being an immune-privileged organ [110,161].”
Real-world studies: bridging the gap between trial-assessed efficacy and routine care
Chen, D. (2022) · Journal of Biomedical Research · doi:10.7555/jbr.36.20220040 · Cited by 26
Sisi, M., Fusaroli, M., Giglio, A. D., Facchinetti, F., Ardizzoni, A., Raschi, E., & Gelsomino, F. (2022) · Targeted Oncology · doi:10.1007/s11523-021-00865-8 · Cited by 27
“The study was conceived as an observational, retrospective pharmacovigilance analysis of FAERS, a recognized source for timely real-world safety assessment of anticancer drugs [16].”
BackgroundSelf-citationReporting of late-onset immune-related adverse events with immune checkpoint inhibitors in VigiBase
Noseda, R., Bedussi, F., Giunchi, V., Fusaroli, M., Raschi, E., & Ceschi, A. (2024) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2024-009902 · Cited by 28
“…(ICSRs) of suspected adverse drug reactions (ADRs) represents a privileged setting to characterize their spectrum and relevant clinical features, 19 20 together with their onset timing from drug discontinuation and possible drug-related and patient-related characteristics associated with their…”
Self-citationCheng, Y., Ling, F., Li, J., Chen, Y., Xu, M., Li, S., & Zhu, L. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1190850 · Cited by 23
Zhang, Y., Fang, Y. V., Wu, J., Huang, G., Bin, J., Liao, Y., Shi, M., Liao, W., & Huang, N. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.817662 · Cited by 23
“For example, gastrointestinal (colitis) and endocrine toxicity (hypophysitis, adrenal insufficiency, hypopituitarism) were more preferentially reported with anti-CTLA-4, whereas thyroid dysfunction, pneumonitis and myocarditis were more frequently recorded with anti-PD-1/PD-L1 (Raschi et al., 2020).”
BackgroundRaschi, E., Salvo, F., & Khouri, C. (2022) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.15269 · Cited by 21
“planned protocol, together with the relative simplicity in data analyses, generated a plethora of publications, sometimes redundant, especially in the cardiovascular and oncological areas.(1) The latest metaepidemiological investigations found major concerns on transparency and reporting of disproportionality analyses…”
BackgroundSelf-citationFusaroli, M., Salvo, F., Bernardeau, C., Idris, M., Dolladille, C., Pariente, A., Poluzzi, E., Raschi, E., & Khouri, C. (2023) · Drug Safety · doi:10.1007/s40264-023-01329-w · Cited by 21
“Despite being a starting evidence, disproportionality signals are increasingly published in the literature, with hundreds of safety signals generated each year [2, 13, 16].”
BackgroundSelf-citationRaschi, E., Fusaroli, M., Giunchi, V., Repaci, A., Pelusi, C., Mollica, V., Massari, F., Ardizzoni, A., Poluzzi, E., Pagotto, U., et al. (2022) · Cancers · doi:10.3390/cancers14194610 · Cited by 21
“The analysis of spontaneous reporting databases, such as the FDA Adverse Event Reporting System (FAERS), allows a broader perspective by collecting unpublished reports of AEs submitted worldwide occurring in real-world unselected subjects with comorbidities, poly-pharmacotherapy and complex anticancer combination regi…”
BackgroundSelf-citationJiang, T., Su, H., Li, Y., Wu, Y., Ming, Y., Li, C., Fu, R., Feng, L., Li, Z., Li, L., et al. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.989032 · Cited by 21
“contains patient data outside clinical trials and can be used for post-marketing surveillance (Raschi et al., 2019; Raschi et al., 2020).”
Fusaroli, M., Salvo, F., Khouri, C., & Raschi, E. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1488725 · Cited by 18
Self-citationRaschi, E., Fusaroli, M., Massari, F., Mollica, V., Repaci, A., Ardizzoni, A., Poluzzi, E., Pagotto, U., & Di Dalmazi, G. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgac359 · Cited by 17
Self-citationAdverse Events Associated with Immune Checkpoint Inhibitors: Overview of Systematic Reviews
Kanji, S., Morin, S., Agtarap, K., Purkayastha, D., Thabet, P., Bossé, D., Wang, X., Lunny, C., & Hutton, B. (2022) · Drugs · doi:10.1007/s40265-022-01707-1 · Cited by 18
“It is worth mentioning that pharmacovigilance, particularly through spontaneous reporting databases, may be a practical way to characterize rare AEs [90].”
