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We're now going to move on to talking about specifically neurocognitive and functional adverse events and how to recognize these early. From a clinician perspective, here are some general principles for monitoring and managing AE's associated with. Lurlatnib You want to prepare the patient and their caregiver for What's to come. We discussed this earlier, you want to review the most common side effects and give some indication of when we might expect these side effects to occur. With lorlatinib, as with our other ALECTKIs and actually many of our TKIs that we use in lung cancer, side effects tend to come on fairly quickly. Um, I usually see most of the side effects within days to weeks. And so, I think it's important for, for patients to know that. Um, We want to understand, you know, do they have any of the side effects that we might expect to see at baseline. So Maria, for example, already had some peripheral neuropathy at baseline. We can certainly see new or worsening peripheral neuropathy with drugs like lorlatinib. And so understanding, you know, where the baseline is, is important to assessing whether these things are, are worsening on treatment. Um, and so, with any of these adverse effects, we wanna understand how are they affecting the patient, you know, in the case of Mild liver enzyme elevations, that's not gonna be affecting the patient in their day to day life. Something we wanna keep an eye on, but it's not something that is, is going to impact that patient. Neurocognitive changes or peripheral neuropathy on the other hand, can be very impactful and limiting in patients' day to day lives, so we want to understand how, how that's happening. And second, is it affecting, affecting their ability to function on a day to day basis. So in terms of managing these side effects, you know, if they're not really affecting the patient in their day to day lives, we can think about mitigation strategies or we can just monitor, as with the liver enzymes, for example. If they are moderately or severely affecting patients in their day to day lives, we want to think about making some changes to the treatment. Do we interrupt, um, treatment? Do we reduce doses of treatment, um. With most therapies, including the 3rd generation AC inhibitor lolatinib, in fact, dose interruptions, dose reductions can be very, very effective in mitigating some of these side effects. As I alluded to earlier, I will often even start these patients on a lower dose of lolotinib because we see significantly less side effects at the lower doses, and we still see good efficacy even with 50 mg or 75 mg as opposed to the label dose of 100 mg. And then it's important anytime we make any of these changes to reassess and make sure that the changes we made had the effect that we wanted to see, um, and if they didn't, that we make additional changes. Again, from a clinician perspective, how do we recognize cognitive and mood changes? This, this can be very challenging, um, especially in some of our older patients who are already coming into treatment with maybe some mild cognitive impairment. It's really important to get a good assessment at baseline. And then to kind of follow longitudinally and be on the lookout for changes. So symptoms that we can ask about and document if they're present or not are things like forgetfulness, word finding difficulty, decreased attention concentration, sleep changes, irritability, apathy, and mood swings. And I'll highlight here that it's obviously important to ask the patients about these things, but these are, these are symptoms that often the people around them will notice before the patients do. And so talking to the caregivers and, and, and the folks who are with the patient about these symptoms can also be really helpful in kind of getting a sense of whether they're happening or not. We also want to talk about their functional status, you know, are they making mistakes at work? Are they getting lost, are we needing reminders to, to do tasks, as these can kind of be indicators of some of these neurologic symptoms. And then again, asking the caregiver, you know, incorporating the kind of insight of the people around the patient to, to get a sense of whether these things are happening. And what do we do once, once we Identify some of these symptoms, and doing a rapid assessment either in person or over the phone if these are being reported from home. We can ask simple orientation questions, name, date, location, um, simple attention tasks like counting backwards or reciting the months backwards, item recall, um, and doing a functional screen, asking about their ability to do things like take their medication or, or work. Um. Things that are really concerning to hear about are, are really acute changes like new onset confusion, hallucinations, obviously seizures, um. Acute personality changes, any sort of focal neurologic deficits, um, Inability to perform um activities that we're usually able to perform. I think if we're, if we're hearing about any of these acute changes, the first thing we, we obviously wanna make sure is that we're not missing an acute neurologic event, um, you know, like a stroke or a seizure or something like that. So, if patients are reporting these sort of acute changes, I think those, those are triggers to get a patient evaluated, um, you know, preferably in a, in an urgent or emergent care setting to, to make sure they're not having a stroke, to make sure they're not having seizures, um, get neurology involved to, to kind of help rule those things out. If we're able to rule those things out, then, and then I think, you know, we can reasonably ascribe these, these side effects of, of your treatment, and then, You know, think about how to address that. Um, like I alluded to before with Most of our TKIs, including VA TKIs, including Llonib. Dose holds, dose reductions are very, very effective in addressing some of these toxicities. So if someone's having this kind of, you know, acute severe change in their neurologic status, um, and we sort of rule out all the, all the other dangerous things, um, I would advocate to, you know, hold the drug for at least a few days, kind of let them get back to their baseline, and then resume treatment at a lower dose. Again, you know, from a clinician perspective, we want to make sure that we're, you know, not missing any acute medical event before we ascribe these neurologic effects to A side effect of, of their treatment, we, you know, wanna get vitals, we wanna check their blood sugar, make sure we haven't started any other new medications or supplements that might be interacting with their treatment, getting labs, um, and then, you know, getting CNS imaging, um, again, hopefully, in sort of an emergent fashion in Um, in conjunction with, with input from, from a neurologist so that we're evaluating for all the right things, like, you know, like stroke, like, um, progressive cancer of the brain, all those sorts of things. In terms of a team, you know, we want to make sure that we're documenting our conversations with the patient, documenting the neurologic status. It's really important, um, so that everyone kind of has a sense of the timeline of things, getting the oncologist involved to, to make decisions about holding treatment or changing the dose. Again, with, with some of these acute changes, getting them evaluated quickly by other consultants, neurology, um, and then involving pharmacy as well to make sure that, you know, if they're starting any new treatments or, or supplements or anything like that, that we, that we're not dealing with any sort of significant drug-drug interaction. And then again, just documenting everything very clearly, documenting timeline so that as more people are getting involved, everyone kind of has a clear sense of, of the timeline. For patients and their care partners, you know, I think it's important to counsel them about monitoring for some of these neurocognitive changes, you know, for care partners, especially for being mindful, being cognizant of, of what their loved one is doing, if they're, you know, acting differently, speaking differently, um, sleeping more, having mood changes, having falls, that they are sort of on the lookout for these things, and, um, And reporting them to us, and we can also prompt. You know, patients to, patients and their caregivers to keep track of these things in, in a diary or, or something of the sorts, kind of prompting them with questions about memory, about confusion, about sleep. Um, and then, you know, asking for concrete examples of, of things that care partners have observed to kind of get a sense of, of what kind of deficits patients might be experiencing. All right. Um, we're gonna move into our question and answer session here. We're gonna start with this one here. How soon should we hold a 3rd generation AKA inhibitor for neurocognitive symptoms and when can we safely rechallenge? I think what else