Early Detection of ADC-Associated ILD/Pneumonitis Through Imaging and Clinical Vigilance

Drs Kathleen Moore and Jonathan Chung discuss how to detect ADC-associated ILD/pneumonitis early using imaging, risk assessment, and proactive team-based clinical vigilance.

To learn more, view the full series: From Early Signs to Clinical Action: A 2-Part Series on ADC-Associated ILD and Pneumonitis in Oncology Care

Dr Moore: Hello, everyone. Welcome to the Oncology Learning Network video series on ILD and pneumonitis. This is video number one in a two-video series. My name is Dr Kathleen Moore. I'm the Deputy Director and Director of Phase I Clinical Research at the Buffett Cancer Center in Omaha, Nebraska, and I'm very happy to be hosting this video. We are going to have a nice discussion today between myself as well as my guest, who is a ILD expert in radiology. So Dr Chung, would you please introduce yourself? 

Dr Chung: So a pleasure to be here. Thanks for that lead in, Dr Moore. So I'm Dr Jonathan Chung. I'm a professor of radiology at the University of Chicago Medicine, where I'm also the vice chair of quality and clinical innovation. So pretty much my whole career in terms of the academic side of things has been interstitial lung disease, but I think increasingly that's included a lot of these drug-related pneumonitis cases just because these ADCs make patients so much more prone to developing pneumonitis. And so it's become one of my sub-interests, and I'm really excited to be here.  

Dr Moore: I'm excited to have you. Because I think oncology, as we all know, is evolving. And that is wonderful for our patients. The treatment landscape has evolved beyond sometimes the exclusion of just traditional cytotoxics into more targeted-based therapies that include things that impact the lungs. PARP inhibitors, for example, have a low but present rate of pneumonitis. Immune checkpoint inhibitors, we've known that for a while. mTOR inhibitors, we've known that for a while. But now antibody drug conjugates, I feel like have really pushed the environment to develop rapid response, early diagnosis and intervention in a way that we really haven't ever emphasized before. The challenge here is that the rates of clinically significant ILD, which I would say anything that's symptomatic, I think can be higher with antibody drug conjugates than we've seen with some of these other agents, maybe mTOR inhibitors are the exception there. But we do need to stay vigilant around early identification of these adverse events, which if undiagnosed and we continue treatment can be serious, unfortunately. These require prompt evaluation and appropriate management based on severity, and it can be very challenging to detect early because often, especially because of high-res CT, and we'll talk about that, you find all sorts of things on the chest CT that may or may not be early pneumonitis. When do you call it and when do you hold and when do you sort of monitor? Is it a clinical challenge? And we'll talk about that today with our guest, Dr Chung. So with that, I'm going to turn it over to you to kind of launch the discussion.  

Dr Chung: OK, great. So the first topic we want to cover here, and I'm going to throw it back to you here, really is risk context. So Dr Moore. Before you start an ADC in a patient, what are the things that go through your mind when you're considering, well, is this worth the risk? Because anytime you start a medication, obviously there's going to be risks associated with it.  

Dr Moore: Yeah. And this is a hard one. So I'm trained as a gynecologic oncologist and we've just sort of really recently gotten access to some of these medications that do have a risk of pneumonitis, but they also work really, really well in patients that have previously not had effective therapies. And so I think we were very excited to use them and maybe weren't looking for reasons not to use them. So it's a hard question you just asked me, because I'm not looking for a reason to not use these medications in a patient with recurrent disease. But we are learning and there are kind of relative risks that make me get a pulmonology consult earlier, and then there's just absolute contraindication.  

So patients who have any history of lung pathology, so patients with significant emphysema or COPD, those are patients I'm a little more worried about really just following any changes in their lungs on radiology exams during treatment, like making sure I can catch changes that would to clinically significant pneumonitis. Any patient with prior chest radiation, which we increasingly use, you know, to do local regional therapy, prior therapies is becoming increasingly important. So patients that had prior immunotherapy, and maybe they had grade one pneumonitis and it resolved and someone maybe did or didn't call it ever. Now those patients are coming on and getting antibody-drug conjugates. Are they at higher risk? Probably. Will I not use the medication? I got to think about that. Heavy smoking use, that kind of goes along with emphysema. So, and there's a myriad of other things.

