Recognizing and Managing ADC-Associated Pulmonary Toxicities-এর সম্পূর্ণ প্রতিলিপি

00:02:41.919 What we've also seen is that there's toxicity involved in patients who are treated with these drugs, and similar to toxicities that we see in all different cancer therapeutics. 00:02:42.159 --> 00:02:52.879 And the overall range of incidence of interstitial lung disease or pneumonitis, and we can use those terms interchangeably, is around 8 to 10%. 00:02:53.520 --> 00:03:07.039 However, these toxicities, although typically readily manageable, can lead to fatal cases in some individuals with fatality rates up to 3% in some of the early trials of antibody drug conjugates. 00:03:07.120 --> 00:03:10.319 And that is the area that, of course, we're focusing on. 00:03:10.960 --> 00:03:23.039 And one of the reasons for toxicity related to antibody drug conjugates is the cumulative toxicity that occurs if the pneumonitis or ILD is detected late. 00:03:23.360 --> 00:03:33.520 So then what are the missed opportunities that have been observed in these cases that can be mitigated and reduce the risk of this toxicity becoming fatal? 00:03:33.680 --> 00:03:38.560 I'd say we can focus perhaps on two potential missed opportunities. 00:03:39.919 --> 00:03:50.080 The first would be the inability to recognize that there is a new imaging abnormality in the chest on patients who are treated with antibody drug conjugates. 00:03:50.639 --> 00:03:54.080 And that can happen because of one or two reasons. 00:03:54.319 --> 00:04:04.240 One reason would be that there would not have been, in some cases, a baseline imaging study in the patient before they were exposed to antibody drug conjugates. 00:04:04.400 --> 00:04:14.080 And then, of course, the follow-up CT scan that would be done to assess treatment response may be abnormal, but it would be unclear whether that abnormality was new or old. 00:04:14.319 --> 00:04:32.240 So that means that it is imperative for any patient who's being considered for treatment with an antibody drug conjugate, or for that matter, any drug that is associated with a significant risk of lung toxicity to have examination of a baseline chest CT scan prior to administration of the dose. 00:04:32.560 --> 00:04:59.279 The second related reason for the inability to detect a clinically important finding on a chest CT scan would be the poor communication that sometimes is observed between the radiologist who is reviewing the study and the ability to communicate an abnormality or to recognize an abnormality in a manner that can be directed to the clinician before the administration of the next dose of the drug. 00:04:59.439 --> 00:05:01.120 There are two ways to mitigate that. 00:05:01.360 --> 00:05:20.480 One is to try and focus on having trained thoracic radiologists or radiologists who are trained in recognizing lung toxicity in patients receiving antibody drug conjugates or other advanced therapeutics to know when there is a finding that is clinically relevant in the setting. 00:05:20.639 --> 00:05:33.040 And then the next piece, which is equally important, is to have a channel of communication such that the clinician can have that information available as soon as possible and before the time of the next administration. 00:05:33.279 --> 00:05:42.800 We've seen many cases where the patient receives a dose of the study drug, and then afterwards it's determined that, yeah, there was a finding that was abnormal, but the clinician just didn't know. 00:05:43.040 --> 00:05:50.800 So that sums up the first missed opportunity, which is recognition and communication about abnormal imaging findings. 00:05:50.959 --> 00:06:00.240 And the second missed opportunity is when there's an abnormality detected by the patient that's not communicated to the team. 00:06:00.480 --> 00:06:02.399 And that can happen for one of two reasons. 00:06:02.560 --> 00:06:06.879 One is the patient may not appreciate that the change that they notice. 00:06:07.040 --> 00:06:14.399 And by change, what I'm focusing on here are changes that are associated with the development of interstitial lung disease. 00:06:14.480 --> 00:06:26.800 And some of the first changes they would notice, or first symptoms they would notice, would be dysthmia on exertion, doing activities that they previously could do before, or new cough that is lingering that they didn't have before. 