Marianne Davies, NP, DNP, MSN, BSN, discussed the potential severity of immune-related adverse effects and detailed recommended management strategies for patients receiving checkpoint inhibitors, especially in lung cancer.
Although rare, immune-related adverse effects (irAEs), such as colitis and myocarditis, can be severe consequences of improper toxicity management, explained Marianne Davies, NP, DNP, MSN, BSN, who added that baseline evaluations, thorough assessment of etiology with stool cultures and labs, and early intervention with steroids and immunosuppressive agents can help curb the incidence of high-grade immune-mediate AEs.
“There are a lot of resources that are available for health care professionals, which are particularly important for people who are in the community and not at an academic center to get a step-by-step approach on how to manage these toxicities. Guidelines have been developed from the American Society of Clinical Oncology, the Society for Immunotherapy in Cancer, the National Comprehensive Cancer Network, and there’s also AIM with Immunotherapy,” said Davies. “All of these have online resources that one can use in clinical practice, which can be really quite helpful. Some of them even have apps that you can download for your phone to help provide some guidance.”
In an interview with OncLive®, Davies, a lecturer in nursing at the Yale School of Nursing, discussed the potential severity of irAEs and detailed recommended management strategies for patients receiving checkpoint inhibitors, especially in lung cancer.
Davies: I’ve been on the NCCN’s Management of Immunotherapy Toxicity Guideline Panel for the past several years. We have been publishing the guidelines for several years based on consensus expert opinion, because we’re gaining more and more experience with the use of immune checkpoint inhibitors, [such that] we based our management of toxicities on our experience with autoimmune diseases. These were just mostly consensus guidelines; they really weren’t randomized clinical trials looking at how we manage immune checkpoint–induced toxicities.
Our group gets together virtually a few times a year to look at all the literature and look at all the latest updates and also new research on specific management strategies for each of the toxicities, and then we update our guidelines accordingly. Last year, we elected to focus on the management of gastrointestinal [GI] toxicities. The most common GI toxicity is diarrhea or colitis. We updated the guidelines, [such that] for grade 1 toxicity our typical management for lower-grade toxicity, based on the [Common Terminology Criteria for Adverse Events] is the use of supportive treatments, such as loperamide or diphenoxylate atropine. Those are initially used for symptom management over the course of time.
We have now taken it to the next level and suggested that in patients who do not have improving symptoms within 2 to 3 days, we need to be more aggressive in looking for other etiologies, such as potential infectious etiologies, such that stool cultures and labs should be obtained to rule out infectious etiology. If symptoms still persist, while that’s being worked up, the recommendation is that if a facility has the ability to obtain stool and perform lactoferrin, or calprotectin, stool sample measurements, that that can be very helpful in really discerning an inflammatory process, so it can really help guide our management.
The lactoferrin and calprotectin are both inflammatory markers, which lead us to believe that may be an immune-related toxicity. If the lactoferrin is positive, it’s recommended now that we escalate our treatment to follow the guidelines for grade 2 toxicity, assuming that it’s an immune-related toxicity. If lactoferrin is positive, then there’s a strong recommendation that perhaps the patient should undergo flexible sigmoidoscopy to rule out ulcerations and true colitis. If the lactoferrin is negative, meaning that it’s not showing a strong signal for inflammation, we should continue on with our infectious workup and look at other etiology and add an additional antidiarrheal agent to the management strategy. For grade 2 toxicity, with a higher number of stools per day, steroids should still be initiated, which was in alignment with our previous guidelines.
However, we have now updated them to recommend that if within 2 weeks of steroids patients are not improving, then the addition of additional immunosuppressive agents should be initiated and the agents of choice for colitis are infliximab or vedolizumab. That can assist us in that in suppressing that immune toxicity. If we do initiate infliximab, the goal is to attempt to taper steroids over less than 4 weeks, so that we can minimize any complication on steroids.
The other toxicity that we focused on in an article last year was cardiovascular toxicity, specifically myocarditis. In the smaller clinical trials that led to drug approval, a very small percentage of patients were diagnosed with myocarditis, and the percentage is still relatively low, but it can be a fatal toxicity if it’s not managed very swiftly.
We know the toxicity occurs at a higher frequency if dual checkpoint inhibitors are used, such as the combination of an anti–CTLA-4 and anti–PD-1 agent. There’s also a higher risk of potentially developing these in patients that have underlying cardiovascular disease. Those patients should be particularly monitored closely for that risk. We also recommend that patients should have baseline EKG and troponin levels done so that, if there are changes in the evaluation of potential for cardiovascular toxicity, that we would understand what a baseline is and that one should move swiftly after steroid therapy to additional immunosuppressant therapy if a patient is unresponsive to the initial steroid, and that should be done within 2 to 3 days to reduce the risk of fatal outcome in those patients.
A really exciting development in the past few years has been the approval of durvalumab [Imfinzi] for patients with stage III disease. Typically, for stage III non–small cell lung cancer, our therapy, which had been a standard of care for several years was combination chemotherapy with radiation therapy, which is typically done over about 7 weeks, after which time patients, hopefully, recover from the toxicities associated with those therapies.
