CE / CME
Pharmacists: 1.00 contact hour (0.1 CEUs)
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: May 25, 2023
Expiration: May 24, 2024
Timeline of Select FDA Approvals of ICIs
Eric Jonasch, MD:
I am going to start this activity by discussing how to manage AEs in patients receiving ICIs as monotherapy. I will then review guidance on managing AEs in patients receiving ICIs in combination with VEGF-targeted agents. My colleague, Dr Kathleen Moore, will discuss both guidance on managing AEs with monotherapy and emerging data on managing AEs in patients receiving the investigational combination of an ICI plus a PARPi.
ICIs have become a mainstay in the treatment of advanced cancers, as shown here in this timeline.1 Starting with the approval of the CTLA-4 inhibitor ipilimumab for melanoma in 2011, numerous agents targeting PD-1 or PD-L1 have been approved for several cancers during the past decade, including the combination of nivolumab and the LAG-3 inhibitor relatlimab for melanoma in 2022. ICIs not only are highly efficacious agents, but also have some challenges, as we will discuss today.
ICI Treatment: Place in Therapy
Eric Jonasch, MD:
One challenge is deciding where to sequence ICIs in treatment.1 For example, in RCC, we must consider whether to use ICIs as neoadjuvant or adjuvant therapy in the setting of resectable disease or for advanced disease in the first line, or wait until later lines of treatment. For RCC in 2023, we are not routinely using ICIs in neoadjuvant therapy, but we definitely use them in the adjuvant setting.
Another challenge is whether to use ICIs alone or in combination with other ICIs, chemotherapy, or targeted therapies. In advanced RCC, we typically combine several ICIs or combine an ICI with a targeted agent.
A New Spectrum of Adverse Events With ICIs
Eric Jonasch, MD:
There is an entire spectrum of immune-related AEs (irAEs)—the “-itises”—associated with ICIs; these essentially are autoimmune conditions resulting from global immune activation.2-5 Most common are diarrhea/colitis and dermatitis, including rash, but we also see hypophysitis, encephalitis, orbital inflammation, and uveitis. Pneumonitis, hepatitis, pancreatitis, and nephritis also occur, underscoring that any organ system can become inflamed from these therapies. Of interest, irAEs sometimes are associated with better outcomes, which we will discuss a little later, but these toxicities obviously still require treatment.
Time of Onset and Toxicity Grade of irAEs in Patients Receiving PD-1/PD-L1 Antibodies
Eric Jonasch, MD:
The time of onset of irAEs varies depending on the organ system and specific event, with cutaneous reactions being relatively early and more serious toxicities, such as colitis and hepatitis, occurring later.6,7
Kathleen Moore, MD:
Some of the earliest events you can see are itching and rash starting at a median of 4-6 weeks into therapy. Like Dr Jonasch said, diarrhea and hepatitis typically start a little later—no earlier than 8 weeks. The median onset for endocrine irAEs is approximately 10-11 weeks.
Incidence of irAEs and Fatality Rates Associated With ICIs
Kathleen Moore, MD:
The rates of diarrhea/colitis and other irAEs vary somewhat by the target of the ICI and whether the ICI is given as a single agent or in combination with another ICI. As shown in the table here, any-grade diarrhea affects 14% to 19% of patients receiving anti–PD-1 ICIs, 33% of patients receiving anti–CTLA-4 ICIs, and 44% of patients receiving an anti–PD-1 plus anti–CTLA-4 ICI.8
Cutaneous irAEs are also quite common. Any-grade pruritus affects 14% to 19% of patients receiving anti–PD-1 ICIs, and rash was reported in 13% to 26% of patients. Most other irAEs with anti–PD-1 ICIs affect <5% of patients, apart from endocrine toxicities, which affect approximately 8%.
Despite the high prevalence of cutaneous irAEs, a retrospective review from 2021 reported that racial and ethnic minority patients were half as likely to be diagnosed with these irAEs as White patients.9 To learn more about mitigating health inequities in ICI access and irAE management, please see this on-demand webcast featuring a dynamic presentation and discussion between pharmacists Jessica Davis, PharmD, BCOP, CPP, and Kamakshi V. Rao, PharmD, BCOP, FASHP.
Eric Jonasch, MD:
It is important to remember that the frequency of irAEs does not necessarily correlate with their mortality.10 Diarrhea/colitis is a common irAE with ICIs, but the fatality rate is low and getting lower as we improve treatment. By contrast, myocarditis and myositis are relatively rare yet extremely dangerous, with high fatality rates. These irAEs need to be recognized early and managed accordingly, which we will discuss shortly.
