Naidoo Discusses Advances in the Management of Immunotherapy-Related AEs

Jarushka Naidoo, MBBCh

As the use of immunotherapy continues to expand in the treatment of cancer, including lung cancer, it becomes increasingly important to educate providers, patients, and caregivers on the potential side effects associated with these treatments, explains Jarushka Naidoo, MBBCh.

In patients with lung cancer, pneumonitis is the most commonly seen immune-related adverse event (irAE), which is a subset of side effects that can occur after treatment with immunotherapy. There have been several advancements in recent years to help guide providers in managing these side effects, including the publication of guidelines for diagnosing and treating irAEs.

OncLive: Can you provide an overview of your talk on managing irAEs?

What are some of the irAEs you talked about?

During the 5th Annual Miami Lung Cancer Conference, Naidoo, assistant professor of oncology, Johns Hopkins University, discussed some of the most commonly seen irAEs in patients with lung cancer, how to manage these irAEs, and other recent advancements in this area.Naidoo: irAEs are a subset of side effects that may occur as a result of immunotherapy treatment for cancer. The talk was focused on what some of these common irAEs are—particularly in the context of patients with lung cancer—how we might identify them, and what we have learned since these side effects were first recognized in the early clinical trials. I focused on some of the advances that have come about in the field of immune-related toxicity in the last number of years. The first is that there have been a number of published guidelines to assist clinicians and any type of oncology provider in their ability to diagnose and identify an immune-related side effect. These include the ESMO guidelines, the SITC guidelines, and, more recently, a collaboration between the American Society of Clinical Oncology (ASCO) and the National Cancer Control Network (NCCN).

From there, I focused much of my talk on pneumonitis, because this is the side effect that most plagues lung cancer patients. It can be difficult to discern between pneumonitis, which is defined as a focal or diffuse inflammation of the lung parenchyma, or pneumonia, or progression of a patient's lung cancer. We talked a little bit about what the recommendations are and how these have changed over the years. It is widely accepted now that patients need a high-resolution CT scan, however, they can have a chest x-ray initially according to the recently published guidelines. In patients who are symptomatic, it is encouraged to consider a bronchoscopy with or without a lung biopsy to discern if somebody has pneumonitis or not. In some instances, where it is difficult to discern between either of these, patients may be treated with corticosteroids as well as empiric antibiotics. We would hope that with time some of these algorithms may be further refined.

Have there been any studies in particular that have really allowed us to learn about these irAEs?

From there, we also touched a little bit on colitis. This hasn't been something that we have seen a lot in the lung cancer field, but now that we have been giving the combination of nivolumab [Opdivo] and ipilimumab [Yervoy] for small cell lung cancer, ipilimumab is associated with colitis and we are starting to see that now as a toxicity, particularly with giving the combination. We talked a little bit about the fact that this can sometimes be a steroid-refractory clinical event, and that patients may respond to infliximab [Remicade] and there may be newer immunosuppressants, such as the agent vedolizumab [Entyvio] that has been described in a couple of case studies and is included in the guideline. In the pneumonitis field, I was very fortunate to publish a study in the Journal of Clinical Oncology last year that was a large reported series, a collaboration between Memorial Sloan Kettering and the Melanoma Institute of Australia. That series included more than 40 patients with pneumonitis from immune checkpoint inhibitors from all solid tumors, but mainly included lung cancer and melanoma patients. What was novel about that study was that it comprehensively reported that pneumonitis can occur at any time during the treatment of a patient with immunotherapy. It has since been reported that this can even occur after immunotherapy has stopped.

What are your recommendations for discussing irAEs with patients?

