Immunotherapy agents represent a transformational advance in our ability to treat many cancers. Rather than introducing a therapy that kills both healthy and malignant cells, immunotherapy agents harness the body’s natural ability to recognize and control the invasive cells that can form tumors.

Most patients who receive immunotherapies will experience few, if any, treatment-related adverse effects (AEs). But some patients receiving these treatments can experience serious AEs caused by an overactivation of the immune system and its effects on healthy cells. 

It is important for clinicians to identify AEs quickly and assign such toxicities an appropriate grade using the standard Common Terminology Criteria for Adverse Events 5.0 grading system. Based on that grading, treatment should be designed using standard guidelines developed by oncology societies, including the Society for Immunotherapy of Cancer and American Society of Clinical Oncology (ASCO). Most of the toxicities caused by immunotherapy drugs are reversible by using steroid or other immunosuppressive therapies.

It is critical to ensure clinicians recognize and know how to manage these treatment-emergent AEs so patients can seek appropriate medical attention quickly and continue to take advantage of the benefits of immunotherapy.

Several immunotherapy drugs have been approved by the FDA to treat various types of advanced cancers. Approved immunotherapies include CTLA-4 inhibitor ipilimumab (Yervoy); PD-1 inhibitors pembrolizumab (Keytruda), nivolumab (Opdivo), and cemiplimab (Libtayo); and PD-L1 inhibitors atezolizumab (Tecentriq) and avelumab (Bavencio) (TABLE 1

Immunotherapy AEs can be difficult to identify because they can cause symptoms that are associated with common ailments and infections. Some of these adverse reactions might resemble another medical issue but require a very different course of action. For example, pneumonitis, which a small number of patients on checkpoint inhibitor immunotherapy may experience, can cause some of the same symptoms as viral or bacterial respiratory infection but should be treated with steroids instead of antibiotics. The primary immunotherapy-related AEs patients and clinicians should be aware of include flu-like symptoms, asthenia, arthralgias, and rash. Endocrinopathies such as thyroiditis, hypophysitis, adrenal insufficiency, and type I diabetes must be recognized quickly, as these complications may lead to the need for lifelong hormonal replacement therapy.

There have been reports of inflammation of organs, including pneumonitis, pancreatitis, hepatitis, nephritis, colitis, dermatitis (redness, itchiness, or rash), neuritis, uveitis, and myocarditis. Although myocarditis occurs in fewer than 1% of patients receiving immunotherapy, it is likely the most serious adverse reaction that can occur because of these agents.

 Early detection of this potentially fatal AE, which carries a 40% to 50% risk of death, is critical, but there are currently no clear ways to accurately predict or identify this type of immunotherapy-associated toxicity.

I was recently part of a multidisciplinary team at Roswell Park Comprehensive Cancer Center (Roswell Park) that identified troponin, a protein that enters the bloodstream only when the heart is damaged, as an early and reliable predictor of myocarditis in patients with cancer receiving immunotherapy with immune checkpoint inhibitors.

Findings of this retrospective study, which reviewed the records of 1001 patients with cancer who were treated with 1 or more immunotherapy agents at Roswell Park from 2016 to 2020, suggested that weekly troponin monitoring during the first 6 weeks of treatment could help physicians detect this rare but potentially fatal AE of immunotherapy. Any patient showing an elevation in troponin levels or signs of cardiotoxicity, such as angina or arrhythmia, should be referred to a cardio-oncology team for complete evaluation, including electrocardiogram, echocardiogram, or cardiac MRI.

Although immunotherapy-related myocarditis is extremely rare, it occurs with greater frequency and severity when immunotherapy drugs are given in combination, and early recognition is critical. For example, in a multicenter analysis, my colleagues and I identified 2 cases of myocarditis that developed in patients with metastatic melanoma following treatment with a combination of ipilimumab and nivolumab, which are 2 commonly used immune checkpoint inhibitors.

Reduction of immunotherapy-related AEs relies heavily on corticosteroids and other immunomodulatory agents, which should be prescribed to reduce the potential for short-term and long-term complications. It remains unclear whether prophylactic antibiotics should routinely be prescribed to reduce the potential for opportunistic infection in patients receiving steroids. Treatment should be individualized depending on each patient’s medical history, comorbidities, and underlying disease status, as well as the type, number, and severity of AEs.

Because immunotherapy is a relatively new treatment option, many of these agents have AEs that have not been previously observed. AEs stemming from immunotherapy use can affect the skin, lungs, gastrointestinal and endocrine systems, joints, heart, and other organs. Some of these AEs are just beginning to be described, therefore clinicians need guidance on how to recognize early signs, how to treat AEs, and when to refer a patient to a disease specialist.

For this reason, I have been helping to create guidance for medical professionals who care for patients receiving immunotherapy drugs. Along with other experts in this field, I helped write the first consensus guidelines on how to recognize and respond to immunotherapy-related AEs and am contributing to similar resources to be issued by ASCO and the National Comprehensive Cancer Network (TABLE 2

Information is key in identifying and managing any AEs of immunotherapy. It is critical for medical professionals to give patients clear written guidance before a course of immunotherapy is started and to keep that flow of information going back and forth during clinic visits and between appointments.

When my patients on immunotherapy ask me about possible AEs, I stress that immunotherapy is an incredibly important and effective option for treating many cancers and that AEs are rare. I also strongly encourage my patients to become active participants in their treatment by learning about these possible AEs, monitor for these adverse reactions, and respond to any symptoms that develop. Together, we can help to ensure these new and advanced treatments are as effective as possible.