Diarrhea/Colitis From Immunotherapies Predicts for Longer Survival
Eric Jonasch, MD:
Although we do not want our patients to develop irAEs, data do suggest that patients with irAEs are more likely to have better outcomes than those without irAEs. For example, the retrospective analysis shown here reported that diarrhea/colitis was associated with a significant improvement in overall survival (OS) vs those who did not experience diarrhea/colitis (P <.001).11
This is likely because if the ICIs are not adequately stimulating the immune system—which leads to these irAEs—we probably will not see a benefit with these treatments to the same degree. It is perhaps unsurprising that AEs arising from an immune response are associated with better survival in some patients. Of course, when irAEs arise, we still need to identify and manage these toxicities, as we will now discuss.
Workup for More Common irAEs: Colitis
Eric Jonasch, MD:
We will move now to the workup for 4 of the more common irAEs: colitis, hepatitis, nephritis, and pneumonitis.12 For colitis, we want imaging and labs to rule out infectious causes. Simple tests such as fecal lactoferrin and calprotectin can provide you with information on how much inflammation is in the bowel.
It is also important to refer patients to your gastroenterology colleagues with expertise in managing these irAEs. Our institution’s GI department has members who have become colitis experts, and these are people who should be included early in the management of patients with colitis.
Workup for More Common irAEs: Hepatitis
Eric Jonasch, MD:
The workup for hepatitis is similar to that of colitis, with imaging and labs to rule out other causes.12 Obviously, if you see transaminases rise after the initiation of an ICI, you know it might be related, but you also need to make sure there is no reactivation of a latent virus.
You also need to check for autoimmune antibodies and work with your nurse and pharmacist colleagues to perform a thorough medication review, which I will discuss more when we go over the workup for nephritis. With more serious events, consider a GI/hepatology consultation.
Workup for More Common irAEs: Nephritis
Eric Jonasch, MD:
For nephritis, assess the spot urine protein/creatinine ratio, antinuclear antibodies, rheumatoid factor, and antineutrophil cytoplasmic antibodies to help with the differential diagnosis.12 You have to rule out other factors here, and—once again—early nephrology consultation is indicated when nephritis is more than transient.
It is also important to note that a major part of the workup for alternative causes of nephritis and hepatitis is a medication review for possible drug-related etiologies. At my institution, we have pharmacists run the patient’s list of medications to determine whether any can be causing or contributing to the suspected irAE. Our genitourinary department has a very large patient volume, so we have 6 pharmacists who work specifically with us and who are experts on our oncology drugs and their toxicities. Most of the pharmacists also rotate between managing outpatient and inpatient settings in our department, so they get to see these toxicities when they are early and less serious vs later on, when they are very serious. As a result, our pharmacists have a great deal of useful personal knowledge and experience.
Workup for More Common irAEs: Pneumonitis
Eric Jonasch, MD:
The workup for pneumonitis includes imaging, but you also want to rule out infectious causes.12 An early pulmonary consultation is helpful when there is ambiguity. For grade ≥3 pneumonitis, a bronchoscopy with bronchoalveolar lavage may provide value and help determine if the patient is immunocompromised.
Workup for Rarer and/or More Lethal irAEs: Hypophysitis
Eric Jonasch, MD:
We will move on to the workup for 4 rarer and/or more lethal irAEs: hypophysitis, myasthenia gravis, myocarditis, and myositis.12 For these and other more serious toxicities, early intervention with aggressive immunosuppression and a multidisciplinary approach can be lifesaving.
Hypophysitis is relatively straightforward, provided you pick it up early. If a patient develops terrible fatigue, blood pressure changes, and nausea, you need to consider hypophysitis. You should draw blood to check posterior pituitary hormones. It is important to see whether they are universally low, and some might drop at different frequencies than others.
The management for hypophysitis is hormone replacement, which is simple and easy, but if you miss this diagnosis, patients can get very sick and die.
Workup for Rarer and/or More Lethal irAEs: Myasthenia Gravis
Eric Jonasch, MD:
When patients start developing myasthenic symptoms (eg, muscle weakness), do a blood workup to check for anti–acetylcholine receptor antibodies, anti–muscle-specific tyrosine kinase antibodies, and antistriational antibodies.12 An early neurology consult, pulmonary functional assessments, and aggressive intervention should be used as required for these patients.