Really, the other thing is that anybody on baseline chest CT that has inflammatory changes that haven't otherwise been assessed by a pulmonologist, that's somebody that I'm worried about using without some assessment, multidisciplinary sort of collaboration on that patient to make sure, you know, that we're starting off on the right foot. So that baseline assessment, that baseline CT, where we kind of just used to say, okay, these are my lesions, this is what I'm going to follow, now has to include, I think must include, a notation by radiology. And I ask, you can comment on this, I ask them, do you see any evidence of baseline ILD in this patient right now that I should be worrying about. That's one of my things now that I do to make sure I'm not putting someone at risk unknowingly who already has baseline changes. So really understanding what that baseline CT shows, I think is pretty critical.  

Dr Chung: It's so true. It was only in the recent like three or four years where now this actually becomes sort of a key differentiator of how we're going to approach therapy based on the MDD discussion. So if someone does ask me, they say, well, we're considering these -this therapy, which has been associated with a drug-related pneumonitis, the first thing I look for is essentially anything that is a sequelae of a healed lung inflammation. So these areas of interstitial changes, show that these lungs are not normal lungs, and these patients are going to be at higher risk for some sort of pneumonitis, whether drug-related or otherwise.  

Dr Moore: And so I think the risk factors right now, other than known baseline ILD, which I think would be pretty close to an absolute contraindication to using some of these medications. Everything else is sort of a relative contraindication that you have to put into clinical context along with that baseline scan to really help counsel your patient as to her risk along with the potential benefit of the medication. So let's say we've started our patient, and let's say the baseline CT was good, and now we're following one thing. We have to get chest CTs. Even if there's no disease in the chest, when we're using these medications, we have to get chest CTs. If you're using these medications, we have to look at a chest CT to monitor. But this is hard. I mean, if it's just flat out obvious pneumonitis, okay. But that's really what it is. It is watching that patient's clinical presentation and putting it in context with what you're seeing on imaging. Oftentimes patients present, they feel great. And they're happy because this drug is working. And their O2 set is over 96%. And they come in with some subtle this or that. You're kind of sitting there wondering what I should do in the setting of a patient who looks just fine. And they get mad at you when you hold their medication, when they're feeling really good and the drug is working.  

In the symptomatic setting, it can be equally as hard because patients can be symptomatic for all sorts of reasons. They could have COVID, they could have pneumonia, they could be having an asthma attack, or they could have pneumonitis. And so we have this sort of clinical assessment that goes into that, you know, what's the temporal nature of the symptoms. Do they have a fever or not? Do they have other signs of infection? We can look at the imaging and try to sort this out. And so Dr Chung, kind of take me through a patient who's got a low-grade temp on an antibody-drug conjugate, a little short of breath, but a low-grade tab, but comes in with some changes on imaging. I get a chest x-ray, let's say, because she's in my clinic. What are you looking for and how do you differentiate on an image? Pneumonia, pneumonitis, some viral upper respiratory infection, or can you? 

Dr Chung: This is difficult. So it depends where we catch the patient in their course of disease. And so the scenario that you describe, it's pretty early on in disease. And so in those cases, even if we got a CT, at most you're going to see some patchy ground glass opacities within the lungs, maybe some concomitant consolidation. But usually you don't have this fluid pulmonary opacity. If you had bilateral diffuse pulmonary opacities in someone who's at risk in the outpatient setting, so we know it's likely not fluid pulmonary edema, then it's almost always a drug-related pneumonitis. And so that's fairly easy. However, if you've gotten to that point, usually that patient's pretty darn sick. And so they're usually going to present clinically before that. So on CT, if I see multi-lobar disease, so ground glass opacity and/or consolidation, especially if it's bilateral and really especially if it's symmetric, now I'm like, well, highly likely be drug-related pneumonitis. But there are going to be cases where it's going to be unilateral or maybe even unilobar. And so there's a lot of overlap. We really have to discuss this in the MDD setting, multidisciplinary setting. So those are cases where I would call the oncologist, or a lot of times the oncologist calls me and says, hey, Jonathan, what do you think is going on? And we take it from there.  

