Well thank you very much and um yeah I do actually he's, I literally have uh my medical oncologist on sort of my automatic dial because um I think what you're gonna see is uh managing these patients requires a lot of coordination and communication and I feel very fortunate because the guys, I think you're all guys, not all guys that I work with, um, are really terrific, um. All right, so, uh, I'm gonna be talking about management of, um, uh, uh, CNS metastases from non-small cell. Uh, we focus a lot on the EGFR because we have the most data on that, but I am gonna address some of the other, um, actionable mutations. Um, So this is, if you look, this is the gold standard for treating brain metastases, all right? And, um, essentially just to take you through this, and, and, I'm disease site agnostic right here in the moment, we first think of the number of brain metastases and the reason that's important is that guides what treatment you recommend. If there's a single brain met, so whether or not they have extracranial disease, there's actually a survival benefit if you do some form of ablative therapy, meaning either surgery. Or radio or radiosurgery is very focused high dose radiation to the lesion compared, and this is the key to our old standard of care which is whole brain radiation. There is felt to be equipoise between radiosurgery and surgery. There's never been a head to head trial. There never will be because there's just too much patient and physician preference, but both, uh, in both spaces you see that, uh, an ablative therapy gives you a survival benefit. Over whole brain, so that's important because that means it gives you two options, um, and you do, however, need to send a patient to surgery if you're either unsure of pathology for some reason, it's the first site maybe of metastases, or if you place a patient on dexamethasone, they remain symptomatic and it doesn't seem like you're gonna get them off in the near future just for the patient's therapy that's important but also a lot of these guys are just about to go on to some new. Uh, or maybe they're completely naive to systemic therapy, and with the, um, immunotherapy world we want them off of steroids, so there's still a very active role for surgery for these patients. We have 4 very good randomized trials that show for patients with, uh, 2 to 4, uh, lesions, radiosurgery it should be the standard of care over whole brain, and there's a very clever. Um, uh, phase two trial that supports doing the same for up to 10 lesions, so we're very comfortable doing radiosurgery. FSRT is fractionated stereotactic radiosurgery, which is the same concept, but you do it over a few days, and the thinking is there may be, uh, less toxicity, um, which is why I like that. And we're, you know, right now the standard of care is more than 10 lesions. They get whole brain. With or without memantine to support neurocognition and uh hippocampal avoidance was, which also basically you, you do a plan that de-escalates the dose over the hippocampus and there's data to support better cognitive outcomes. Uh, I can tell you that number is gonna be changing soon. It'll probably be uh SRS for up to 15 lesions and eventually probably more and we don't know where that ceiling is, uh, where we can still be. Uh, efficacious and safe with radiosurgery before having to go on to a whole brain. So again this is disease site agnostic. This is the gold standard for brain metastases. But then you have to think, OK, well now we've got these, uh, lung cancers with actual mutations and how do we filter this in now? The NCCN, uh, you know, I, we just had our meeting and this is not really changing very much, uh, will tell you that radiosurgery for, you know, limited disease is still. The preferred standard of care, however, I think, you know, everybody acknowledges that there are patients who it's really, it's very appropriate and probably in their interest to try some sort of targeted, uh, agent, and we do this all the time and I've been doing this, uh, you know, what you know for well over a decade very comfortably. Uh, so I think the key here, which, you know, you can see is, uh, that the little caveat they put is these have to be small lesions, uh, and they really strongly recommend you consult with your radiation oncologist and do frequent MRI surveillance, and I do want to underscore that they're practically speaking two reasons to have a radiation oncologist involved up front and certainly this can vary place to place depending on how specialized people are. But first of all, there's the practical side. If the patient is not an extremist, you send them to me now and we can talk about what to do. I could schedule them for a follow up and everything's very well controlled as opposed to every now and then you see a patient who's been managed, uh, you know, on drug and suddenly there's now there are a lot of edema, there's progression, and I'm on speed dial and I have to find a space for the patient. It's just not in their best interest, um. Essentially there's no data uh from prospective clinical trial that assesses the impact of delayed radiation in terms of survival, uh, or delay on the incidence of neurologic deficits from progression and this is why they still put SRS as preferred but again it's really very well acknowledged that, uh, it's really not a matter of what can you use for these patients, but rather when, when should you, uh, you know, think about trying a targeted agent alone and. You can see that this list gets larger, uh, longer and longer. Uh, unfortunately there's nothing in the HER2, uh, realm here, uh, yet, although I will tell you that, uh, anecdotally, you know, um, to catnib and, uh, trastuzumab, uh, drootecan. Uh, you know, I'm very confident has efficacy because we see this in the breast space, and I've had, uh, we fought to have patients, um, go on some of these, uh, agents after they've had radiation, after they've