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(SITC) Clinical Practice Guideline on Immune Checkpoint Inhibitor-Related­ Adverse Events

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(SITC) Clinical Practice Guideline on Immune Checkpoint Inhibitor-Related­ Adverse Events Open access Position article and guidelines J Immunother Cancer: first published as 10.1136/jitc-2021-002435 on 25 June 2021. Downloaded from Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events 1 2 3 4 Julie R Brahmer, Hamzah Abu- Sbeih, Paolo Antonio Ascierto , Jill Brufsky, Laura C Cappelli,5 Frank B Cortazar,6,7 David E Gerber,8 Lamya Hamad,9 Eric Hansen,10 Douglas B Johnson,11 Mario E Lacouture,12 Gregory A Masters,13 Jarushka Naidoo,1,14 Michele Nanni,10 Miguel- Angel Perales,12 Igor Puzanov,10 Bianca D Santomasso,15 Satish P Shanbhag,5,16 Rajeev Sharma,10 17 18 1 19 Dimitra Skondra, Jeffrey A Sosman, Michelle Turner, Marc S Ernstoff To cite: Brahmer JR, Abu- ABSTRACT a wide variety of cancer types. A study of ICI Sbeih H, Ascierto PA, et al. Immune checkpoint inhibitors (ICIs) are the standard of usage estimated that in 2018, 44% of patients Society for Immunotherapy of care for the treatment of several cancers. While these with metastatic solid or hematological tumors Cancer (SITC) clinical practice immunotherapies have improved patient outcomes in guideline on immune checkpoint in the US were eligible for treatment with many clinical settings, they bring accompanying risks 2 inhibitor- related adverse events. ICIs. ICIs are also a focus of active drug of toxicity, specifically immune- related adverse events Journal for ImmunoTherapy development, and a number of ongoing trials (irAEs). There is a need for clear, effective guidelines for of Cancer 2021;9:e002435. are evaluating novel antibodies or testing doi:10.1136/jitc-2021-002435 the management of irAEs during ICI treatment, motivating the Society for Immunotherapy of Cancer (SITC) to convene approved ICIs in combination with other treatment modalities including chemother- Accepted 24 March 2021 an expert panel to develop a clinical practice guideline. The panel discussed the recognition and management of apies or targeted agents. The use of ICIs as single and combination ICI irAEs and ultimately developed adjuvant therapy has been approved for high- evidence- and consensus- based recommendations to risk melanoma and esophageal and gastro- assist medical professionals in clinical decision- making esophageal junction (GEJ) cancers, and and to improve outcomes for patients. studies of peri-operative checkpoint blockade http://jitc.bmj.com/ (including in the neoadjuvant setting) are INTRODUCTION ongoing for a wide variety of other cancers. The introduction of new cancer immuno- Because ICIs are used across the spectrum therapies for the treatment of metastatic of disease from early to late stage, the risks cancer and for the adjuvant therapy for high- of treatment (including the potential for risk primary disease has enabled long- term, long- lasting side effects) should be weighed on September 29, 2021 by guest. Protected copyright. potentially curative responses in subsets of against the goals of therapy. populations of patients with cancer. Immune As with any modality, treatment with ICIs checkpoint inhibitors (ICIs) are antibodies can result in adverse events (AEs). AEs designed to block key regulatory signals that related to the immunological mechanism dampen immune responses, counteracting of action of immunotherapy are commonly immune suppression in the tumor microen- referred to as immune-related AEs (irAEs). vironment and thus enabling tumor- reactive AEs, including irAEs, are graded according T cells to mount an effective anticancer to a standard scale of severity such as the © Author(s) (or their response. Currently, US Food and Drug Common Terminology Criteria for Adverse employer(s)) 2021. Re- use Administration (FDA)- approved ICIs fall Events (CTCAE v5.0),3 which also assists in permitted under CC BY-NC. No commercial re- use. See rights into two major classes: those that target the comparing toxicities across trials. A systematic and permissions. Published by programmed cell death protein 1 (PD-1) and review found that patients treated with anti- BMJ. programmed death- ligand 1 (PD-L1) (anti- PD- (L)1 inhibitors developed irAEs at a rate For numbered affiliations see bodies to the PD- (L)1 axis) and those that of 74% (14% grade ≥3), those treated with end of article. target the cytotoxic T lymphocyte antigen-4 anti- CTLA-4 inhibitors at a rate of 89% (34% Correspondence to (CTLA-4) in the context of the CTLA-4- CD28 grade ≥3), and those treated with combina- 1 4 Dr Marc S Ernstoff; axis (anti- CTLA-4 antibodies). These thera- tion ICIs at a rate of 90% (55% grade ≥3). marc. ernstoff@ nih. gov pies have been approved for the treatment of Importantly, the presentation of common Brahmer