00:06:26.879 --> 00:06:34.800 Those are the two common symptoms of early onset of interstitial lung disease: shortness of breath with exertion and new cough. 00:06:35.040 --> 00:06:53.120 If the patient notices that, they need to be educated that it's incredibly important for them to communicate with their clinical team that they have these new findings, and that can then lead to a prompt clinical evaluation to do the appropriate testing to evaluate the cause of those symptoms. 00:06:53.279 --> 00:06:58.720 Amongst the causes could be interstitial lung disease related to the drug, and then the appropriate actions can be taken. 00:06:58.879 --> 00:07:14.959 So education of the patients, having it be clear that it's so important to know as soon as possible for there to be a change so that the change can be managed quickly, and that'll offer the best opportunity for the patient to be safely and continuously treated with the effective drug. 00:07:16.079 --> 00:07:16.560 Awesome. 00:07:16.800 --> 00:07:27.439 So if I just to summarize, that it's very important is that it's for what I'm hearing is it's very important to have baseline imaging, usually a CT scan. 00:07:28.079 --> 00:07:47.199 And if there's anything abnormal in CT scan, just making sure that there's a clear communication between radiologists and the clinical team to make sure that appropriates take action and also patient education, if there are any changes, so they are aware, so they can communicate with the clinical team. 00:07:48.480 --> 00:07:48.800 Exactly. 00:07:50.959 --> 00:08:02.319 So I think some of the issues that we sometimes see in clinic is patients that have pre-existent lung disease

or baseline abnormalities. 00:08:02.560 --> 00:08:06.079 And I think in the article that is mentioned as a major risk factor. 00:08:06.399 --> 00:08:17.199 So what do you recommend we do if we have a patient that has one of these pre-existent lung disease and we're thinking about using an antibiotic conjugate? 00:08:17.519 --> 00:08:35.600 So we've published that pre-existing lung diseases, typically chronic lung diseases, such as COPD and prior fibrotic lung diseases, are associated with an increased risk for the development of antibody drug conjugate associated ILD. 00:08:35.840 --> 00:08:43.440 Most clinical trials that are evaluating these compounds will exclude patients who have active ILD, and that is reasonable. 00:08:43.600 --> 00:08:50.240 However, they will include patients who have other forms of chronic lung disease, such as COPD, and that is reasonable too. 00:08:50.399 --> 00:08:54.720 The toxicity, as we discussed before, is manageable. 00:08:54.879 --> 00:09:00.960 And so being able to treat patients even if they come in with chronic lung disease is important. 00:09:01.360 --> 00:09:09.600 We just need to be more vigilant than we might otherwise be if the patients had a pristine CT scan and no prior history of lung disease. 00:09:09.759 --> 00:09:32.799 And so that vigilance can take the form of more intense education for the patients, consideration of using at-home remote monitoring approaches, such as monitoring pulse oximetry oxygen levels with exercise, and also consideration of a more frequent monitoring scheme in the clinic for patients who have prior lung disease. 00:09:33.120 --> 00:09:41.200 This has the best chance of affording patients to have the opportunity to be treated with these drugs, even if they have prior lung disease. 00:09:41.519 --> 00:09:53.519 So have you been in a situation in which you know you get a patient referred to your clinic and you have recommended not the antibiotic conjugate because they have significant lung disease? 00:09:53.600 --> 00:10:06.320 Or put it the other way, is there any reason in terms of pulmonary status in which you would be against someone using an antibiotic conjugate with known risk factors for pneumonitis or uh ILD? 00:10:07.120 --> 00:10:22.000 The only situation I've encountered when I advise not to use the antibody drug conjugate or for that matter another advanced cancer therapeutic, we're in situations where the interstitial disease is still in progress. 00:10:22.159 --> 00:10:29.679 So if there's ongoing interstitial lung disease, that is not the time to start a drug that is associated with increased toxicity in the lung. 00:10:29.919 --> 00:10:30.240 Okay. 00:10:30.639 --> 00:10:34.639 Many patients that we're talking about, they don't have other therapeutic options. 