Dr Moore: So these decisions are often unclear. But you really have to think through it with your MDT team. And so it's sort of a…making sure that this assessment, like I call it my antennas and my team's antennas, really has to be a structured part of your practice, your nurses, advanced practice providers, if you work with trainees, making sure that that's sort of one of the early things that you're talking about. So they're systematically either asking about pulmonary symptoms or if they get a call from a patient with any sort of pulmonary symptom that's new or a change that they are sort of escalating that relatively quickly and not sending them to urgent care to get, you know, a Z-Pak, which happens. So we, you know, we want to make sure that that constant vigilance around this is sort of part of your clinical practice. And so I'm going to come back to you, Dr Chung. You know, how often do you see these kind of imaging patterns that we've been talking about on the chest CTs before patients have any symptoms? They're completely asymptomatic. They're getting you know, restaging scans. How often are you seeing things on patients that are on these medications that make you worried about potential pneumonitis?  

Dr Chung: It happens all the time. It really does. And so either it's extremely mild where you see a little bit of wispy ground glass opacity, oftentimes at the lung apices. So I don't know if that's a different histology. Maybe there's more eosinophilic pneumonia up there. But bottom line, that's a common phenotype that I see at the lung apices. New, very, very mild ground glass opacity. If we know that a patient is on some protocol that has something like this, has a high level of drug-related pneumonitis risk, we have to over-call. You've got to augment your sensitivity, your ROC curve, to be as sensitive as possible so we can catch these early cases of pneumonitis as early as possible. Because in my experience, the earlier you catch it, the better the patient does. If you catch the patient when they're when they have like diffuse pulmonary opacities or consolidation all over the place, well, now that patient is going to be at higher risk of having a bad outcome.  

Dr Moore: Yeah. And when you just, one of the things you just said is so important. I just was like, well, I don't think I do that. I'm not communicating with them what drug they're getting, what class of drug. And you just said that. I was like, well, that's something maybe I need to put in the order. Patient on an ADC. So they have a heads up that this is maybe a higher risk thing or maybe it's a place that they might want to overhaul or flag something to me. I don't think that's something that we necessarily do kind of routinely. So that was actually really, you made my, my antennas go up again for something I need to do for process improvement.  

Dr Chung: There's definitely radiology literature actually in the chest imaging space that shows that the clinical history, an accurate clinical history, that's actually even more important, an accurate clinical history can completely change the way that a chest radiologist approaches an imaging study. So I love the fact you're going to put that into your clinical history. It will help a lot of patients.  

Dr Moore: Yeah. I don't know why I've never, until you said that, I'm like, well, I don't do that. So note to everybody, let's all do this. So I guess that brings us back to the point of, if you mentioned something to me that's subtle, I'm like, yeah, they've always had this waxing and waning ground glass opacity. The patient feels fine. Do I need to care about this? How should I be thinking about that clinically in the setting where it's just all the time, some inflammatory change? 

Dr Chung: I think in this setting, the setting of your patients who are extremely sick, and again, are at high risk for drug-related pneumonitis, I think you have to just have that side level of clinical suspicion and almost assume that that's a drug-related pneumonitis unless there's some other obvious... some clinical binding or symptom or sign or lab value that tells you it's some alternative diagnosis. And I think that's probably the best way to treat it.  

Dr Moore: Yeah. And so these can be tricky. So the little caveats, again, we've been talking a lot about MDT, multidisciplinary teams. If you're confused, hold the drug. But the hard part, and you and I are kind of alluding to this, is do I start steroids? Or if it's infection, do I start antibiotics? Those are kind of diametrically, you know, opposed. And with pneumonitis, sometimes patients can present with low-grade temps. They can also present with weight loss if it's been this sort of slow, progressive thing that maybe was or wasn't called on the imaging. Sometimes it's subtle. So this is hard to differentiate sometimes, and you have to just make an empiric choice when someone presents this way. Bronchoscopy can help in a symptomatic setting, often the interventional pulmonologist will get them in pretty quickly and do bronchoscopy. We'll do viral swabs, you know, all of the infectious workup before we start steroids if we can. But if they're symptomatic, sometimes we're starting steroids right out of the gates just to prevent rapid deterioration. 

And so how do you, I brought up the scenario earlier where we've got someone with low grade temp, maybe she's losing a little weight, comes in short of breath. How do you think about with the, when the findings aren't specific, how do you think about ILD versus infection or progression, lymphogenic spread, you know, also is on the differential for some of our patients. How are you thinking about that? 

