Charles A. Powell, MD, MBA: The question that often comes up is, what is the most appropriate strategy for monitoring patients who are being treated with a drug such as an anti-HER2 therapy for the development of interstitial lung disease [ILD]? I think the most important monitoring is done by the patient, to be aware of a change in symptoms, specifically symptoms that include shortness of breath. In particular, this refers to shortness of breath in doing activities that previously could be done, let’s say, without any shortness of breath. Also, they should be aware of a new cough. If the patient develops any of those new symptoms, then it’s important to identify that event to the treating physician. That’s the most important part. The second part is monitoring with imaging. That can usually be done in the setting of imaging that is typically performed to assess the response to treatment. There is no recommendation for a specific imaging interval to detect interstitial lung disease in an asymptomatic patient, other than imaging that is required for the clinical treatment of the patient with the drug for their tumor.

Now, let’s say a new symptom develops, and that new symptom then gets reported to the treating physician. Then the next important step is to hold off further treatment of a compound such as in HER2 until the nature of the complaint can be more fully investigated, and that is because interstitial lung disease is certainly a manageable toxicity in most of the cases. Over 80% of the cases are grade 1 or grade 2. However, some patients do progress beyond grade 1 and grade 2, and typically that occurs in patients in whom treatment is continued in the setting of an underlying or present interstitial lung disease due to the study drug. So it’s important to stop the study drug if interstitial lung disease is being contemplated as a new diagnosis or is actually diagnosed in a patient. Holding the treatment is the most important step to do. Then comes time to evaluate whether those new symptoms may be due to interstitial lung disease. An important principle to keep in mind is that the symptoms we’re talking about—cough and shortness of breath—and interstitial lung disease for that matter can be caused by a variety of different conditions. Certainly one of the conditions can be a pneumonitis or interstitial lung disease directly attributable to the study drug, but there are other conditions that can cause interstitial lung disease and symptoms. They include infections, aspiration events, exposures to other inhaled toxins or other drugs that can cause lung disease.

So it’s important, then, to be able to determine first, if a patient does have interstitial lung disease. The most important modality for determining that is to use chest imaging, and that will require a CT scan of the chest. If interstitial lung disease is detected on the CT scan, then it will be important to determine whether that disease is attributable to the study drug. Most often that is done as a matter of excluding other causes for the findings on the chest imaging. That is typically done by a pulmonologist, or it can be done by another specialist who has familiarity with these conditions as well. That may require further diagnostic testing for infections with cultures of the sputum, cultures of the blood. Perhaps a procedure called a bronchoscopy that pulmonologists perform will be required to acquire specimens from the lung, from the fluid within the lung, and from the tissue surrounding the lung, depending upon the findings on the imaging and the test that is most likely to be appropriate. The pulmonologist then will work with the oncologist to know whether there is a high probability of there being interstitial lung disease caused by a study drug, and then that will help the oncologist decide on the next steps for treating the patient for their cancer and for treating the patient for the interstitial lung disease as it is diagnosed.

Joyce A. O’Shaughnessy, MD: With regard to ILD that’s documented or highly suspected based on imaging in the patient’s clinical course, there are well defined algorithms thankfully to tell us what to do to prevent ILD from becoming a significant issue for the patient. Even for asymptomatic ILD that you just find on imaging studies where the patient feels fine, I’ll get the patient to the pulmonologist. Sometimes, they’ll just watch the patient super carefully. But if it’s more widespread or it’s more diffuse in the lungs, even if it’s asymptomatic, we’ll hold the medication and treat with a course of steroids and wait 4 weeks and repeat the chest CT scan. If things are in the right direction, and the patient is still asymptomatic, we’ll go ahead and resume the medication. Sometimes, we’ll resume the medication at a lower dose if it’s something amenable to dose reduction. Immune checkpoint inhibitors are not, but if it’s another agent that’s amenable to dose reduction, we will. If a patient is symptomatic however, and you find changes on imaging consistent with ILD, for sure you’ll stop the agent. You interrupt it, and you treat the patient with steroids, outpatient steroids if it’s minimal symptomatology, inpatient steroids if it’s more and the patients are quite dyspneic on exertion or coughing. Certainly for any need for outpatient oxygen, of course they need to be in the hospital to get high-dose IV [intravenous] steroids.