00:10:35.360 --> 00:10:46.080 And so it's incredibly important for us to do whatever we can to safely be able to have that patient have the opportunity to be treated with the drug. 00:10:46.320 --> 00:10:51.919 Most of the time, if patients develop toxicity from an antibody drug conjugate, it's mild. 00:10:52.000 --> 00:10:53.440 It's grade one or two. 00:10:53.600 --> 00:10:56.879 That's typically 80% of the time, it's grade one or two. 00:10:57.279 --> 00:11:15.120 And so that suggests that if the patients do develop toxicity, we have an opportunity to address it quickly, hold the drug, treat with steroids as appropriate, and the patient would hopefully have the opportunity to be treated again once the event has resolved. 00:11:15.360 --> 00:11:29.919 So given that this is a manageable toxicity, given that there often are not other therapeutic options, then it's very unusual to recommend against using a drug such as an antibiotic drug conjugate in a patient who has prior lung disease. 00:11:30.799 --> 00:11:31.440 Great. 00:11:31.759 --> 00:11:42.399 So, you know, we have established that getting a baseline CT scan is extremely important, education is very important, and that most of the patients should be able to receive these kind of therapies. 00:11:42.639 --> 00:11:51.039 What do you recommend as routine follow-up for these patients that are getting these antibody conjugates with high risk of long toxicities? 00:11:51.279 --> 00:11:52.799 Like, do you recommend imaging? 00:11:52.960 --> 00:11:54.000 How often? 00:11:54.159 --> 00:11:59.679 And what are kind of like the imaging findings that would make you worry if something appears? 00:12:00.080 --> 00:12:01.279 That's a wonderful question. 00:12:01.360 --> 00:12:02.480 It comes up all the time. 00:12:02.639 --> 00:12:05.919 And we've learned a lot from the clinical trial setting. 00:12:06.000 --> 00:12:15.519 And in the clinical trial setting, patients would in the trials would typically have imaging performed every three cycles or so to assess therapeutic response. 00:12:15.679 --> 00:12:24.480 And those images are very helpful to determine if there is development of a new finding that would be suggestive of interstitial lung disease. 00:12:24.799 --> 00:12:28.320 We talk about findings that are suggestive of interstitial lung disease. 00:12:28.399 --> 00:12:32.399 What we're looking for typically is a new opacity. 00:12:32.559 --> 00:12:36.639 The most common opacity pattern is called organizing pneumonia. 00:12:36.720 --> 00:12:47.600 And in organizing pneumonia, the pattern is such that the patients will develop typically more than one peripheral rounded opacity in the outside of the lung. 00:12:47.840 --> 00:12:53.679 It often will have a solid component and then be surrounded by a ground glass component. 00:12:53.840 --> 00:12:55.440 That's the most common pattern. 00:12:55.600 --> 00:13:08.080 There are other patterns where one might see more diffuse haziness in bilateral lungs, more of a ground glass appearance that could be a non-specific interstitial pneumonitis pattern. 00:13:08.399 --> 00:13:13.759 And those are the typical types of patterns that we would see in patients

who develop pneumonitis. 00:13:13.919 --> 00:13:19.360 Other patterns include a hypersensitivity pneumonitis pattern that's concentrated in the upper lobes. 00:13:19.519 --> 00:13:31.600 And then there's another pattern called acute interstitial pneumonia or AIP, which is a severe form of drug-induced pneumonitis where there's bilateral consolidation and volume loss. 00:13:31.840 --> 00:13:36.080 That typically occurs late in patients, but the organized pneumonia is common. 00:13:36.320 --> 00:13:43.440 So to get back to the question at hand, what we've learned from the trials is that that frequency is sufficient. 00:13:43.600 --> 00:13:59.519 So then when we think about patients who are being treated in the post-marketing phase after the drugs are approved, the typical recommendation is that the imaging that is performed to assess response to the drug is sufficient in most patients who are being treated with antibody drug conjugates. 