Dr Chung: It's hard. It really is. But so many cases have that overlap where there's just white stuff in the lungs. There's a little patchy ground glass, patchy consolidation. It's like, well, it's bilateral, but it's a little bit lower lobe independent. Is it just aspiration? Is it an infection?  

Dr Moore: Yeah, exactly. I think really having early input from radiology, pulmonology, and the oncology team help us move forward more quickly with the ILD workup, which is really how we optimize care for our patients. But I mean, as an oncologist, as a clinician, we often make decisions about drug-induced ILD, or we should be saying pneumonitis, before there's certainty about what we're dealing with, what the diagnosis is due to the potential severe consequences if it's not managed property. It is reasonable to consider a parallel approach of continuing the diagnostic workup while also responding to the possibility of drug-related toxicity guided by clinical judgment and what is outlined in the drug labeling for the available medications. If the findings are concerning, you can hold treatment, and we actually have a lot of grace here, the tumors don't tend to start growing right away. So hold treatment, initiate the workup, and in some cases, start corticosteroids, especially if someone's symptomatic, even mildly so, while continuing the diagnostic workup. If it's not ILD or pneumonitis, stop the steroids and resume therapy. You haven't had them on for that long. If it is ILD pneumonitis, you've done the right thing, you continue steroids and adjust therapy accordingly, depending on the grade of ILD. So the key point here is to act early. Even when the diagnosis isn't fully confirmed, you often, I would say almost always, can't wait for 100% certainty before you make the decision to hold and start steroids. And this may kind of impact your patient's outcomes.  

So we often think about this in terms of what we call CTCAE grading. There's also definitions from ESMO that help us grade suspected drug-induced ILD or pneumonitis. So how do you think about, we're showing you some of the differences in grading. They largely overlap. But Dr Chung, how do you think about this grading in terms of, from the perspective of someone looking at the imaging? 

Dr Chung: Yeah, so I'm more familiar with CTCAE than ESMO in terms of the grading severity. But if you look at it, it's actually really quite similar. There's more of a call out to imaging with ESMO, just a little bit more. But for the most part, I think they're almost completely interchangeable. I don't know, Dr Moore, what do you think about the interchangeability of the two criteria?  

Dr Moore: I think they're really interchangeable. It's just, and the associated interventions are the same. So I think they're, they're largely overlapping.  

Dr Chung: It probably just depends on local practice.  

Dr Moore: Yeah. So let me ask you this. If I have a patient who's asymptomatic, totally asymptomatic, O2 set's fine. I'm referring her for new findings of ground glass opacity. So she's technically grade one by CTCA, she's asymptomatic. But there's differences, right? Like there's, I have a peripheral ground glass opacity versus bilateral ground glass opacities or central, like there's the different imaging types that Dr Powell and others have talked about in terms of classifying ILD. Does any of that, like as a radiologist, would you ever look at something and say, you got to be really worried about this, Dr Moore, like this is something that's going to progress. This is a lot. I would start steroids. Or this looks like nothing or nope, it's grade one. And, you know, the decision to use steroids or not is up to your kind of clinical acumen. Does the amount of inflammatory change weigh into what you say at all? 

Dr Chung: It does. So regardless of the grade, these grades are mostly clinical, as you could see. But if there's a lot of lung involvement, it's pretty easy. If there's a lot of white stuff in the lungs, it means that there's a lot of inflammation. And inflammation begets inflammation. We just know this. And the lungs are proving that they can get inflamed. And so if I see a lot of pulmonary opacity, regardless of how the patient is feeling, I say, we should probably get on top of this. You know, make sure that steroid dose is nice and big, right? It's actually a therapeutic dose. So for me, it's all about extent of pulmonary opacities, especially if it's this ground glass opacity. The consolidation, even though it's more dense, it looks scarier. Usually histopathologically, if you were to take a hunk of lung and actually look it under a microscope, most of those cases are going to be organizing pneumonia or eosinophilic pneumonia. So that histopathology is usually very, very sensitive to corticosteroids. If it's more ground glass, histopathologically, usually most of those cases are going to be diffuse alveolar damage. So the imaging histological correlate for ARDS, and we all know ARDS is not good. And so those don't respond to corticosteroids as well, or some people will say they don't respond to corticosteroids at all. So removing the patient from the stimulus, which is causing this drug-related pneumonitis is going to be more imperative.  

