W. Kimryn Rathmell, MD, PhD
Director, Division of Hematology and Oncology
Cornelius Abernathy Craig Chair, Department of Medicine
Vanderbilt University Medical Center
Keywords: immune checkpoint blockade, immune-related adverse effects, checkpoint inhibitors, PD-1, CTLA-4, dermatologic, pulmonary, endocrine, management, corticosteroids.
Corresponding Author: Kathryn Eby Beckermann, MD, PhD, Chief Academic Fellow, Division of Hematology/ Oncology Vanderbilt University, 1211 Medical Center Drive, Nashville, TN 37232 Email: email@example.com
As the population of patients treated with immune checkpoint blockade expands and with even more agents likely to be approved there is a growing need for guidelines on managing immune-related adverse effects. New recommendations from several national societies could not be more timely because these now commonplace therapies do not exhibit the typical side effects of cytotoxic or targeted agents. Clinicians find themselves facing daily challenges to manage immune-related adverse effects with appropriate strategies and to recognize subtle complications that could be overlooked or underestimated. This report highlights valuable resources and strategies to adopt the latest advisories on managing adverse events arising from immune checkpoint blockade.
As the footprint of immune checkpoint inhibitors (ICI) grows larger across the landscape of oncology, especially in renal cell carcinoma (RCC), this revolutionary change in therapy is undergoing even closer scrutiny in view of the speed with which these drugs have been adopted in clinical practice after approval by the FDA. The speed of approval, as noted in a recently published study1, is one of the most important aspects of the ICI story, an aspect sometimes overlooked in view of the potential benefits conferred by these agents.
A recently published study showed that the majority of patients eligible for ICI received treatment within a few months of FDA approval, indicating an extremely rapid implementation timeline.1 One of the long-standing concerns about the adoption of novel therapeutics is that they enter the market based on data from a selective group of patients established by particular clinical trial inclusion and exclusion criteria. For clinicians in the community this can pose a challenge treating the general population with key issues regarding lack of knowledge surrounding the full side effect profiles.2,3 The good news for those who have or are considering adopting ICI is that there is a rapidly growing wealth of information on the adverse effects likely to be encountered as well as emerging effective consensus guidelines from leading medical oncology societies.
Another challenge from the findings is the need to reevaluate new and changing distributions of immune related adverse events (ir-AE), in particular with the use of recently approved combinations of immunotherapies in RCC treatment. Postow et al tackled ten essential questions practitioners will encounter as they consider the use of ICI in RCC.4 The questions range from the most basic (Why do these ir-AE occur? Can we predict who will have ir-AE?), to a more nuanced consideration involving issues including whether it is safe to continue or restart ICI after patients experience an ir-AE. As the experience with ICI expands beyond the early studies establishing their clinical benefit, there is a growing awareness of an expanding range of issues. In view of all the new studies, we have reached an inflection point in the use of ICI in terms of managing the associated adverse effects so that we can move on to optimizing the benefit/risk ratio. In RCC, support for the use of ICI began several years ago with the report of phase 2 results on the safety of nivolumab in patients with metastatic RCC.5
The rationale for ICI begins with an understanding of mechanisms involved in the pathogenesis of RCC, mechanisms that go beyond historically standard of care targeted therapeutics inhibiting such signaling as vascular endothelial growth factor (VEGF) or the mammalian target of rapamycin (mTOR) pathway. Multiple mechanisms evolve during tumorigenesis including systemic dysfunction in T cell signaling and exploitation of immune checkpoints.6-11 These mechanisms help tumors evade specific immune responses despite the presentation of tumor antigens to the immune system.12 Further elucidation of these immune evasive mechanisms in the host-tumor immune environment led to the development of novel antibodies directed against immune checkpoint proteins.13,14
Few agents have ushered in as much excitement as that seen with FDA approval of the novel human immunoglobulin G4 programmed death (PD-1) ICI that selectively blocks the interaction between PD-1 and its ligands PD-L1 and PD-L2.15 By blocking this negative regulator on T cells, the first drug approved in this class, nivolumab, ostensibly inhibits events that normally lead to downregulation of a cellular immune response. The important message from early phase clinical trials is that nivolumab can enhance T-cell function and thus, result in antitumor activity.16 The pivotal study demonstrated benefits in progression-free survival, overall response rate and overall survival, supporting the use of nivolumab as monotherapy to restore T-cell immune activity in patients with RCC.17
Although the precise pathophysiology underlying immune-related adverse effects is still unknown, various hypotheses help delineate some potential mechanisms. These adverse events may be related to the role that ICI agents play in maintaining immunologic homeostasis. As this connection has been explored, a better understanding has emerged concerning the way in which unique checkpoint blocks down regulate immunity.4 There are some clear-cut distinctions proposed. For example the checkpoint protein CTLA-4 is upregulated in the periphery during immune priming.18 It is expected that varying ir-AE arising from PD-1 blockade vs CTLA-4 blockade might be related to timing or sight of action, for example, PD-1 blockade is generally believed to inhibit T cells at the site of the tumor.19,20 Additionally, mice lacking PD-1 have variable autoimmunity including arthritis and cardiomyopathy.21,22 The pathophysiology of ir-AE remains highly controversial and we are only beginning to understand why the effects of anti-CTLA-4 or anti-PD-1 blockade differ from one another in severity, timing, and preponderance of specific ir-AE. This review will focus on practical aspects and implications for managing ir-AE, particularly in the setting of expanding FDA approval of ICI in patients with RCC.