00:13:59.679 --> 00:14:12.080 Of course, the imaging needs to include the chest, which is particularly relevant for your specialty, where you may think that an abdominal pelvic CT may be sufficient if that's where the disease is restricted to. 00:14:12.240 --> 00:14:19.679 But here we're talking about it's important while you're doing that scan to include the chest as well at the same cadence. 00:14:19.919 --> 00:14:26.480 Now, for patients who are at higher risk, there may be utility to considering more intensive monitoring approaches. 00:14:26.720 --> 00:14:34.159 Those would include consideration of a more frequent monitoring strategy, although there's no data to support that at this point in time. 00:14:34.320 --> 00:14:43.200 And then to employ more frequent check-ins at home via the clinical team or consideration of remote monitoring approaches again. 00:14:43.679 --> 00:14:52.480 So imaging of the chest at least every three cycles would be the usual recommendation, unless there is something else that the clinical team is worried about. 00:14:52.799 --> 00:14:53.200 Yeah. 00:14:53.360 --> 00:15:08.879 And that's why it's just so important to reinforce the concept that we talked about up front, which is the importance of making sure we have educated the patient about feeling free and comfortable to report any change in symptoms, because that would prompt a more frequent check-in. 00:15:09.759 --> 00:15:10.399 Perfect. 00:15:10.639 --> 00:15:14.159 So let's just talk about kind of the management of ILD. 00:15:14.320 --> 00:15:18.559 So, you know, there are obviously different grades of uh pneumonitis. 00:15:18.720 --> 00:15:26.720 You know, if you can just summarize what are the usual regimens in terms of one patient has active lung disease. 00:15:27.440 --> 00:15:28.000 Sure. 00:15:28.320 --> 00:15:45.759 So for the principles of management of drug-associated ILD, the first principle is once there is suspicion of a new event of ILD, the first step is to suspend administration of the drug while evaluation is being performed. 00:15:46.159 --> 00:16:10.240 That evaluation would typically involve a history, a physical exam, testing for common viral pathogens that can cause some of the symptoms and imaging abnormalities that we're talking about, keeping in mind that drug-associated ILD is a diagnosis of exclusion, and keeping in mind that our patients are at increasing risk of developing infections. 00:16:10.559 --> 00:16:16.799 So we have to rule out infections as the cause of the new symptoms and imaging findings, of course. 00:16:17.120 --> 00:16:21.519 And so that can include our typical microbiology testing. 00:16:21.679 --> 00:16:26.320 We have to think about causes of interstitial changes, such as heart failure. 00:16:26.480 --> 00:16:29.519 There may be appropriate testing that needs to be done in that setting. 00:16:29.679 --> 00:16:45.919 And so we do that evaluation, and that's tailored to the patient's presentation and is done by the treating oncologist, sometimes and often in collaboration with specialists in related disciplines, infectious disease, pulmonary cardiology, et cetera. 00:16:46.080 --> 00:16:48.399 So that evaluation is ongoing. 00:16:48.639 --> 00:16:50.080 The drug is held. 00:16:50.240 --> 00:16:59.360 If it's determined that there is a drug-related ILD, then the treatment for that specific process should proceed. 00:16:59.519 --> 00:17:04.559 Now, the treatment is guided by the severity of the interstitial lung disease. 00:17:04.799 --> 00:17:11.759 And for standardization purposes, the severity is graded using the NCI, CTCAE scheme. 00:17:11.839 --> 00:17:16.000 And patients who are asymptomatic are graded as grade one. 00:17:16.480 --> 00:17:26.319 For patients who are symptomatic or patients who are treated specifically for their ILD, typically with prednisone here, then they're grade two. 00:17:26.640 --> 00:17:34.000 For patients who are hypoxemic or require hospitalization for the management of their ILD, they're grade three. 00:17:34.160 --> 00:17:46.400 For patients with respiratory failure who require ventilation, non-invasive ventilation, invasive ventilation, or high flow nasal cannula oxygen for support, those patients are grade four. 00:17:46.640 --> 00:17:49.200 And patients who expire grade five. 00:17:50.079 --> 00:18:06.720 For grade one patients, sometimes all that's needed is to hold the drug, wait for the pneumonitis to resolve, and then to proceed with the next dose of the drug, either on the same schedule or delayed, depending upon how long it takes for it to resolve. 00:18:07.119 --> 00:18:11.359 Some patients with grade one are found to benefit by treatment with steroids. 00:18:11.519 --> 00:18:26.079 Typically, that's used in patients who have extensive findings on their imaging studies, or patients, as we discussed before, who might be at high risk and not be as tolerable of the lung toxicity because of underlying chronic disease. 00:18:26.240 --> 00:18:33.200 And if those patients are grade one,