Dr Moore: Yeah. And I think this is where the management becomes more individualized for the patient, but just preaching again, so dependent on multidisciplinary team-based interface with radiology and pulmonology, so you really understand what's happening in the lung. So ultimately, we integrate the two grading systems that we talk about, but we integrate our management based on the clinical presentation and severity of what you're seeing on imaging, and then we apply guideline and label-informed approaches when deciding whether to interrupt treatment, which we certainly are if it's symptomatic, initiating corticosteroids, and depending on severity and how things evolve, that may also include treatment modifications and potentially discontinuation for some of these very active medications in the setting of concerning pneumonitis. Before we wrap up this first video, I'd love to get your perspective, Dr Chung, on one key takeaway that you would want clinicians to keep in mind when it comes to treatment-related ILD. 

Dr Chung: I think there's two now, right? So the first one is don't blow off mild ground glass opacity in the lungs, especially if it's bilateral. You got to stay on top of that. These patients are at high risk for developing a drug-related pneumonitis, and they can be fulminant. And so catching them early is going to be the name of the game. And then secondarily, if you could help out the radiologist, if you put in the clinical indication that these patients are at risk for drug-related pneumonitis, and that's really what you're looking for. They will give you what they want, what you want, right? The problem is that sometimes the radiologist, if it's just, if the indication is just for lung cancer or gynecological cancer workup or Rhesus reads, then they'll give you that. That'll be the primary focus of what they're looking at. But if you ask for both, they will give you both.  

Dr Moore: Right. That's key. That was a great learning point. So from the clinical side, it's important to understand baseline risk, really looking at baseline risk just in terms of risk factors and also baseline imaging, even before starting an antibody-drug conjugate. And once you start in ADC, it's important to know that ILD can develop early often before patients have any symptoms. So recognizing those signals and acting promptly allows us to apply appropriate management guided by severity and labeling and make more informed treatment decisions. A multidisciplinary approach is essential to bringing all the pieces of the picture together and recognizing ILD earlier.  

So thank you so much for taking the time to join us. As we've discussed, recognizing and managing ADC-associated pulmonary toxicities requires a thoughtful, multidisciplinary approach. For a complementary perspective, please be sure to watch the other video in this series where we focus on the practical challenges of differentiating and managing ADC-related pneumonitis. Thank you so much for joining us, and thank you to my co-presenter, Dr Chung. 

Dr Chung: Thank you for having me. It was a true pleasure. 

Kathleen Moore, MD, is a professor in the Section of Gynecologic Oncology, and deputy director and director of the Phase I Program for the Buffett Cancer Center at the University of Nebraska Medical Center. She attended medical school at the University of Washington School of Medicine and completed her residency in obstetrics and gynecology at the University Health Center of Pittsburgh. Dr Moore completed a fellowship in gynecologic oncology at the University of Oklahoma Health Sciences Center while simultaneously earning a master's degree in epidemiology. She is board-certified in obstetrics and gynecology, gynecologic oncology, and hospice and palliative care. She has published over 400 peer-reviewed publications and has a clinical research interest in drug development and phase I–III clinical trials.

Jonathan H. Chung, MD, analyzes and interprets chest radiographs and CT scans for thoracic diseases. Dr Chung has expertise in interstitial lung disease, occupational lung disease, nontuberculous mycobacterial pneumonia, and large and small airway diseases. 

Through his research, Dr Chung is studying how imaging can play a more significant role in patient care for those with chronic lung diseases, specifically interstitial lung disease, pulmonary fibrosis, occupational lung disease, and nontuberculous mycobacterial pneumonia. He has authored over 210 peer-reviewed articles, as well as published multiple books that focus on chest diagnostics. 

Dr Chung’s quality work has mainly leveraged the synergy of technology and quality improvement to enhance patient safety, optimize radiologist workflows, support ease of practice, and augment diagnostic accuracy and efficiency. 

In addition to his clinical work and research efforts, Dr Chung also dedicates himself to educating medical students, residents and fellows, performing numerous one-on-one teaching sessions and mentoring younger physicians. His devotion to education has been recognized several times, including when he received the Radiological Society of North America Honored Educator Award in 2013 and the Marc Tetalman Award in 2016.