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Management of Immune-Related Adverse Events and Kinetics of Response With Ipilimumab
Abstract
Monoclonal antibodies directed against the immune checkpoint protein cytotoxic T-lymphocyte antigen-4 (CTLA-4; CD152)—ipilimumab and tremelimumab—have been investigated in metastatic melanoma and other cancers and have shown promising results. Recently, ipilimumab was approved by the US Food and Drug Administration for the treatment of metastatic melanoma. We review the literature on managing the adverse effects and kinetics of tumor regression with ipilimumab and provide guidelines on their management. During treatment with these antibodies, a unique set of adverse effects may occur, called immune-related adverse events (irAEs). These include rashes, which may rarely progress to life-threatening toxic epidermal necrolysis, and colitis, characterized by a mild to moderate, but occasionally also severe and persistent diarrhea. Hypophysitis, hepatitis, pancreatitis, iridocyclitis, lymphadenopathy, neuropathies, and nephritis have also been reported with ipilimumab. Early recognition of irAEs and initiation of treatment are critical to reduce the risk of sequelae. Interestingly, irAEs correlated with treatment response in some studies. Unique kinetics of response have been observed with CTLA-4 blockade with at least four patterns: (1) response in baseline lesions by week 12, with no new lesions seen; (2) stable disease, followed by a slow, steady decline in total tumor burden; (3) regression of tumor after initial increase in total tumor burden; and (4) reduction in total tumor burden during or after the appearance of new lesion(s) after week 12. We provide a detailed description of irAEs and recommendations for practicing oncologists who are managing them, along with the unusual kinetics of response associated with ipilimumab therapy.
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“We observed an association between irAEs and improved PFS using a landmark analysis, in agreement with previous studies58–60, and uncovered that baseline gut microbiome composition segregated PD-1-treated patients who developed irAEs from those who did not.”
From Intestinal microbiota signatures of clinical response and immune-related adverse events in melanoma patients treated with anti-PD-1 (2022) · cites this paper as [60]
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New toxicity profile for novel immunotherapy agents: focus on immune-checkpoint inhibitors
Ciccarese, C., Alfieri, S., Santoni, M., Santini, D., Brunelli, M., Bergamini, C., Licitra, L. F., Montironi, R., Tortora, G., & Massari, F. (2015) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.2016.1120287 · Cited by 62
“hypophysitis) occur in 1–6% of patients in a latter period of observation (after about 9 weeks).[15] Moreover, several analyses demonstrated the lack of differences in terms of safety among diverse subgroups of melanoma patients treated with IPI.”
ResultQuagliariello, V., Passariello, M., Coppola, C., Rea, D., Barbieri, A., Scherillo, M., Monti, M. G., Iaffaioli, R. V., Laurentiis, M. D., Ascierto, P. A., et al. (2019) · International Journal of Cardiology · doi:10.1016/j.ijcard.2019.05.028 · Cited by 62
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Ragoonanan, D. S., Khazal, S. J., Abdel‐Azim, H., McCall, D. C., Cuglievan, B., Tambaro, F. P., Ahmad, A. H., Rowan, C. M., Gutiérrez, C., Schadler, K., et al. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-021-00474-4 · Cited by 62
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“Endocrinopathies and hepatotoxicity occurred later, typically between weeks 6 and 8 [8].”
BackgroundAssociation Between Ipilimumab and Celiac Disease
Gentile, N. M., D’Souza, A., Fujii, L. L., Wu, T., & Murray, J. A. (2013) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2013.01.015 · Cited by 61
Immune Checkpoint Blockade: A New Paradigm in Treating Advanced Cancer
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Adverse Events in Cancer Immunotherapy
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“6 weeks with CTLA-4 inhibitors.(33,34) Despite the high frequency of mild skin reactions these are fortunately not typically treatment-limiting and can be managed”
BackgroundNovel Drugs and Combination Therapies for the Treatment of Metastatic Melanoma
Vennepureddy, A., Thumallapally, N., Nehru, V. M., Atallah, J. P., & Terjanian, T. O. (2015) · Journal of Clinical Medicine Research · doi:10.14740/jocmr2424w · Cited by 61
“IrAEs can affect any organ system, but they typically involve the skin, gastrointestinal, hepatic, and endocrine systems [36].”
BackgroundSolinas, C., Porcu, M., Hlavatá, Z., Silva, P. D., Puzzoni, M., Willard-Gallo, K., Scartozzi, M., & Saba, L. (2017) · Critical reviews in oncology/hematology · doi:10.1016/j.critrevonc.2017.09.017 · Cited by 57
“…adverse reactions such as hepatitis, pancreatitis, myositis, fascitis, benign or sarcoid-like lymphadenopathy and retroperitoneal fat haziness (Weber et al., 2012; Horvat et al., 2015; Michot et al., 2016; Kim et al., 2013a,b; Rao and Grumett, 2016; Min and Ibrahim, 2013; Albarel et al.,…”
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Chera, A., Stancu, A. L., & Bucur, O. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1010279 · Cited by 62
“Unfortunately, endocrinopathies induced by ICIs are usually irreversible (50% recovery of the pituitary-thyroid axis, 50-60% recovery of the pituitary-gonadal axis) (9, 62, 70, 103).”