the typical dose here would be a half milligram per kilogram of prednisone. 00:18:33.440 --> 00:18:37.599 And typically those patients are treated for at least three to four weeks. 00:18:37.839 --> 00:18:44.079 And then once there's resolution of the symptoms and the imaging findings, then there's a taper performed. 00:18:44.160 --> 00:18:46.720 And that taper can take two to three weeks. 00:18:46.880 --> 00:18:51.759 For patients with grade two, it's a similar approach for those who are treated with prednisone. 00:18:51.839 --> 00:19:00.799 However, now we're talking about using doses similar to one milligram per kilogram of prednisone for the similar duration that we would use in grade one. 00:19:00.960 --> 00:19:04.400 For patients who are grade three and in the hospital, they're treated with IV steroids. 00:19:04.559 --> 00:19:16.960 Sometimes it's just IV hydrocartosone, or for more severe patients, high dose dexamethasone, high dose three days, a gram a day, and then followed by a taper of steroids. 00:19:17.359 --> 00:19:21.039 Similar dosing regimens are used in grade four patients. 00:19:21.200 --> 00:19:25.839 For patients who do not respond, there are at least two possibilities to consider. 00:19:26.079 --> 00:19:30.079 One possibility would be that the diagnosis may not be correct. 00:19:30.240 --> 00:19:40.400 So we have to revisit the diagnosis and think about other alternative etiologies for the imaging findings and the respiratory symptoms that the patient has. 00:19:40.640 --> 00:19:47.359 And then the other possibility is that perhaps the patients have what is considered to be steroid refractory drug-related ILD. 00:19:47.519 --> 00:20:02.160 There are multiple case reports and individual institution experience with other drugs that are used in this setting, infliximab, cell set, rituxan, with varying degrees of success from varying agents. 00:20:02.400 --> 00:20:09.680 There are no formal trials done to evaluate the efficacy of one rescue regimen versus another. 00:20:14.480 --> 00:20:23.200 But the general approach would be to use a rescue drug if patients have severe ILD that's not responding to high dose intravenous steroids. 00:20:23.519 --> 00:20:29.759 Is there a point in which, depending on the severity, that you would not recommend using the antibodoconjugate anymore? 00:20:29.920 --> 00:20:38.480 Is there like a cutoff that we use or a type of toxicity that we would say, you know, this patient should not ever see this kind of antibodoconjugate again? 00:20:38.880 --> 00:20:55.920 So the clinical trials protocols that were set up initially for the first approved antibody drug conjugate in the in in breast cancer setting, and that was trastusumabderxtacan, which is now used in many cancers, including ovarian and uterine cancer. 00:20:56.079 --> 00:21:03.599 The protocol was established such that if patients had symptomatic ILD, they were to be permanently discontinued from the drug. 00:21:03.759 --> 00:21:13.440 So that

set the precedent, if you will, that for patients with grade two and above, grade two meaning symptomatic ILD, those patients would not be retreated. 00:21:13.599 --> 00:21:19.680 Now, the question remained open as to whether or not retreatment was safe in grade one ILD patients. 00:21:19.759 --> 00:21:21.519 And we have data to address that. 00:21:21.599 --> 00:21:28.640 And those data were presented at ESMOBREST and they're published in ESMO breast as well. 00:21:29.119 --> 00:21:39.359 And the experience included 65 patients who had asymptomatic drug-related ILD who were treated with Trastuzumabderuxican. 00:21:39.759 --> 00:21:45.519 They were rechallenged after resolution of their ILD with Trastuzumaberoxican. 00:21:45.759 --> 00:21:53.279 And what was observed was that about a third of the patients did recur, got another episode of ILD, but that was managed. 