Patients taking checkpoint inhibitors or immunotherapy in combination with other treatments need to be aware of this potential side effect and the associated symptoms.
A dry cough, fatigue and chest pain are all signs of COVID-19, but for those on cancer treatments, another culprit may be at fault. Interstitial lung disease, also referred to as ILD, is a potential side effect of immunotherapy, which works by activating the immune system to better attack rapidly growing cancer cells. CDK 4/6 inhibitors, another potent cancer therapy, works by a different mechanism — interrupting the activity of CDK 4/6 proteins that activate the cell cycle and cell division. Both of these treatments can cause ILD.
Although “ILD” is an umbrella term for more than 200 diverse lung disorders, they all have the common characteristic of causing inflammation that can lead to scarring of the lungs if left untreated. The inflammation makes it difficult for patients to breathe and get oxygen into the bloodstream. The term “pneumonitis,” which refers to lung inflammation, includes infectious causes, yet is often used interchangeably with ILD when it occurs in patients who are receiving drugs such as immunotherapy or CDK inhibitors.
The development of ILD as a side effect to immunotherapy has only recently been better characterized. “We were aware from clinical trials back in 2015 that (programmed cell death, or PD-1/PD-1 ligand inhibitors), a kind of immunotherapy used to treat non-small cell lung cancer and other solid tumors, can cause lung toxicity,” says Dr. Karthik Suresh, a pulmonologist at Johns Hopkins Medicine in Baltimore. “But according to the literature, it is a rare event. About 2.5% to 3% of patients on immunotherapy develop ILD. But there is still much to learn about this relatively new phenomenon.”
Although ILD can occur in patients with any kind of solid tumor, it appears to be most prevalent in patients with non-small cell lung cancer, where underlying lung disease is more common. ILD can also develop from CDK 4/6 inhibitors prescribed for breast cancer, but this side effect occurs infrequently. According to Dr. Hope Rugo, director of breast oncology and clinical trials education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, a safety analysis of the adjuvant monarchE trial showed that about 2.9% of patients receiving the CDK 4/6 inhibitor Verzenio (abemaciclib) developed ILD/ pneumonitis. Most of these events were asymptomatic, and about 50% received treatment with antibiotics or steroids.
The way to ensure that the ILD doesn’t progress is for both patients and physicians to be vigilant and to catch it early. “Patients should know that if they have a cough, and are experiencing shortness of breath or excessive fatigue, they should let their doctors know immediately,” says Suresh. “The faster the condition is diagnosed, the better the outcome.”
Data began to emerge in 2015 suggesting that PD-L1 inhibitors could result in ILD. One study conducted in Europe looked at 1,826 patients with cancer admitted to the hospital between December 2015 and April 2016. Of that group, 64 patients, or 3.5%, developed ILD. Most of the cases were of moderate severity, but 9.4% had serious disease. The majority of the patients were men and former smokers.
Although this study identified characteristics of patients who developed ILD, most studies have not found smoking or gender to be risk factors for this disease. At this point in time, studies have not identified any clear-cut risk factors. “Immunotherapy-related ILD is a relatively new phenomenon, so we’re asking basic questions, trying to pinpoint who is likely to get it,” says Suresh. “We’re looking at the nature of the inflammation and how damage occurs. Because PD-L1 inhibitors release the brakes on immune activity, and we’re seeing activated immune cells along with ILD in patients with non-small cell lung cancer, it is logical to conclude that those with vulnerable lungs are more susceptible to ILD.”
Dr. Tanzira Zaman, medical director of Interstitial Lung Diseases at Cedars-Sinai in Los Angeles, concurs, adding that the presence of an autoimmune disease also appears to be a risk factor. “If patients already have an overactive immune system, it’s not surprising that kicking it up even more would result in ILD,” she says.
The first reported cases of lung distress associated with CDK 4/6 inhibitors began trickling in about 2017, with isolated cases reported in a study of women with breast cancer receiving Kisqali (ribociclib). In another study, one woman died after receiving Ibrance (palbociclib). Interestingly, this research also shows that some women tolerate Kisqali but not Ibrance, and vice versa.