Spectrum of Therapy and Epidemiology of Immune Related Adverse Events
Since 2011, beginning with the approval of the CTLA-4 antibody ipilimumab in melanoma, there has been an influx into the market of drugs targeting both pathways including the PD-1/PD-L1 inhibitors: nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab as well as the CTLA-4 inhibitor ipilimumab. There are many more in development.23 The incidence of any grade ir-AE in clinical trials is reportedly as low as 15% to as high as 90%, and toxicities range from mild requiring treatment with topical cream to severe enough that drug discontinuation and the initiation of systemic immunosuppressive medications occur 10–55% of the time.24,25
The reason for this huge variability may be due to the lack of agreed upon uniform definitions as to what constitutes a particular ir-AE, although recently there have been attempts to standardize grading and criteria for ir-AE.26-28 Possible underreporting of toxicities within clinical trials may also lead to heterogeneity in the reported incidence of these adverse events.29 While the spectrum and rate of various ir-AE is different between PD-1/PD-L1 inhibitors and CTLA4 inhibitors, trials are increasingly investigating the potential of using these drugs in combination, which has been shown to be more toxic than targeting either pathway alone.30,31 While there are many combination regimens being tested in mRCC, the combination of two uniquely targeting immunotherapy agents or combination of an anti-VEGF agent with an immunotherapy agent have recently been reported.31-33 Results from the CheckMate 214 trial showed that overall survival and objective response rates were significantly higher with the combination of nivolumab and ipilimumab vs sunitinib (risk of death was 37% lower with nivolumab and ipilimumab and objective response rate was 42% vs 27%). CheckMate214 also provided a detailed analysis of the safety profile of this combination (nivolumab and ipilimumab), now part of the first-line treatment algorithm in intermediate- and poor-risk patients with previously untreated RCC.31 The safety profile of nivolumab plus ipilimumab was consistent with that in previous studies in multiple tumor types, including advanced RCC with a lower incidence of grade 3 and 4 treatment-related adverse events than observed with sunitinib. The frequencies of treatment-related gastrointestinal, skin, and hepatic adverse events were lower than those seen in a trial involving patients with melanoma, in which a higher dose of ipilimumab (3 mg per kilogram) and a lower dose of nivolumab (1 mg per kilogram) were used.34 Patients in CheckMate214 reported better health-related quality of life, as measured by the FKSI-19, with nivolumab plus ipilimumab than with sunitinib. Dose delays, treatment with glucocorticoids, and prompt diagnostic workup to rule out noninflammatory causes were used to manage toxic effects according to management algorithms developed for immuno-oncology treatment-related adverse events.27 Therefore, recognizing and treating ir-AE promptly is of paramount importance.<
Mapping Immune Related Adverse Events by Organ System Involvement
New guidelines have been issued by groups like the European Society of Medical Oncology (ESMO), the American Society of Clinical Oncology (ASCO), and the Society for Immunotherapy of Cancer (SITC).26-28 Each of these groups addresses the importance of managing the most common toxicities based on organ system involvement. The majority of ir-AE are in the range from mild to moderate, but treatment-related deaths have been known to occur in up to 2% of patients. Skin, gut, endocrine, lung, and musculoskeletal AE are relatively common, whereas cardiovascular, hematologic, renal, neurologic, and ophthalmologic AE occur much less frequently.26
Immune related adverse events can be characterized by the following:
- Compared to cytotoxic chemotherapy, ir-AE may have a delayed onset and prolonged duration.
- Inflammation of target tissue, characterized by an influx of immune cells, granuloma formation, or fibrosis.