In the PACIFIC trial, investigators evaluated the addition of durvalumab following chemotherapy and radiation to see whether we could improve overall survival and outcomes in this population, and it was a successful trial. There are some caveats for managing these patients.
On the trial, the best improvement was noted when patients started durvalumab treatment within a few weeks after the completion of the chemotherapy and radiation therapy. However, some adverse effects [AEs] might still be lingering, and they may actually overlap with some of the toxicities that we might see with checkpoint inhibitors. The first and foremost that we think about for radiation therapy is the potential for pneumonitis, which sometimes can be demonstrated on CT scans shortly after the completion of the radiation, or even several weeks, or sometimes months after the completion. We know that checkpoint inhibitors [can cause an] inflammatory process in the lungs, which can lead to pneumonitis, so it might be a little difficult to discern the etiology of the pneumonitis if the patient develops that.
If a CT scan is done and a patient does develop pneumonitis, which may look like ground glass patchy opacities on a lung, we can look at whether this is occurring in the field of radiation, or whether it is more dispersed and more bilateral. It’s not always a guarantee that it’s going to exclude the checkpoint inhibitor, but it may indicate that it could be from the radiation and not a true immune-mediated AE. Nonetheless, if a patient is symptomatic at all, and has this demonstrated on a CT scan, it would be managed in exactly the same way, which is by holding the checkpoint inhibitor and initiating corticosteroids.
Some of the other toxicities that may be residual from chemotherapy might be things like peripheral neuropathy that can occur with some of the chemotherapy. Typically, those toxicities are assessed along the way as the patient is getting their cycles of chemotherapy. It’s really important to have an understanding of the patient’s baseline symptoms following completion of the chemoradiation, assess how they’ve improved over a couple of weeks before you start the immunotherapy, so that if there are changes as the patient is on durvalumab, we’re able to understand that this is a new phenomenon that needs to be managed, or whether this is a residual toxicity that has not yet resolved.
Sometimes now we are administering checkpoints inhibitors with chemotherapy, and some of the toxicities of the chemotherapy are going to overlap. Since you’re starting the agents at the same time, the onset of the symptoms, and the pattern with how they develop can be important. Some of the chemotherapies can cause peripheral neuropathy, and those do tend to occur after several cycles of chemotherapy, so that may align with the same timing of when immune-related toxicity can occur.
In contrast, if we were looking at renal dysfunction or hepatic dysfunction, those can also be toxicities of chemotherapy. The pattern of that typically occurs within 1 to 2 weeks after a patient receives the chemotherapeutic agents. Typically, it will improve over the next couple of weeks in time for their next cycle of chemotherapy, so that kind of bell curve pattern of that toxicity can give you insight into whether that toxicity is from the chemotherapy and not the immune therapy. If these hepatic or renal toxicities occur after several cycles of chemotherapy, one has to then look a little bit more closely at the pattern and the sustained levels of elevation to help discern whether those are ongoing chemotherapy AEs or whether there is the addition of immune-related toxicity.
In general, the immune toxicity will be more persistent for a period of time and take a little bit longer to improve if you don’t initiate corticosteroid therapy. In fact, it can take weeks and weeks. If one makes the assessment or interpretation that it’s chemotherapy induced, some of the management strategies might include holding one of the chemotherapy agents, or perhaps doing a dose reduction.
With immune-related toxicities, we don’t do dose reductions. Our decision [is going to depend on whether we want to] keep administering this drug or hold the drug and whether we need to initiate corticosteroid therapy. Looking at each toxicity in the pattern of presentation is very important to the management. In addition, for those types of overlapping toxicities, it’s important to keep in mind that patients are on a lot of other medications as well, such as over-the-counter medications, and there can be other viral illnesses that may trigger those spikes. A really thorough review of systems and physical exam are really essential to help in your differential diagnosis, which will guide your management strategies.
We have an immune-related toxicity clinic in which our immunologists and other researchers are looking at biomarkers for patients that develop toxicities. One, we are trying to see if there is anything that can be detected in serum to see whether there are specific patterns that we can help identify. The other thing that several organizations are also looking at is conducting research on specific management strategies for each of the toxicities, customizing it to the patient and moving beyond just the steroid management. This is a field that is really exploding. There has been such an interest from our subspecialists in personalized management of these toxicities.
[It’s important] not to be afraid or hesitant to consult with your other subspecialist colleagues. They can be very helpful in looking at organ-specific toxicities and management. I’ve got them on speed dial in my phone for each of the different organ systems because sometimes you need a little bit more of a creative approach to the assessment and management of patients.
Certainly, one of our big considerations over the past year has been our differential with COVID-19 because there’s a lot of overlapping symptoms, so it can really mimic COVID-19–like symptoms. The other thing to keep in mind is that it is possible that a patient may have kind of overlapping etiologies that may present. In the case, let’s say of respiratory toxicity, one may have an overlapping infection at the same time that they have an inflammatory pneumonitis, so you may need to also manage an infection at the same time. So don’t completely exclude the potential for other overlapping etiologies or specific symptoms.