Workup for Rarer and/or More Lethal irAEs: Myocarditis
Eric Jonasch, MD:
Similarly, myocarditis also needs an early cardiology consult and evaluation of myocardial markers (troponin I or T, creatinine kinase) along with brain natriuretic peptide to see whether there is early heart failure.12
Workup for Rarer and/or More Lethal irAEs: Myositis
Eric Jonasch, MD:
With myositis, a blood workup should include looking at anti–cyclic citrullinated peptide antibodies, along with a functional evaluation of muscle strength.12
Now we will turn to a discussion of general management.
General Guidelines for Management of irAEs
Kathleen Moore, MD:
The guidelines for managing irAEs are organ system specific.13 In general, however, if a patient has a grade 1 irAE and is doing fine, you should observe them and provide supportive care, and in many cases you can continue ICI therapy. You also can consider holding therapy depending on the patient and your worry about symptoms worsening, but usually you can continue treatment.
Eric Jonasch, MD:
I agree. The main thing is to watch and keep people on therapy.
Kathleen Moore, MD:
For grade 2 irAEs, meaning those with moderate symptoms, you need local or noninvasive intervention. Here you should consider holding the ICI, but you can consider resuming therapy if the irAE completely resolves to grade ≤1 without tremendous delay or excessive steroid use. Consider low-dose steroids (eg, prednisone or prednisolone equivalent at 0.5-1 mg/kg/day). Again, you can usually restart the ICI—at least if this is the first occurrence of an irAE.
I am very fortunate to have a GI specialist at my institution who is an irAE expert, and he has been transformational in helping us get these patients better. Sometimes we can even help patients with grade 2 diarrhea continue with an ICI without systemic steroids by using budesonide, an oral steroid that is not absorbed systemically but protects the gut. Some of our expert colleagues outside of oncology are great at thinking outside the box and helping us take the best care of patients.
Eric Jonasch, MD:
Moving on to grade 3 irAEs, this is when prednisone at higher doses or IV steroids would come into play. We would definitely stop the ICI.
Kathleen Moore, MD:
Yes. Grade 3 irAEs are medically significant but not immediately life-threatening. It is usually preferred to discontinue the ICI, but sometimes a patient who is responding to therapy can be restarted, perhaps even while receiving a physiologic dose of steroids. That has to be done with a great deal of care and only considered for patients lacking alternative effect options.
Patients with grade 3 irAEs have to be monitored very closely and sometimes, if not always, admitted. Because these irAEs require higher-dose steroids, the steroid tapers should be slow and spread for at least 4 weeks.
Symptoms must resolve to grade ≤1 while receiving steroids. Sometimes when tapering, symptoms reescalate, so you need to raise the steroid dose back up and restart the taper, making these tapers potentially quite long. One learning point is that patients should feel better pretty quickly with steroids. Some of the rare neurologic irAEs do not always improve right away, which is frustrating, but irAEs such as diarrhea and rash should improve quickly. If these events do not, plan to escalate the immunosuppression, and if you have not already, get consults for biopsies, colonoscopies, etc.
Grade 4 toxicities require urgent intervention in the hospital with high-dose steroids and expert consultation. In general, grade 4 toxicities warrant permanent discontinuation of ICIs apart from endocrinopathies controlled with hormone replacement.
Immunomodulatory Agents to Manage irAEs
Eric Jonasch, MD:
Once we identify an irAE, we need to manage it. Depending on the grade, you can withhold the ICI to see whether that cools down the toxicity. The next level of treatment is to start steroids (prednisone, methylprednisolone). These can be oral or IV, depending on the severity.12
There are also immune modulators such as mycophenolate, which is a relatively selective inhibitor of B-cells and T-cells.
We also have several biologic agents: infliximab, which targets TNF-α; rituximab, which targets CD20 on B-cells; abatacept, which inhibits T-cell activation by binding to CD80 and CD86 to block interaction with CD28; tocilizumab, which targets interleukin-6; and vedolizumab, which is an α4β7 integrin inhibitor that acts at the level of the gut wall.
There are some important nuances about when to use these immunosuppressive agents. For example, mycophenolate is recommended for patients experiencing steroid-refractory hepatitis. There is concern that infliximab is hepatotoxic, so this agent should not be used for hepatitis. By contrast, infliximab or vedolizumab is recommended for patients with steroid-refractory colitis. Depending on your institution, fecal transplant may be an option for those with colitis that is refractory to all other immunosuppressants.
Kathleen Moore, MD:
Abatacept has evidence supporting its activity in steroid-refractory myocarditis. Unfortunately, I know about this personally because we just had a case of myocarditis, and we worked closely with a cardiologist who understands irAEs. This just speaks to the importance of engaging specialists.
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