BackgroundStrecker, M. I., Wlotzka, K., Straßheimer, F., Roller, B., Ludmirski, G., König, S., Röder, J., Opitz, C., Alekseeva, T., Reul, J., et al. (2022) · OncoImmunology · doi:10.1080/2162402x.2022.2127508 · Cited by 60
“Additionally, the occurrence of immune-related adverse events limits the applicability of systemic ICIs, and represents an obstacle in particular toward the development of combination immunotherapies.(27) By local or systemic injection of adeno-associated viral vectors (AAVs), local expression and secretion of ICIs af…”
BackgroundLigand-activated BMP signaling inhibits cell differentiation and death to promote melanoma
Venkatesan, A. M., Vyas, R., Gramann, A. K., Dresser, K., Gujja, S., Bhatnagar, S., Chhangawala, S., Gomes, C. B. F., Xi, H. S., Lian, C. G., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci92513 · Cited by 60
“Despite this progress, many patients do not respond to certain therapies, whereas others suffer from drug toxicity, therapy resistance, or disease relapse (9–11), underscoring the need to identify additional targets for therapeutic intervention.”
BackgroundNeoplasia and intraocular inflammation: From masquerade syndromes to immunotherapy-induced uveitis
Touhami, S., Audo, I. S., Terrada, C., Gaudric, A., LeHoang, P., Touitou, V., & Bodaghi, B. (2019) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2019.05.002 · Cited by 60
Bostwick, A. D., Salama, A. K. S., & Hanks, B. A. (2015) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-015-0064-2 · Cited by 59
Autoimmune Colitis and Subsequent CMV-induced Hepatitis After Treatment With Ipilimumab
Uslu, U., Agaimy, A., Hundorfean, G., Harrer, T., Schuler, G., & Heinzerling, L. (2015) · Journal of Immunotherapy · doi:10.1097/cji.0000000000000081 · Cited by 59
Identification and management of toxicities from immune checkpoint-blocking drugs.
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“However, T-cell activation may cause immune-related adverse events (irAEs), including skin reactions, thyroid dysfunction, pneumonitis, and hepatitis [8], that are not triggered by conventional cytotoxic anticancer agents and may”
BackgroundImmune Checkpoint Inhibitor Therapy Associated Hypophysitis
Mahzari, M. M., Liu, D., Arnaout, A., & Lochnan, H. A. (2015) · Clinical Medicine Insights Endocrinology and Diabetes · doi:10.4137/cmed.s22469 · Cited by 58
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“Colonoscopy, including biopsy of colonic mucosa, is currently the only validated diagnostic tool to confirm immune-related colitis, but physicians are using less invasive methods, such as CT scans, as aproxy for colonoscopy (10, 11).”
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Ocular Toxicity of Targeted Anticancer Agents
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Gaining momentum: New options and opportunities for the treatment of advanced melanoma
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“Early recognition of these AEs and appropriate initiation of supportive care are critical to maximise the benefit of treatment and reduce the risk of severe or life-threatening complications, which may involve the gastrointestinal, liver, skin, nervous, endocrine or other organ systems [121–123].”
BackgroundTargeted therapy-induced diarrhea: A review of the literature
Pessi, M. A., Zilembo, N., Haspinger, E. R., Molino, L., Cosimo, S. D., Garassino, M. C., & Ripamonti, C. I. (2013) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2013.11.008 · Cited by 58
Current and future immunotherapies for thyroid cancer
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“immune-related adverse events, however, is variable [37].”
Metadata
- Authors
- Weber, J. S., Kähler, K. C., & Hauschild, A.
- Affiliations
- Moffitt Cancer Center (US)
- Venue
- Journal of Clinical Oncology
- Published
- 2012-07-20
- Volume
- 30
- Issue
- 21
- Pages
- 2691-2697
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2109653150
- Cited by
- 1,415
- References
- 33
- Citations by year
- 2026: 24 · 2025: 35 · 2024: 59 · 2023: 79 · 2022: 84 · 2021: 117 · 2020: 129 · 2019: 123 · 2018: 146 · 2017: 153 · 2016: 152 · 2015: 145 · 2014: 94 · 2013: 65 · 2012: 9
- FWCI
- 10.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Keywords
- ipilimumab, immune-related adverse events, CTLA-4 blockade, metastatic melanoma, immune checkpoint inhibitors, toxic epidermal necrolysis, colitis, hypophysitis, hepatitis, iridocyclitis, neuropathy, nephritis, adverse event management
- MeSH terms
- Ipilimumab, Antibodies, Monoclonal, Antineoplastic Agents, Colitis, Drug Eruptions, Diarrhea, Humans, Liver, Lymphatic Diseases, Melanoma, Mucous Membrane, Pancreatitis, Peripheral Nervous System Diseases, Pituitary Gland, Skin, Skin Neoplasms, Stevens-Johnson Syndrome, Uveitis, Scleritis, Chemical and Drug Induced Liver Injury, CTLA-4 Antigen, Antibodies, Monoclonal, Humanized
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