00:21:53.359 --> 00:21:59.759 And none of the patients had severe grade four or five events in this cohort who were managed with. 00:22:00.160 --> 00:22:06.000 Retreatment with close follow-up, such that if there was a recurrent event, that was managed expeditiously as well. 00:22:06.240 --> 00:22:13.440 So we've learned that it is possible and safe to retreat patients who are asymptomatic with resolved ILD. 00:22:14.000 --> 00:22:28.160 And I think there's more clinical data emerging suggesting that in patients who have symptomatic ILD, who are successfully treated with steroids, there may be opportunities to consider retreatment in those patients too. 00:22:28.480 --> 00:22:34.079 The clinical protocols for the trials have not been modified to accommodate that. 00:22:34.240 --> 00:22:41.119 But I think it's fair to say that there are many clinicians who are evaluating this possibility and gaining experience in that. 00:22:41.359 --> 00:22:44.160 So it sounds like grade one, it would be fine to rechallenge. 00:22:44.319 --> 00:22:46.000 Grade three would not. 00:22:46.240 --> 00:22:48.799 I think that grade three and four for sure not. 00:22:48.960 --> 00:23:02.000 And grade two, there's this gray area that maybe for the right patient that might be responding very well to therapy, that has quick resolution of her some symptoms, you can discuss with the patient to restart. 00:23:02.240 --> 00:23:03.359 I uh yeah, absolutely. 00:23:03.440 --> 00:23:12.000 And I like that construct very much because you're specifically taking into consideration the response of the tumor to the drug. 00:23:12.400 --> 00:23:18.000 The the imperative to really find a way to continue to treat is high. 00:23:18.240 --> 00:23:20.880 And so I I like that construct very much. 00:23:21.200 --> 00:23:30.640 And and symptoms, and just to make sure that we are clear, do you refer the patient having any symptoms like cough, shortness of breath, all two requirements? 00:23:30.799 --> 00:23:33.680 Are those the symptoms that we're talking about to make it grade two? 00:23:33.920 --> 00:23:41.519 Or yeah, so the symptoms

that we'll uh focus on for grade two would be the cough and shortness of breath. 00:23:41.680 --> 00:23:47.279 If a patient has desaturation, then that that's moving them towards the grade three. 00:23:47.519 --> 00:23:48.000 Got it, okay. 00:23:48.240 --> 00:23:56.160 Where there'd be a higher risk of there being a clinically serious outcome should that ILD progress or worsen. 00:23:56.559 --> 00:24:20.480 And one other question about restarting ADC is that comes, I think, in clinic often is do you have to wait until the imaging findings have resolved, or or there's a lagging time in which the you know there's some imaging findings might be there for you know weeks, and we can restart the therapy before there's resolution of imaging findings. 00:24:21.039 --> 00:24:32.960 In my opinion, resolved means that there's no further progression and that the active components, specifically the ground glass components, have gone away. 00:24:33.200 --> 00:24:40.400 I don't expect the imaging study to look normal or to look as good as it did before the ILD event happened. 00:24:40.640 --> 00:24:48.799 The lung scars up and is often left with some reticular findings and some atelectasis. 00:24:48.960 --> 00:24:49.920 It won't be normal. 00:24:50.079 --> 00:24:56.960 But what we're looking for is evidence to suggest that the active component of the pneumonitis has stopped. 00:24:57.200 --> 00:25:02.079 In my mind, that's resolution, and that means it's time to consider retreatment. 00:25:02.400 --> 00:25:02.720 Got it. 00:25:02.960 --> 00:25:13.440 So we I think we've covered a lot of like clinical practice tips about managing ILD in patients uh taking uh or using ADCs. 00:25:13.680 --> 00:25:24.480 Just to close up, is there anything else that you want to add or do you foresee any changes in future clinical trials uh or management of ILD? 00:25:24.640 --> 00:25:29.359 Is there anything that we should expect to become in the next year or a couple of years? 00:25:29.680 --> 00:25:30.400 Yeah, sure. 00:25:30.640 --> 00:25:34.400 So I'd say there are two themes to think about here. 00:25:34.720 --> 00:26:04.799 One is what we've learned in the experience of developing the trials for the ADCs is that each time the ADCs are introduced in an organ system disease that is not accustomed to managing or evaluating or detecting lung toxicity, there's often early on an increased incidence of significant and severe ILD events that are often attributed to late recognition. 