- A detailed summary of pre-treatment evaluation and diagnostic tests to consider in all patients prior to initiating checkpoint inhibitor therapy is indicated in Table 1 (click here to view a larger version of the table).26
Immune-related Skin Toxicity
The spectrum of dermatologic reactions to immune checkpoint blockade is fully described in clinical practice guidelines from ESMO.28 Skin AE are the most frequent ir-AE (43%-45% with ipilimumab, and 34% with nivolumab and pembrolizumab) and usually develop within the first few weeks after initiation of treatment. The good news is that serious reactions are rare and generally grade 1 reactions do not require dose reductions or treatment discontinuation. ICI is most commonly associated with a maculopapular rash, pruritus, psoriasis, and vitiligo with the
latter seen more commonly in melanoma than RCC.35 An example is shown in the Figure. One statistic suggests combination ICI therapy is more likely to show significantly elevated rates of AE vs monotherapy, with rash reported in 40% of patients receiving nivolumab and ipilimumab vs 24% on ipilimumab alone or 15% on single- nivolumab or pembrolizumab. Although pruritus is commonly seen with both categories of checkpoint inhibitors (anti-PD-1 and anti-CTLA-4), it only reaches grade 3 or 4 in fewer than 2.5% of patients.36
The ESMO guidelines divide skin reactions histopathologically into four groups:
- Inflammatory skin disorders involving acute, subacute, or chronic inflammation,
associated with epidermal changes.
- Immunobullous skin lesions, similar to dermatitis herpetiformis or bullous pemphigoid.
- Keratinocyte alteration.
- Immune-reaction mediated by alteration of melanocytes, as in vitiligo
Endocrine-related Adverse Effects on the Rise With Immunotherapy
The introduction of ICI has resulted in an increase in both transient hyperthyroidism and the more commonly observed hypothyroidism.28 Hyperthyroidism tends to be transient and may precede hypothyroidism. While still unclear, it is thought that the pathogenesis of thyroid disorders is mediated by T cells and not B cell autoimmunity. The incidence of thyroid dysfunction requiring thyroid hormone replacement in a study of 51 patients was 21% compared with 8% in patients who did not develop thyroid dysfunction.37
Reviewing data with respect to each type of checkpoint blockade, Haanen et al27 suggest that thyroid dysfunction is most common upon treatment with anti- PD-1/PD-L1 or combination of anti-CTLA4 and agents blocking the PD-1/PD-L1 axis. Regardless of tumor type, thyroid dysfunction rates vary from 5% to 10% with either anti-PD-1 (pembro-lizumab or nivolumab) or anti-PD-L1 therapy (atezolizumab). A sharp impact on thyroid dysfunction has been noted with combination therapy. The incidence with combination of nivolumab and ipilimumab, for example, rises markedly to 20%; however, the events are rarely higher than grade 2. Routine blood tests (TSH and FT4) are most likely to reveal thyroid dysfunction and should be done before every infusion of therapy, at least once a month when 2 weekly infusions are administered.
Another sometimes overlooked endocrine side effect of these medications is immunotherapy-induced hypophysitis. Inflammation of the pituitary gland can contribute to hypothyroidism as indicated above, but also disordered expression of cortisol, ACTH, LH, FSH, and prolactin. Routine screening of thyroid function tests has become the norm, along with serial measurement of ACTH and serum cortisol.38
Highlighting Less Common Immune Related Adverse Events:
Pulmonary, Cardiac and GI Toxicity
It is critical to remember that occasional severe adverse events can be triggered upon treatment with these agents that can produce fatal consequences. Particularly as we advance these drugs into the adjuvant and neoadjuvant settings, it is critical to consider the potential consequences. While any of the events reported above can lead to fatality, these less common events have a greater potential to become severe and irreversible rapidly.