If patients are symptomatic with ILD, generally speaking, we don’t go back to the agent. Sometimes for immune checkpoint inhibitors, that may not be the case if they had mild symptomatology that was readily taken care of and particularly if they have evidence of having benefited from the therapy. Sometimes, you can go back. But when patients have ILD that’s symptomatic, usually they’re going to be off of therapy for 4 to 6 weeks, while you’re making sure that they get the steroids. You’re slowly weaning it down. You’re reimaging. You’re showing that things definitely improved. But usually, as I said for certain of the agents such as trastuzumab deruxtecan, if they are symptomatic with ILD, we’re not going to resume it. But if it’s an immune checkpoint inhibitor, and patients are only minimally symptomatic, then we could go ahead and reintroduce it, but with careful collaboration with your pulmonologist. But patients generally are off of the therapy for 4 to 8 weeks because if it’s an immune checkpoint-related immune adverse event, then you have to wean the steroids quite slowly or else it will recur. You have to go slowly. Patients can be off of their therapy for 4, 6, 8 weeks, or sometimes longer.

Mark D. Pegram, MD: Since ILD is a diagnosis of exclusion, it’s often necessary to involve a pulmonologist. They may need to consider doing testing for infectious agents, for example, some of which may be serologic. But some may require procedures, for example, bronchoscopy with bronchoalveolar lavage can be very useful to look for infectious agents. The bronchoalveolar lavage fluid may also be infiltrated by tumor cells if you have, let’s say, a pattern of metastasis that can mimic ILD. Lymphangitic spread, for example, can have a radiographic appearance and signs and symptoms that could mimic ILD. You want to look for tumor cells in the bronchoalveolar lavage to see if there’s cytologic evidence of cancer. You can also look at cell counts, in particular, eosinophil counts, and bronchoalveolar lavage specimens can be a clue for drug-induced ILD scenarios. So it’s really a diagnosis of exclusion. If the bronchoscopy is unrevealing and there’s still uncertainty about the diagnosis, sometimes you actually have to do a lung biopsy in order to make a firm diagnosis and especially, to rule out malignancy in lung metastases to make sure that’s not the problem rather than drug-induced ILD.

Once you’ve ruled out everything that’s possible clinically to rule out, then the diagnosis becomes a clinical diagnosis of suspected ILD. The first treatment intervention is to hold the offending agent, obviously, and then monitor the clinical progress after you’ve held that agent to see whether holding the agent is associated with improvement in pulmonary signs and symptoms or not. Moreover, depending on the severity of the ILD, you may want to consider steroid treatment. For example, in the case of trastuzumab deruxtecan, even for grade 1 asymptomatic ILD, you’re to hold the drug, consider steroids at 0.5 mg/kg prednisolone equivalent, and then monitor for 28 days. If it’s resolved, you can resume the trastuzumab deruxtecan at the same dose, but if it hasn’t resolved in 28 days, then you should do a dose reduction if you’re going to consider continuing the drug when the adverse events are resolved back to grade zero. If it gets to day 49 or later, then you’re to discontinue the drug permanently even for grade 1 ILD for trastuzumab deruxtecan. For symptomatic grade 2 ILD, you stop the drug permanently, in the case of trastuzumab deruxtecan, and give steroids at a dose of 1 mg/kg prednisolone equivalent with a gradual taper until resolution. But it’s permanent discontinuation for any symptomatic ILD in the case of trastuzumab deruxtecan. That’s different than everolimus, where you can treat through subclinical ILD, for example. It’s a little bit different from the checkpoint antibodies as well, where steroid intervention has profound therapeutic effects and can be managed pretty easily in many cases.

Transcript Edited for Clarity