BackgroundMatsukane, R., Suetsugu, K., Hata, K., Matsuda, K., Nakao, S., Minami, H., Watanabe, H. A., Hirota, T., Egashira, N., & Ieiri, I. (2023) · International Journal of Clinical Oncology · doi:10.1007/s10147-023-02349-3 · Cited by 19
“However, information on irAE from clinical trials or pharmacovigilance databases is insufficient to improve irAE management [12, 13].”
BackgroundManaging Select Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitors
Cheema, P. K., Iafolla, M. A. J., Abdel-Qadir, H. M., Bellini, A. B., Chatur, N., Chandok, N., Comondore, V. R., Cunningham, M. E., Halperin, I. J., Hu, A. C., et al. (2024) · Current Oncology · doi:10.3390/curroncol31100473 · Cited by 18
“The incidence and onset of irAEs vary based on the class and dose of the ICI administered, the type of cancer, and patient-related factors [3].”
Backgroundde Moraes, F. C. A., Kreuz, M., de Lara, I. C. A., Lôbo, A. D. O. M., & Burbano, R. M. R. (2024) · BMC Cancer · doi:10.1186/s12885-024-13129-1 · Cited by 18
“Adverse events associated with cancer treatment, especially those of grade 3 or higher, significantly impact the quality of life in cancer patients, particularly those with MCC, which often develops in the older population, affecting both their physical and emotional well-being [38, 49–52].”
BackgroundLiang, Y., Zheng, Y., Zeng, Y., Hu, C., Si, Y., Fan, X., & Chen, Q. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1691608 · Cited by 18
Fusaroli, M., Raschi, E., Gatti, M., Ponti, F. D., & Poluzzi, E. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.740707 · Cited by 15
Self-citationChitnis, S. D., & Mortazavi, A. (2023) · Journal of Hospital Medicine · doi:10.1002/jhm.13097 · Cited by 14
Goldman, A., Raschi, E., Druyan, A., Sharif, Κ., Lahat, A., Ben‐Zvi, I., & Ben‐Horin, S. (2024) · United European Gastroenterology Journal · doi:10.1002/ueg2.12736 · Cited by 14
Self-citationHuang, J., Zhao, Y., Cao, Y., Zhang, Q., Ran, D., Li, J., Luo, L., Qiu, F., & Meng, L. (2022) · International Journal of Clinical Pharmacy · doi:10.1007/s11096-022-01425-4 · Cited by 14
“In other words, the ROR or IC suggests an increased risk of AEs reported rather than the risk of AE occurrence [31].”
BackgroundNoseda, R., Bonaldo, G., Motola, D., Stathis, A., & Ceschi, A. (2021) · Cancers · doi:10.3390/cancers13051131 · Cited by 14
“Disproportionality analysis is a valuable methodological approach well consolidated and extensively used in pharmacovigilance studies on databases of spontaneous reporting to characterize ICI toxicity [19].”
BackgroundMethodInfluentialImmune-related adverse events in older adults: Data mining of the FDA Adverse Event Reporting System
Chen, C., Zhang, C., Wu, B., & Xu, T. (2022) · Journal of Geriatric Oncology · doi:10.1016/j.jgo.2022.05.009 · Cited by 14
Sugai, M., Amino, Y., Fujishima, S., Nibuya, K., Iso, H., Ito, M., Tsugitomi, R., Ariyasu, R., Uchibori, K., Yanagitani, N., et al. (2025) · Lung Cancer · doi:10.1016/j.lungcan.2025.108555 · Cited by 15
Cui, C., Deng, L., Wang, W., Ren, X., Wang, Y., & Cui, W. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.941079 · Cited by 12
Peng, Y., Yan, H., Mei, W., Zhang, P., & Zeng, C. (2023) · Current Treatment Options in Oncology · doi:10.1007/s11864-023-01128-6 · Cited by 11
Gatti, M., Raschi, E., Moretti, U., Ardizzoni, A., Poluzzi, E., & Diemberger, I. (2021) · Vaccines · doi:10.3390/vaccines9010019 · Cited by 11
“By offering a global epidemiological perspective, these pharmacovigilance studies have been pursued to test the hypothesis of potential associations, including refusing the likelihood of interactions [3,16,17], especially for rare, unexpected, and delayed AEs, such as MP.”