Yervoy. Prescribing information. Bristol Myers Squibb; 2022. Accessed April 7, 2022. bit.ly/38px6Go

Keytruda. Prescribing information. Merck Sharp & Dohme Corp; 2022. Accessed April 7, 2022. bit.ly/3ul9M52

Opdivo. Prescribing information. Bristol Myers Squibb; 2022. Accessed April 7, 2022. bit.ly/3Klihmx

Libtayo. Prescribing information. Regeneron Pharmaceuticals Inc; 2021. Accessed April 7, 2022. bit.ly/3DSfK0D

Tecentriq. Prescribing information. Genentech; 2022. Accessed April 7, 2022. bit.ly/3Kof1GP

Bavencio. Prescribing information. EMD Sereno, Inc; 2019. Accessed April 7, 2022. bit.ly/3raRCBe

Puzanov I, Subramanian P, Yatsynovich YV, et al. Clinical characteristics, time course, treatment and outcomes of patients with immune checkpoint inhibitor-associated myocarditis. 

. 2021;9(6):e002553. doi:10.1136/jitc-2021-002553

Tawbi HA, Forsyth PA, Algazi A, et al. Combined nivolumab and ipilimumab in melanoma metastatic to the brain. 

. 2018;379(8):722-730. doi:10.1056/NEJMoa1805453

Puzanov I, Diab A, Abdallah K, et al; Society for Immunotherapy of Cancer Toxicity Management Working Group. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. 

. 2017;5(1):95. doi:10.1186/s40425-017-0300-z

Articles

Igor Puzanov, MD, MSCI, FACP, discusses the adverse effects associated with immunotherapy and how to manage them.

Tackling the Adverse Effects  of Immunotherapy

Director, Early Phase Clinical Trials Program

Co-Leader, CCSG Experimental Therapeutics Program

Professor of Oncology in the Department of Medicine

Immune checkpoint inhibitors significantly improve clinical outcomes in numerous malignancies, and combination therapy with ipilimumab and nivolumab has been shown to improve both objective response rate and progression-free survival in patients with melanoma. However, along with this increased efficacy, we have seen an increase in immune-related adverse events, leading to a discontinuation rate of 30% to 40%. Interestingly, a majority of these patients experienced a durable response even after they discontinued therapy. And while they are rare, some high-grade, potentially fatal events have been identified as well.

The good news is that these side effects are not a deal-breaker for using these critical new therapies. However, it is essential to know about them, monitor patients for early warning signs, and manage them appropriately. Characterizing these toxicities and grading them accurately is a priority for the practicing oncologist, as more patients with many types of malignancies will be treated with these therapies.

Most of the adverse events are low-grade, including skin rashes and diarrhea. However, some cases involve inflammation of the lungs, bowel, pancreas, or liver, potentially leading to pneumonitis, colitis, pancreatitis, diabetes, and liver damage. Endocrine effects such as irregular levels of thyroid, adrenal, and/or pituitary hormones have been observed. These events are generally completely reversible in over 90% of patients through treatment with high-dose glucocorticoids. Among these patients, up to half will require hormone replacement for life despite early steroid therapy.

Rarely, severe and potentially fatal side effects can occur, including immune-mediated myocarditis. For patients on combination immunotherapy with ipilimumab/nivolumab, it is advised that physicians monitor baseline and weekly troponin levels during weeks 1 through 12, and continue careful monitoring throughout active treatment. Proper monitoring, detection, and therapy are a subject of active research at Roswell Park and other experienced immuno-oncology cancer centers.

Clinicians must educate their patients and provide written instructions with a list of warning signs, as well as what actions to take in the event that they experience side effects between clinic visits. For patients who do not live in the vicinity of a treatment center, physicians make every effort to get them in touch with nurses to help elucidate how severe their symptoms may be. Sometimes, physicians can begin treatment by calling in glucocorticoids to their local pharmacy. Other times, physicians ask the patient to go to a local emergency room or to come to the clinic to have an in-person evaluation by a physician.

We must remember that these therapies are new. Personal communication between oncologists and primary care physicians, emergency care providers, hospitalists, and other frontline medical professionals is critical for appropriate care and evaluation of the patients and optimal treatment selection.

For 60% of patients on ipilimumab/nivolumab therapy, immune-related events can be properly treated with steroids, and the immune therapy subsequently restarted. However, it is encouraging to see that a majority of patients for whom immunotherapy had to be stopped continued to respond once therapy was discontinued. These data and the analysis showing that use of steroids did not lower response rates or duration of response are reassuring.

Cancer therapies, whether chemotherapy, genetic-mutation-targeted therapy or immunotherapy, have side effects. Adverse events with chemotherapy and radiotherapy are well documented, and unfortunately common. Targeted therapies—which by their mechanism of action spare the majority of, but not all, healthy cells&mdash;are associated with adverse events in 25% of patients, including cardiac-related side effects that are well described with many of them. Anti-VEGF inhibitors are a prime example, with up to 10% of patients experiencing cardiac-related side effects.

The observed adverse events that have been associated with immunotherapy, especially immunotherapy combinations, have to be properly assessed against their clearly improved efficacy in patients with otherwise dismal prognosis from stage IV cancers. As we gain more experience with these drugs, as more treatments become standard of care, and as we analyze the data to determine guidelines for predicting and ameliorating adverse events, the benefits of immunotherapies will continue to grow.

The observed adverse events that have been associated with immunotherapy, especially immunotherapy combinations, have to be properly assessed against their clearly improved efficacy in patients with otherwise dismal prognosis from stage IV cancers.

Igor Puzanov, MD, MSCI, FACP

Articles

Tackling the Adverse Effects of Immunotherapy

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