JR, et al. J Immunother Cancer 2021;9:e002435. doi:10.1136/jitc-2021-002435 1 Open access J Immunother Cancer: first published as 10.1136/jitc-2021-002435 on 25 June 2021. Downloaded from irAEs (eg, thryoiditis, dermatitis, etc) differs from that a transparent process where both funding sources and of chemotherapy- related AEs. In addition, the timing of conflicts of interest are readily reported. This clinical irAEs is far less predictable, with the potential for events practice guideline is intended to provide guidance and to occur and persist long after cessation of treatment. is not a substitute for the professional judgment of indi- The difference in expected frequencies of AEs between vidual treating physicians. immunotherapy and chemotherapy or other modalities is typically attributed to the unique mechanism of action Conflict of interest management of ICIs.4 5 As outlined by IOM standards, all financial relationships A number of guidelines detail recommendations for of expert panel members that might result in actual, the management of immunotherapy- related toxicities, potential, or perceived conflicts of interest were individ- including the American Society for Clinical Oncology ually reported. Disclosures were made prior to the onset (ASCO), the European Society for Medical Oncology of manuscript development and updated on an annual (ESMO), the National Comprehensive Cancer Network basis. In addition, panel members were asked to articu- (NCCN), and a prior consensus statement from the late any actual or potential conflicts at all key decision Society for Immunotherapy of Cancer (SITC).6–9 The points during guideline development, so that participants overall goal of any guideline, including this one, is to would understand all possible influences, biases, and/ assist in clinical decision-making to provide the best or the diversity of perspectives on the panel. Although outcomes for patients. Guidelines from different organi- some degree of relationships with outside interests are zations should be complementary in helping providers to be expected among experts, panel candidates with care for their patients. Since the publication of the 2017 significant financial connections that may compromise consensus statement on toxicity management from SITC, their ability to fairly weigh evidence (either actual or rapid progress in the field of immunotherapy leading perceived) were not eligible to participate in guideline to expansion in the number of clinical trials and anal- development. yses of toxicities have resulted in a concordant increase Recognizing that guideline panel members are among in the data available about irAEs, including additional the leading experts on the subject matter under consid- insight on optimal management strategies as well as a new eration and guideline recommendations should have appreciation for uncommon presentations such as ICI- the benefit of their expertize, any identified potential associated celiac disease. Coupled with ever-expanding conflicts of interests were managed as outlined in SITC’s FDA approvals for new therapies and indications, and disclosure and conflict of interest resolution policies. enhanced public awareness of immunotherapy, these As noted in these policies, panel members disclosing a new data necessitated the development of updated clin- real or perceived potential conflict of interest may be ical practice guidelines. As the leading member- driven permitted to participate in consideration and decision- international organization devoted to advancing the making of a matter related to that conflict, but only if science and application of cancer immunotherapy, SITC deemed appropriate after discussion and agreement by http://jitc.bmj.com/ assembled an expert panel to develop evidence- and the expert panel. consensus- based recommendations to provide guidance The financial support for the development of this to clinicians in the management of ICI- associated toxic- guideline was provided solely by SITC. No commercial ities. The expert panel discussed and generated recom- funding was received. mendations on the diagnosis, treatment, and risk factors associated with toxicities occurring during ICI treatment. Recommendation development on September 29, 2021 by guest. Protected copyright. This manuscript reports the panel’s recommendations Panel recommendations are based on literature evidence, and provides guidance to medical professionals, with the where possible, and clinical experience, where appro- goal of improving patient outcomes during and following priate.11 Consensus for the recommendations herein was treatment with ICIs. These recommendations are not generated by open communication and scientific debate intended to supplant sound clinical judgment, but to in small- group and whole- group settings, surveying and provide clinicians with
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