00:26:04.960 --> 00:26:22.720 Your field has taken this very seriously to the point where educational initiatives have been going on for a while now, so that clinicians who are treating patients with ovarian and uterine cancer using advanced cancer therapeutics are becoming really quite comfortable with early detection and management of ILD. 00:26:22.880 --> 00:26:24.079 And that's so important. 00:26:24.240 --> 00:26:33.680 So that's to me the most important step in ensuring the safe use of these promising drugs, and it'll extend as more drugs get developed. 00:26:33.920 --> 00:26:43.599 So it's gonna get dicier as we move forward because now the promising ADCs are being coupled with other drugs that are bewn to be promising. 00:26:43.680 --> 00:26:47.200 And some of those other drugs are associated with lung toxicity too. 00:26:47.279 --> 00:26:57.039 So now we're gonna be seeing patients who are gonna be on combination drugs and two, both drugs or three drugs could even be associated with the risk of ILD. 00:26:57.119 --> 00:27:06.799 So we that doesn't mean we have to do anything necessarily differently, but it just increases the importance of taking stock of everything that we're talking about today. 00:27:07.119 --> 00:27:13.680 Now, as a field, if we consider drug-induced ILD a field, there's a lot to learn. 00:27:13.839 --> 00:27:21.920 When we talked about risk for ILD, we use very rough clinical criterion, but we really don't know what makes one person more at risk than another person. 00:27:22.079 --> 00:27:26.720 We just have these clinical findings that are associated with increased risk. 00:27:26.799 --> 00:27:38.240 And so there's a lot of work to do to understand possible risk factors that we can identify and have a more precise view of what an individual's risk could be. 00:27:38.400 --> 00:27:47.279 It could be through work in genetics or epigenetics or evaluating for biomarkers associated with predisposition for lung injury. 00:27:47.440 --> 00:27:49.839 That could be in the blood, it can be on an imaging study. 00:27:50.079 --> 00:27:52.799 So there's a lot of work going on in that regard. 00:27:53.039 --> 00:27:56.880 The next big question is how do these drugs cause lung toxicity? 00:27:57.039 --> 00:28:18.079 We don't even know that because it's not clear whether the toxicity is on target because the epithelial tumor cells that are targeted by the antibody in the ADC is causing toxicity to those cells, or whether the ADC is taken up by macrophages and traffics elsewhere in the lung and causes toxicity in that matter. 00:28:18.319 --> 00:28:19.440 We don't know. 00:28:19.759 --> 00:28:29.839 And it's important to understand more about the mechanism so that we can use that for the design of future drugs and also in strategies for diagnosis and treatment. 00:28:30.000 --> 00:28:36.160 And then finally, when we talk about treatment of ILD, we're talking about using prednisone. 00:28:36.400 --> 00:28:46.160 That's an old standard drug, and it's a very broad therapeutic window for what prednisone attacks, but we don't have anything better and it works. 00:28:46.319 --> 00:28:47.119 So fine. 00:28:47.440 --> 00:28:58.160 We also have cases in which prednisone doesn't work, and so there's work to be done to understand strategies to manage patients who have severe ILD that does not respond to prednisone. 00:28:58.319 --> 00:29:04.079 So those are a couple of areas that really can benefit from increased understanding of this process. 00:29:04.400 --> 00:29:04.720 Great. 00:29:05.119 --> 00:29:07.440 This was an extremely informative talk. 00:29:07.680 --> 00:29:08.640 Thank you so much. 00:29:08.799 --> 00:29:12.079 You know, I think as you said, the future is very interesting. 00:29:12.160 --> 00:29:25.759 I think the combination of therapies of the ADCs and immunotherapy, if we are going to start seeing those combinations, it's going to be tricky to figure out, you know, if a patient comes with neumonitis, how you know how we're going to manage those patients. 00:29:25.920 --> 00:29:32.799 So, you know, I really, really appreciate all the the time, and I encourage everyone to take a look at the article. 00:29:33.039 --> 00:29:34.160 And thank you again.