The other seminal observation, which is highlighted in the guidelines as well, is that pneumonitis is not all created equal. There may be variable radiographic appearances associated with it. Clinicians should be aware that if a patient develops a new cough, shortness of breath, fever, or chest pain, and they do a CAT scan, that pneumonitis doesn't have a classic appearance. The appearances may range from organizing pneumonia, ground glass opacities, hypersensitivity, interstitial, or not otherwise specified, which is a grab bag of all 4 of those appearances.As immunotherapy is becoming a treatment for so many different cancers, it's now FDA approved in 9 different cancer types, it becomes very important to educate not just providers, but also patients and their caregivers, about what to look out for in potential side effects. While we are very concerned about some of the side effects that can occur, in general, immunotherapy is a much more tolerable treatment compared with other traditional cancer therapies. In general, the overall incidence of side effects from these agents is around 5% to 10%, whereas, with chemotherapy and other traditional cancer agents, it's decimals above that—2 to 3 times more incidence of side effects with these agents as opposed to immunotherapy. In general, we are very reassured by that, and patients should be reassured by that.

However, when I speak to a patient, I separate the side effects into generalized side effects or immune-related side effects, which are directly as a result of the immune-stimulating abilities of the treatment. The generalized side effects we usually talk about are fatigue, nausea, and sometimes a non-specific red skin rash and occasionally itch.

The fatigue, patients will often say, is distinct from the fatigue they might have experienced from a previous cancer therapy. Usually, the fatigue patients get from chemotherapy is relatively predictable in terms of when they get the treatment they are usually tired for a number of days afterwards; their blood counts will be at its lowest around 10 days after chemotherapy. That temporal pattern may not be as evident with immunotherapy. Patients do say they just have a constant low-grade rate of tiredness and it's different, almost like they have a flu. That makes sense because we are stimulating the immune system. It may be like they are fighting an ongoing immune-related battle in their bodies.

How can physicians discern between pneumonitis and progression?

From an immune-specific point of view, we would say that any organ system in the body can have inflammation as a side effect of this treatment from top to toe, but the ones that we care about the most or are most common are the hormone-producing glands in the body may be inflamed, such as the thyroid gland, the pituitary gland, the adrenal gland, inflammation of the lungs, called pneumonitis, inflammation of colon, called colitis, which can sometimes just cause diarrhea, inflammation of the liver, which can cause hepatitis, but there are a host of rarer organs that may become inflamed, such as the brain or the nerves causing neurologic immune-related adverse events, but they are particularly rare. First, they should read the guidelines, because they are a great multidisciplinary resource that have taken into account not only the thoughts of oncologists, but also nursing leaders, patients advocates, and multidisciplinary experts, such as pulmonologists and radiologists.

I would recommend that the patient should have a CT scan of the chest and see what percentage of the lung parenchyma may be involved with potential pneumonitis. That can help us to stratify what grade we are dealing with. Particularly, they should take into account the symptoms of the patient, usually if a patient is asymptomatic we say this is grade 1, if they are symptomatic, it could be grade 2 or greater. If they are symptomatic, I would encourage them to arrange a bronchoscopy and a microbial workup, including a sputum culture, blood culture, urine culture, nasal swabs, and viral swabs to rule out common infectious causes.

What are some of the unanswered questions that still exist with regarding to irAEs?

In terms of discerning between that and progression, I would ask the provider when the patient's most recent full-body restaging was. If there is a question that the patient is progressing, and that these lesions in the lung could represent progression, as opposed to pneumonitis, then a bronchoscopy may be helpful, because if one of those lesions is biopsied and it comes back to show cancer cells, rather than inflammatory cells, then that can help to discern between progression versus pneumonitis. I think one of the unanswered questions is what is the overall incidence of these irAEs. Much of the data that we have so far is based on clinical trials. They are very well conducted, extensive clinical trials, but these may not be representative entirely of a real-world population. Patients often are not eligible for trials for various reasons. However, now that these agents are available in terms of regulatory approval, even those patients that may not have qualified for trials are now receiving these agents. Therefore, the overall incidence of irAEs may be higher than what is reported in the studies.

The second area, which we are actively trying to study and I know others are as well, is are there any particular risk factors for the development of these side effects? Are some patients predisposed to getting them, as opposed to others? Are there immune-related side effects that are new and are going to be identified the longer we give treatment? What are the long-term complications or considerations for giving immunotherapy?

These are new kids on the block. We don't have 10-year follow-up or survival data on many of them, except for the very original studies. The same way we monitor patients who have hormonal therapies for long-term effects of those therapies, perhaps as time goes on, we will be monitoring for long term effects of immunotherapy as our patients survive for longer.