BackgroundSelf-citationRelatlimab and nivolumab in untreated advanced melanoma: insight into RELATIVITY
Raschi, E., Comito, F., Massari, F., & Gelsomino, F. (2023) · Immunotherapy · doi:10.2217/imt-2022-0172 · Cited by 11
Self-citationSafety of current immune checkpoint inhibitors in non-small cell lung cancer
Abdayem, P., & Planchard, D. (2021) · Expert Opinion on Drug Safety · doi:10.1080/14740338.2021.1867100 · Cited by 10
18F-FDG PET/CT for Detection of Immunotherapy-Induced Hypophysitis—A Case-Control Study
Fischer, A., Gómez, J. M. M., Mangana, J., Dummer, R., Erlic, Z., Nölting, S., Beuschlein, F., Maurer, A. B., Messerli, M., Huellner, M. W., et al. (2024) · Clinical Nuclear Medicine · doi:10.1097/rlu.0000000000005440 · Cited by 10
Germline prediction of immune checkpoint inhibitor discontinuation for immune-related adverse events
Middha, P., Thummalapalli, R., Quandt, Z., Balaratnam, K., Cardenas, E. R., Falcon, C. J., Princess Margaret Lung Group, Gubens, M. A., Huntsman, S., Khan, K., et al. (2025) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2024-011273 · Cited by 12
Immune Checkpoint Inhibitors Related to Cardiotoxicity
Chen, R., Zhou, M., & Zhu, F. (2022) · Journal of Cardiovascular Development and Disease · doi:10.3390/jcdd9110378 · Cited by 12
“Pembrolizumab PD-1 2014 (FDA) Melanoma, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous cell cancer, Hodgkin’s lymphoma, colorectal cancer, urothelial carcinoma, hepatocellular carcinoma, large B-cell lymphoma, gastric cancer, esophageal cancer, cervical cancer, renal cell carcinoma, and Mer…”
BackgroundCao, J., Li, J., Yang, X. L., Li, P., Yao, Z., Han, D., Ying, L., Wang, L., & Tian, J. (2021) · Cancer Medicine · doi:10.1002/cam4.4071 · Cited by 10
Pulmonary Toxicities of Immunotherapy
Altan, M., Zhong, L., Shannon, V. R., & Sheshadri, A. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-79308-1_14 · Cited by 10
Cortellini, A., Dettorre, G. M., Dafni, U., Castelo-Branco, L., Lambertini, M., Gennatas, S., Angelis, V., Sita-Lumsden, A. R., Rogado, J., Pedrazzoli, P., et al. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-005732 · Cited by 10
Siu, D. H. W., O'Neill, R. S., Harris, C. A., Wang, J., Ardolino, L., Downton, T. D., Tong, M., Hong, J. H., Chin, V. T., Clingan, P. R., et al. (2022) · Immunotherapy · doi:10.2217/imt-2021-0225 · Cited by 13
Lev, D., Leibowitz, A., Lang, A., Shlomai, G., Twig, G., Eden-Friedman, Y., Engel, T., Cukierman-Yaffe, T., Dankner, R. S., Gerstein, H. C., et al. (2026) · Clinical Nutrition · doi:10.1016/j.clnu.2025.106571 · Cited by 12
Immune Checkpoint Inhibitor-Induced Hepatic Injury: A Clinicopathologic Review
Taherian, M., Chatterjee, D., & Wang, H. (2022) · Journal of Clinical and Translational Pathology · doi:10.14218/jctp.2022.00017 · Cited by 9
Levi, J., & Hong, S. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1113924 · Cited by 9
Nakamura, H., Shionoya, A., Arihara, Y., Hayasaka, N., Kubo, T., Usami, M., Sugita, S., Uhara, H., & Takada, K. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1259071 · Cited by 10
Kuusisalo, S., Koivunen, J. P., & Iivanainen, S. (2022) · Cancers · doi:10.3390/cancers14092276 · Cited by 9
“RWE studies of ICI TREAs are scarce, but some investigators have identified that TRAEs are more common in RWE settings [32,33].”
BackgroundYamamoto, T., Mizuno, K., Ito, T., Yokoyama, S., Yamamoto, K., Imai, N., Ishizu, Y., Honda, T., Ishikawa, T., Kanamori, A., et al. (2023) · Investigational New Drugs · doi:10.1007/s10637-023-01366-3 · Cited by 10
Xia, S., Ma, J., Raschi, E., Ma, R., Zhang, B., Guo, L., Noguchi, Y., Sarangdhar, M., Gong, H., & Yan, M. (2023) · Clinical Drug Investigation · doi:10.1007/s40261-023-01308-0 · Cited by 9
“…exploited for the accurate and timely safety assessment of medications, especially for anti-cancer drugs receiving fast-track approval, extended indications, and to characterize serious adverse events (AEs) such as TLS, which may not be fully appreciated in the pre-marketing setting [12].”