had progression, and we just felt it was the best thing for them, and it's a battle, uh, and hopefully that'll change soon. Um, OK, so, you know, essentially there's early data, early-ish, uh, supporting that, uh, the time to intracranial progression. Uh, seemed to be not terribly dissimilar in a retrospective, very small study that looked at patients with EGFR and ALG mutations and compared, uh, uh, uh, radiation plus or minus RT, and the suggestion was that so it may not be unreasonable to hold on the radiation again early study, first generation retrospective, very small, not. The kind of thing that, you know, will, you know, change the landscape, but it was certainly uh uh interesting study. Um, this study looked at radiation versus a first generation, uh, TKI, and it did find that radiation improved intracranial, uh, control and to your survival. Uh, so this is sort of again why the. There were, there were breaks on this notion of, well, just move forward with the TKIs again this is, uh, you know, this is very limited data. Uh, and this trial, which came out in 2017, actually I remember when it came out because. There was sort of a period where uh. We were, we were feeling a little more nervous about moving forward with TKIs only up front and again this is first generation, uh, drugs and if you look here you'll see that, um, patients. No, OK. Patients who had, um, upfront SRS had a better overall survival and even patients who had upfront whole brain radiation had better over survival than, uh, a TKI and I know some people, you know, are afraid of, uh, whole brain because it can delay systemic therapy and they worry that might lead to, uh, overall survival concerns and I think that's certainly in the real world, you know, a, a serious consideration. But this trial um did give us some pause. Of course you know about uh the trials that showed uh um a response to OSC uh compared to first generation uh drugs and an analysis here showed that the um in the CNS progression free survival was not reached, uh, when people were on OC, uh, compared to the first generation drug where the survival was 14 months. Uh, you also had a much better cranial response rate. OK, so, you know, at this point, most of us in the clinic were very comfortable with OC having some efficacy, and we certainly see this not infrequently, and here we had some, uh, data to support that. The RA3 trial looked at the T790M mutation in 46 patients, so again, not huge numbers, uh, but found that patients with CNS Mets, um, the response rate was better, uh, for the OC than the chemotherapy with a better progression free survival. Um, and so then moving forward, this was from ASCO last year. There's this study, uh, looking, is phase two trial looking at, uh, the AME and the lasertinib in patients with EGFR mutated lung cancer and active central nervous system disease, and they divvied these out to patients in terms of patients who had brain mets, uh, distinct brain mets versus lepto meningeal disease. That's what LM is, uh, for. And uh the systemic overall response rate was, you know, pretty equal, uh, in both arms or both groups. The intracranial overall response rate actually, uh, you know, was, was pretty good. It was uh 23% for leptto meningeal disease patients and remember in that area where, you know, people are told you have 6 weeks to live, that's, that's a meaningful difference, um. And you know, nearly 50%, 40% in the brain mets group, uh, the median time, uh, uh, on treatment was actually, uh, uh, longer in the leptto meningeal disease group. So then the question becomes, uh, can TKIs be delivered, uh, concomitantly? There was this trial that suggested that that was not safe, but the, because the survival was better for patients who did not have concomitant TKI and radiation, but that was because these patients were stopping other chemotherapies and going on, uh, the TKI and so the feeling was it was systemic progression, so it didn't really address the safety per se of doing this, uh, together in terms of side effects. We do see that there is um uh a worse uh toxicity for patients who are on um BRAF inhibitors uh and uh it's sort of a a futsy complicated little plot there but essentially, uh, there was about a 25% rate, 28% rate of, uh, some serious side effects intracrannially, uh, just from, uh, doing the two together so. Essentially in terms of doing these uh SRS or radiation together with the TKI, there's no strong evidence, uh, for a concomitant treatment with TKI increasing side effects we typically just hold the drug of the day of the treatment, um, with BRAF inhibitors, however, there's a real instance of severe edema and hemorrhage. So we'll go into, you know, how we, uh, hold that, um, but there is evidence that TKIs, uh, with extracranial. Uh, stereotactic radiotherapy does have increased toxicity, so we remain cautious. Uh, the ECO consensus is for the BRAF and MEC, uh, hold 3 days before and after radiation. Uh, in general, in the body they say 1 day before and after SRS. I think I like 3 days because I'm, uh, conservative in that regard, and this is just for you guys just to have a reference, uh, about, uh, the safety of these drugs with radiation, but bear in mind this is, uh, extracranial as well as cranial radiation. And so summing it up, there's, you know, a lot of targeted agents that are out there, uh, there's not a lot of data, but anecdotally, you know, we see responses very frequently and I think it's a great first step for a lot of patients but again I really urge you. To do, uh, any kind of, uh, non-radiation therapy, uh, which is again the still the gold standard, do it with your radiation oncologist, or at least somebody who's very skilled in making oncologic CNS decisions, whoever that is in your world, because you need them to know what things to be asking before you judge what therapy the patient is getting. And that is it thank you very much.
Related Presenters
