Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs’ therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs are mild to moderate in severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by ICI. Immunotherapy-related irAEs typically have a delayed onset and prolonged duration compared to adverse events from chemotherapy, and effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies.

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There is an urgent need for multidisciplinary guidance reflecting broad-based perspectives on how to recognize, report and manage organ-specific toxicities until evidence-based data are available to inform clinical decision-making. The Society for Immunotherapy of Cancer (SITC) established a multidisciplinary Toxicity Management Working Group, which met for a full-day workshop to develop recommendations to standardize management of irAEs.

Here we present their consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy. Cancer immunotherapy has revolutionized the treatment of cancer ,.

Currently, the most widely used approach is the administration of targeted monoclonal antibodies (mAbs) directed against regulatory immune checkpoint molecules that inhibit T cell activation. At present, six immune checkpoint inhibitors (ICIs) are approved by the U.S Food and Drug Administration (FDA) for use in a variety of solid tumors, and one hematological malignancy (Hodgkin lymphoma). Ipilimumab, a fully human IgG1 mAb that blocks the cytotoxic T lymphocyte-antigen-4 (CTLA-4), a checkpoint inhibitor of T cell activation, was the first ICI approved, in 2011, for use in advanced melanoma. Pembrolizumab and nivolumab, both engineered IgG4 mAbs that regulate T cell activation by blocking the protein programmed death 1 (PD-1), received FDA approval in patients with advanced melanoma in 2014 and the indications for both have subsequently expanded considerably. Indeed, in a landmark regulatory step, the FDA recently approved both pembrolizumab and nivolumab for use in certain patients with mismatch repair deficient (dMMR) and microsatellite instability high (MSI-H) cancers that have progressed following treatment with chemotherapy – the first such ‘tissue-agnostic’, biomarker-driven approvals granted ,. Both anti-PD-1 agents are associated with negligible antibody-dependent cell-mediated cytotoxicity (ADCC), a process that could be detrimental to the activation of T effector cells.

After approval of nivolumab for the treatment of non-small cell lung carcinoma (NSCLC) in 2015, the first immunotherapy combination of ipilimumab plus nivolumab was granted approval later in 2015, again in advanced melanoma. More recently, the FDA approved three new ICIs, atezolizumab, durvalumab and avelumab, all of which are antibodies directed against the protein programmed death-ligand 1 (PD-L1). Both atezolizumab and durvalumab are engineered IgG1 mAbs that include Fc modifications that eliminate ADCC, while avelumab includes a wildtype IgG1 framework with intact ADCC. Since May 2016, atezolizumab and durvalumab have both been approved for the treatment of NSCLC and urothelial carcinoma, and avelumab was approved for use in Merkel cell carcinoma and urothelial carcinoma –. Immune-related adverse events (irAEs) are discrete toxicities caused by non-specific activation of the immune system, and can affect almost any organ system. In some studies, the reported incidence is as high as 90% for any-grade irAEs due to single-agent ICI therapy , but meta-analysis indicates an overall incidence.

With increasing patient exposure to immunotherapy, the nature and range of irAEs is becoming more clearly defined, and several new but serious adverse events have been reported. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas, cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs are well-recognized but occur much less frequently (Fig. Although the majority of irAEs are mild to moderate in severity, serious, occasionally life-threatening irAEs (e.g., severe colitis, pneumonitis, encephalitis, toxic epidermal necrolysis, myocarditis, and autoimmune type I diabetes mellitus T1DM presenting as diabetic ketoacidosis), are reported in the literature, and treatment-related deaths have been reported in up to 2% of patients in clinical trials ,.

As life-threatening irAEs are rare, and may mimic other better-known conditions, there is growing recognition of the need to educate both the oncology and general medical communities in recognizing and instituting urgent and appropriate treatment of these conditions. Immune-related AEs resulting from immunotherapy can have a delayed onset and prolonged duration compared to adverse events resulting from chemotherapy (Fig. ), in part due to pharmacodynamic differences. Moreover, the relationship between irAEs and dose/exposure remains to be fully established. As such, clinicians must remain vigilant to the diverse clinical presentations of irAEs and the possibility that patients may present with irAEs late in the course of treatment, and – in some cases – months or even years after treatment discontinuation ,.

Nonetheless, since diagnostic tests may be invasive and potentially costly, investigations should be undertaken judiciously and reserved for situations when the results will guide patient management. Table provides a list of recommended tests to consider in all patients prior to initiating checkpoint inhibitor therapy. In certain settings, some of these tests may not be readily available. Until their use is firmly supported by evidence, individual physician judgment is recommended aThese tests become very relevant if patients develop irAEs and require immunosuppressive treatment such as steroids and/or anti-TNFα treatment bGiven the rarity of cardiac toxicity, this may not be cost-effective as a routine test. Baseline troponin should be measured although the follow up interval for re-testing is not determined. Consensus group representation In response to the need for a collaborative, multidisciplinary approach to the management of ICI toxicities, the SITC convened a one-day workshop on March 31st, 2017, in Washington D.C.

The meeting was a multi-stakeholder effort with participation from approximately 85 experts from academia, government, industry, scientific organizations and other related entities. Representation was sought from medical oncologists, surgeons, disease subspecialists, basic scientists, pharmacists, industry clinical, regulatory and safety experts and nurses. In order to streamline recommendations across the range of organizations active in the area of cancer immunotherapy, SITC invited representatives from the American Society of Clinical Oncology (ASCO), National Comprehensive Cancer Network (NCCN), Parker Institute for Cancer Immunotherapy, Friends of Cancer Research, American Association for Cancer Research (AACR), Association of Community Cancer Centers (ACCC), NCI and the Oncology Nursing Society (ONS) to participate in the workshop.

To ensure that commercial interests did not influence the outcomes of the workshop, industry representatives participated in group discussions but final approval of the workshop output, and of this manuscript, was the responsibility of the organizing committee, none of whom are employed by a pharmaceutical or biotechnology company. Representatives from the Office of Hematology and Oncology Products, Center for Drug Evaluation and Research (CDER), were invited to review and provide feedback on the final manuscript. Individuals selected as authors were workshop organizers and lead discussants for individual organ-specific toxicity breakout groups.

All participants were required to disclose any potential conflicts of interest prior to participation. Workshop objectives and procedures The overarching goals of the workshop were twofold: 1) to develop treatment algorithms for managing common and rare immunotherapy-related toxicities and 2) to develop standardized templates, including inclusion and exclusion criteria, for irAE management in clinical trial protocols (which will be reported separately).

More broadly, participants were charged with describing the spectrum of immune-related toxicities and providing recommendations on recognizing, monitoring and managing these toxicities. To facilitate discussion among experts in different medical fields, attendees broke out into 11 subgroups (‘breakout groups’) that focused on irAEs identified by body system (dermatologic, gastrointestinal, endocrine, pulmonary, rheumatologic, cardiovascular, hematologic, renal, neurologic and ophthalmologic) as well as infusion reactions. These breakout groups were generally supplemented with disease subspecialty expertise focused on the area of interest. Each breakout group received instructions to guide their discussion, a list of recognized toxicities by system, relevant drug package inserts, several key supporting references, and a copy of CTCAE version 4.0.

A working draft of the Friends of Cancer Research/Parker Institute for Cancer Immunotherapy guidelines on monitoring, management and follow-up of irAEs from anti-PD-1/PD-L1 agents was also distributed. After separate breakout group discussions, one representative from each group presented their recommendations to all participants, and responded to questions and additional suggestions from the wider group. Following the meeting, recom.

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