“Fortunately, most identified cases were grade 1, which is asymptomatic and found only on imaging,” says Rugo. “Although most symptoms occur early, ILD also may emerge several months or even a year after treatment is started. For this reason, respiratory symptoms that emerge at any point during treatment should be taken very seriously, and patients should be told to contact their doctors right away if such symptoms develop.”
The symptoms of ILD resemble many other respiratory infections, congestive heart failure or even COVID-19, making diagnosis challenging. “If a patient has shortness of breath, fatigue, a cough or less energy than usual and is taking a checkpoint inhibitor, then ILD must be considered,” Suresh points out. “The patient’s oncologist may decide to consult with a pulmonologist at this point in the process. Patients should be told what to look for as well.”
One of the first steps in the diagnosis process is having a CT scan done. These images may show an abnormality called ground glass opacity, which appears as gray areas on the scan. Bronchoscopy, a procedure where a thin tube is placed into the nose or mouth and extends to the lungs, may be performed to obtain a sample from the lungs and to rule out other causes of inflammation. Pulmonary function tests quantify lung function and also shed light on the degree of inflammation, including infections. “Sometimes patients are totally asymptomatic, and ILD is picked up through CT screening,” notes Zaman. “On the other hand, these tests can also alert us to a more serious case, which will guide subsequent treatment.”
If a patient has no or mild symptoms, the oncologist, often in consultation with a pulmonologist, may decide to keep the patient on the checkpoint inhibitor; if that decision is made, monitoring the individual for signs of worsening lung disease is essential. If the ILD is more serious, treatment is stopped and the patient is put on steroids for six to eight weeks.
The decision about whether to resume treatment with a check- point inhibitor after a bout of ILD can be a difficult one to make, especially since these drugs work well and are successful at keeping the cancer at bay. “If the case wasn’t too bad and the checkpoint inhibitor was working for that patient, then it may be possible to go back on the treatment,” explains Dr. Carlos Henrique Dos Anjos, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York. “But if the patient had a severe case of ILD, then an alternative therapy will have to be found.”
With growing awareness of the possibility of ILD from immuno- therapy and other treatments, clinicians are now considering ways to monitor for it in real time. Dr. Kelly Westbrook, an oncologist from the Duke Cancer Institute in Durham, North Carolina, and her team developed such a protocol for women with HR-negative, HER2-positive breast cancer receiving Enhertu (fam-trastuzumab deruxtecan-nxki), a type of therapy known as an antibody drug conjugate. This therapy combines chemotherapy with a HER2-targeting antibody to treat metastatic breast cancer. Although not immunotherapy, Enhertu is given to women who have tried many other types of treatment.
“One of the reasons that we wanted to set up this monitoring protocol is that the overall response rates in the trials, which led to approval of Enhertu, were so impressive that we wanted to be able to use it without dose interruptions or dose delays, but we were concerned about the high risk of significant ILD noted in the trials,” says Westbrook. “During clinical trials, almost 9% of patients did develop ILD, and fatal outcomes due to ILD and/or pneumonitis occurred in 2.6% of patients — a number that was somewhat surprising. For that reason, we wanted to be particularly attentive to this potential problem.”
The protocol involved chest imaging and pulmonary function tests before treatment began and then every six weeks during therapy. If pulmonary functioning declined more than 10%, a pulmonologist was called in for a consultation. Fifteen patients were part of the data presented from this study in December 2020; currently, data from over 30 patients are being analyzed.
“Fortunately, we have only had one patient develop ILD thus far; another two patients developed respiratory symptoms that turned out not to be ILD, but because of our protocol, we were able to minimize treatment delays despite those symptoms,” says Westbrook.
Although the protocol has potential for widespread use for patients receiving any drug that could cause ILD, it may be difficult to manage in small community hospitals. The tests can be time-consuming and an extra burden for patients. For this reason, Westbrook and her team are not planning additional studies right now, but that could change.
At this point, the best defense against ILD is patient education and awareness. “Empowering patients to think about this possibility while on any form of immunotherapy is the way to get a diagnosis quickly,” says Zaman. “Although ILD doesn’t happen often, it can be serious. When patients alert their doctors to this problem as soon as they start experiencing any symptoms, the medical team can make a decision about treatment promptly, increasing the chances of a successful outcome.”
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