BackgroundSelf-citationLu, Y., Xu, Q., & Zhu, S. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1486422 · Cited by 8
Gui, J., Wang, L., Meng, L., Zhang, X., Ma, J., & Jiang, L. (2025) · Acta Epileptologica · doi:10.1186/s42494-025-00223-5 · Cited by 8
Abdihamid, O., Athman, A., & Rugambwa, T. K. (2021) · ecancermedicalscience · doi:10.3332/ecancer.2021.1314 · Cited by 9
“Although most irAEs are identified during pre-clinical development, the spectrum, timing and outcomes were only recently investigated through real-world, large-scale pharmacovigilance analyses like the spontaneous reporting systems that looked at the real-time monitoring of these drugs’ safety profiles [16].”
BackgroundGastrointestinal disorders as immune-related adverse events
Balducci, D., Quatraccioni, C., Benedetti, A., Marzioni, M., & Maroni, L. (2021) · Exploration of Targeted Anti-tumor Therapy · doi:10.37349/etat.2021.00039 · Cited by 8
“GI and endocrine disorders were more frequent with anti-CTLA-4 agents, while myocarditis and autoimmune hepatitis were reported predominantly with anti-PD-1/PD-L1 drugs [27].”
BackgroundYang, Y., Xu, L., Wang, D., Hui, B., Li, X., Zhou, Y., Chen, X., & Gu, Y. (2021) · Immunotherapy · doi:10.2217/imt-2020-0327 · Cited by 8
Immune checkpoint inhibitors-induced diabetes mellitus (review)
Chen, J., Hou, X., Yang, Y., Wang, C., Zhou, J., Miao, J., Gong, F., Ge, F., & Chen, W. (2024) · Endocrine · doi:10.1007/s12020-024-03942-w · Cited by 7
“…effects include dermatological issues (such as rashes, pruritus, and xerosis), hand-foot syndrome, gastrointestinal problems (nausea, vomiting, diarrhea, and abdominal pain), decreased appetite, abnormal liver function, elevated blood glucose levels, and immune-related thyroid dysfunctions [5].”
A Real-World Comparison of the Safety Profile for Immune Checkpoint Inhibitors in Oncology Patients
Alwhaibi, A. M., Alenazi, M. A., Alghadeer, S. M., Mansy, W., Alsaif, R., Abualreesh, N. E., Alanazi, R. J., Alroumi, A., & Alanazi, S. A. (2025) · Journal of Clinical Medicine · doi:10.3390/jcm14020388 · Cited by 8
Ito, T., Mizuno, K., Yamamoto, T., Yasuda, T., Yokoyama, S., Yamamoto, K., Imai, N., Ishizu, Y., Honda, T., Hama, M., et al. (2024) · Hepatology Research · doi:10.1111/hepr.14043 · Cited by 7
Abdel-Rahman, O. M. (2021) · Immunotherapy · doi:10.2217/imt-2021-0068 · Cited by 7
Zhu, J., Luo, M., Liang, D., Gao, S., Zheng, Y., He, Z., Zhao, W., Yu, X., Qiu, K., & Wu, J. (2022) · International Immunopharmacology · doi:10.1016/j.intimp.2022.109053 · Cited by 8
Mazzarella, L., Giugliano, F., Nicolò, E., Espósito, A., Crimini, E., Tini, G., Uliano, J., Corti, C., D’Amico, P., Aliaga, P. T., et al. (2023) · The Oncologist · doi:10.1093/oncolo/oyad239 · Cited by 7
Immune-related intestinal pseudo-obstruction caused by immune checkpoint inhibitors: case report
Qian, Y., Zheng, Z., Ai, J., Kang, L., Qiu, G., Huang, X., & Zhao, J. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1415117 · Cited by 7
“GI irAEs are driven by multiple immunological and molecular mechanisms, including autoantibody production (12), molecular mimicry (13), cytokine production (14), and in fl uences from the gut microbiome (15) and genetic factors (16).”