One of the more alarming complications arising from checkpoint inhibitor therapy is pneumonitis. The incidence of pneumonitis is approximately 5%, with grade 3, 4, or 5 reactions occurring less than 2% of the time.39 Physicians should have an index of suspicion especially with PD-1 blockade, where according to one report the median time from drug initiation to the development of pneumonitis was 2.6 months; however, symptoms were seen as soon as 2 weeks or as late as 11.5 months after starting therapy and may occur even later.23 In the case of pneumonitis, there have been some clear-cut differences in the frequency of this AE with the use of single vs combination therapy where the combination raises the incidence up to 3x more all-grade and grade >3 events.34
Although cardiac toxicity is relatively rare, adverse effects with PD-L1 and CTLA-4 blockade have been increasingly recognized in the last few years as a potentially fatal complication.40 Despite being uncommon, reports have emerged on a wide variety of toxicities, particularly since the use of checkpoint blockade has grown. Among the complications noted are asymptomatic cardiomyopathy, symptomatic heart failure, pericarditis, myocarditis, tachyarrhythmias, and bradyarrhythmias.41 A major concern raised by many is that markers of cardiac dysfunction such as left ventricular ejection fraction or cardiac cell death (troponin-I, CK-MB) are not routinely checked in patients on immuno- therapy and thus more likely that cardiac toxicity associated with these medications may be underestimated.42
As is the case with cardiac toxicity, gastrointestinal adverse effects are classified among the more uncommon complications. Diarrhea has been one of the more frequently reported adverse events, and is more likely to be seen with the CTLA-4 inhibitors. Of greater concern is that diarrhea may be a symptom of severe bowel inflammation and as an immune related AE if not properly identified as such improper diagnosis and treatment can be catastrophic. A report by Wang et al, suggests that the rising use of checkpoint inhibitors means that immune-related colitis is increasingly encountered.43 These authors identified 34 studies in a meta-analysis totaling 8863 patients. The overall incidence during ipilimumab mono-therapy was 9.1% for all-grade colitis, 6.8% for severe colitis, and 7.9% for severe diarrhea. The incidence was lowest during PD-1/PD-L1 inhibitor monotherapy with 1.3% for all-grade colitis, 0.9% for severe colitis and 1.2% for severe diarrhea. Combination ipilimumab and nivolumab resulted in the highest incidences of all-grade colitis (13.6%), severe colitis (9.4%) and severe diarrhea (9.2%) among ICI regimens. Among melanoma, NSCLC, and RCC patients, incidences of colitis and diarrhea with PD-1/PD-L1 inhibitor monotherapy did not significantly differ. Severe colitis incidence was similar with ipilimumab monotherapy at 3 mg/kg and 10 mg/kg (7.1% vs 5.1%, respectively), but significantly higher for severe diarrhea with 10mg/kg (11.5% vs 5.2%).
Three major medical groups have published comprehensive guidelines to the management of toxicities related to immune checkpoint blockade.26-28 Working groups within ESMO, SITC, and ASCO have formulated recommendations to standardize management of ir-AE. There is considerable overlap of these consensus guidelines, and some general principles of management can be identified as each group addresses a myriad of issues arising from the increased use of checkpoint inhibitors. The SITC working group offered some overall perspectives that suggest a framework for management:
- Effective management depends on early recognition and prompt intervention with a break in therapy or necessary immune suppression with appropriate immunomodulatory strategies depending on the severity of toxicity.
- A multi-disciplinary team is among the advisories to include specialists such as endocrinology, cardiology, dermatology, etc should be involved early, and hospitalization may be necessary in grade 3 adverse effects that do not respond to therapy or serious (more than grade 4).
- Patient education emerges as a key component prior to the initiation of immunotherapy.
- Short term adverse events related to use of moderate to high-dose corticosteroids should be expected and discussed with patients. Patients receiving long-term or high-dose corticosteroids are at risk for diabetes and osteoporosis and should receive vitamin D and calcium supplementation.
As delineated in Table 2 (click here to view a larger version of the table), the management of ir-AE relies heavily on corticosteroids and other immunomodulatory agents.26 In general a graded approach to steroid management should be applied, and occasional severe toxicities may require the application of additionally potential anti-inflammatories more widely used in rheumatology. The most widely studied of these is the use of anti-tumor necrosis factor (TNF) agents for treatment of severe colitis. Strategies to administer these agents are determined based on the grade of immune-related AE. Use of prophylactic antibiotics is still controversial to reduce the risk of opportunistic infections. In any case, corticosteroids should be used on an individualized basis, depending on medical history, co-morbidities, underlying disease status, type and number of adverse events and ability to tolerate corticosteroids. Keeping in mind that depending on severity of ir-AE a prolonged taper of corticosteroids may be required, which should be factored into decisions to delay or withhold treatment. In general, immune therapy should be held until steroids are nearing a physiologic level, both to avoid recurrence of symptoms, and to apply the agents in a physiologic setting where they can be effective. The SITC guidelines contain specific recommendations for each AE and should be consulted for specific management strategies.26
The treatment algorithm for advanced RCC has undergone dramatic changes with the introduction of immune checkpoint blockade, thus mandating more attention to the risk of adverse effects related to the expanding use of immune checkpoint inhibitors. Comprehensive guidelines from several international groups represent a benchmark in how these ir-AE can be managed. Involvement by a multi-disciplinary team of specialists is one of the cornerstones of management highlighted by each set of guidelines. One of the gaps in our understanding remains the need for more information on the pathophysiology of these untoward effects. As future studies unravel more details on this issue, clinicians may obtain more clues on how to prevent and minimize adverse reactions to a therapy that has revolutionized RCC care.
The authors would like to acknowledge support for mentored education from the NIH: K24CA172355 (WKR), and the generous support of the Carol O’Hare fellowship (KEB).
Conflict of Interest
Research support to the institution of WKR is provided for contracted clinical research studies from: Merck, Pfizer, Bristol-Myers Squibb, Roche/Genentech, Incyte, Calithera, Peloton, and Tracon.
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