BackgroundAiello, V., Fusaroli, M., Raschi, E., Palazzini, M., Hu, L., Barbuto, S., Poluzzi, E., & Capelli, I. (2021) · Kidney International Reports · doi:10.1016/j.ekir.2021.06.028 · Cited by 7
Self-citationRadwan, A., Jani, C., Omari, O. A., Patel, M., Burns, L., Mackay, Z., Li, L., Mahdaviani, K., Davidson, A., Weinberg, J., et al. (2024) · The Oncologist · doi:10.1093/oncolo/oyae279 · Cited by 6
“58 Despite these limitations, this study is the first to demonstrate the association between irAEs and better survival outcomes in patients with NSCLC in a predominantly Black population, further supporting the importance of unbiased treatment recommendations without regard to race or ethnicity.”
Mechanisms underlying immune-related adverse events during checkpoint immunotherapy
Zhou, X., Chen, X., Han, L., & Liu, H. (2022) · Clinical Science · doi:10.1042/cs20210042 · Cited by 6
Ebinama, U., Sheshadri, A., Anand, K., & Iyer, S. P. (2023) · Journal of Immunotherapy and Precision Oncology · doi:10.36401/jipo-22-38 · Cited by 6
“[3,10,11]”
Kielkowski, B. N., Mansour, D., Ebbert, B., Seago, K., Wen, S., Li, H., & Barrett, C. (2024) · Journal of Oncology Pharmacy Practice · doi:10.1177/10781552241303698 · Cited by 6
“18 The onset of irAEs in this study generally aligned with patients in other studies.”
Cesario, S., Genovesi, V., Salani, F., Vasile, E., Fornaro, L., Vivaldi, C., & Masi, G. (2023) · Life · doi:10.3390/life13071562 · Cited by 6
“In general, those receiving anti–PD-1 or PD-L1 monotherapy were exposed to a lower incidence of any-grade irAEs than anti–CTLA-4 agents, with combinations increasing the incidence, severity and onset of irAEs [124].”
Backgroundda Silva, G. F. M., Landim, J. I. V. D., BRASIL, L. T. D. S., Plens, I. C. M., Silva, A. L. C., Scheinberg, M. A., & Rocha, F. A. C. (2020) · Rheumatology International · doi:10.1007/s00296-020-04674-6 · Cited by 6
Wang, Y., Meng, L., & Liu, X. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1412938 · Cited by 5
Inoue, T., & Narukawa, M. (2024) · Clinical Oncology · doi:10.1016/j.clon.2024.10.034 · Cited by 5
Koseki, T., Hamano, H., Hatano, M., Tobe, T., Ieda, R., Nakai, T., Zamami, Y., & Yamada, S. (2025) · Pharmaceuticals · doi:10.3390/ph18030333 · Cited by 5
“Recently, pharmacovigilance signal detection studies have increasingly utilized large-scale databases of adverse drug reactions (ADRs) collected through spontaneous reporting systems [24,25].”
Moffat, G. T., Hanna, L., Hopman, W. M., Fung, A. S., & Gaudreau, P.-O. (2023) · Immunotherapy · doi:10.2217/imt-2022-0257 · Cited by 5
Metadata
- Authors
- Raschi, E., Gatti, M., Gelsomino, F., Ardizzoni, A., Poluzzi, E., & De Ponti, F.
- Affiliations
- University of Bologna (IT)
- IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola (IT)
- Corresponding author
- Raschi, Emanuel
- Venue
- Targeted Oncology
- Published
- 2020-07-28
- Volume
- 15
- Issue
- 4
- Pages
- 449-466
- ISSN
- 1776-2596 (ISSN-L)
- 1776-260X
- PMC
- PMC7434791
- OpenAlex
- W3046013618
- Cited by
- 157
- References
- 103
- Citations by year
- 2026: 16 · 2025: 21 · 2024: 35 · 2023: 22 · 2022: 29 · 2021: 30 · 2020: 3
- FWCI
- 2.25
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Targeted Oncology (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion, cc-by-nc)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
- Health Sciences › Medicine › Pharmacology (medical) › Drug-Induced Adverse Reactions
- Keywords
- immune-related adverse events, immune checkpoint inhibitors, pharmacovigilance, real-world evidence, spontaneous adverse event reporting, CTLA-4 inhibitors, PD-1/PD-L1 inhibitors, irAE management, drug rechallenge, treatment response biomarkers
- MeSH terms
- Immune Checkpoint Inhibitors, Humans, Pharmacovigilance
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