So, um, I have mostly focused on toxicity management related to the combinations, largely because I think when we consider, uh, toxicity management related to Osamartinib, again, it's not to say that there aren't toxicities with monotherapy, but they're generally, you know, managed with, with sort of relatively straightforward regimens. I would say that sometimes a referral to dermatology can be helpful, helpful for patients who are having long-term chronic toxicities, even for most emerin and monotherapy. But when we look at these combinations, I think the toxicity management and the sort of prophylaxis that's required becomes quickly, quite complicated, so I I'm focusing on that. Um, we already sort of looked at this, but you know, with ossuertinib chemotherapy, I think in general we think of carboplatin pemitrexate as a fairly well tolerated chemotherapy regimen, but we do sort of add the toxicities of ossuertinib to chemotherapy, and I will especially highlight again that the. High rates of, of myelosuppression that can be seen with the TKI. You know, we sort of chronically see these low grade myelosuppression events with ossuartinib. A lot of patients have mild thrombocytopenia, mild leukopenia, and you see that cumulatively when you add platinum hemitrexate chemotherapy. And so you know I think that there's not necessarily so much to say about combining platinum hemitrexate with um with osamertinib in terms of the platinum hemitrexate. All of us in our clinics have really good um protocols in place to manage these patients in terms of folic acid. vitamin B12, anti-emetics, which are the same per protocol, you know, Smart Nip does not add to, um, the anti-emetic regimens, but it is important to keep in mind that these are all things that patients have to be compliant with. They require an additional sort of teaching session, the vitamin B12 administration. They require anti-emetics and then again, I would say that in particular for this regimen, maybe even more than for our patients say getting keynote 189 or or carboplatinpemotrexate in other contexts, monitoring the blood counts, particularly during that first cycle. I've had a number of these patients who required GCSF support to help, um, because of neutropenia and so it is important to keep that in mind. But what I wanted to mostly review today is the prophylaxis that's required for Avantumab. This is relevant to the Mariposa regimen, but I think many aspects of this can also be applied to Mariposa too, and the use of Amivanumab in other settings. Again, largely thinking about sort of how can we prevent the dermatologic toxicities and the VTE risk associated with this, and then the infusion reactions. You know, when we look at these sort of tables of onset of AEs, I will note that they've been shown a little bit differently for the Flora 2, versus Mariposa regimen. In Florida to that table that I showed you of toxicities over time were more sort of just the cumulative rates of these toxicities. Here they're showing the first rate, their first onset of these AEs, but this is not necessarily to say that patients are only having rash in the 1st 0 to 4 months. This is just when this started. And you know, really, particularly these dermatologic toxicities can be cumulative over time and so it's really very important, I think, to monitor these patients closely and to be quite proactive about the management because with continued exposure and without sort of good proactive and active management, you can, I think, run into quite a bit of trouble, but I, I will commend, you know, the, the Jansen team, they've done a tremendous job of trying to really develop strategies to help mitigate and prevent these toxicities that are quite effective. So if we look at, you know, they've done a number of trials actually specifically with this goal in mind, which is unique among a lot of our studies, we talked so much about therapeutic studies, not so much about sort of toxicity management studies. And so the Jansen team did the study called the Cocoon trial, which looked at sort of the role of enhanced dermatologic prophylaxis. So in Cocoon, patients were all getting first line. Avantamablazerib, just like in the Mariposa study, but the randomization was actually to an enhanced dermatologic management group, um, or standard of care management. So what did enhanced dermatologic management mean? I think probably the most important part of this was that they got prophylactic antibiotics for the 1st 12 weeks of treatment. So doxycycline or minocycline, 100 mg twice daily. Again, as with everything, there's pros and cons. This can lead to some GI issues and, and skin sensitivity. So you have to be, you know, kind of consult patients about that. But we used to do this back when we gave a lot of fatinib for frontline EGFR. We used to give, um, antibiotics and it can be effective. And then in addition to the oral antibiotics and a number of different topical things. So clindamycin, topical lotion, um, chlorhexidine to the, around the nails to help prevent peridicia, aggressive skin moisturizers, and then the, the clindamycin lotion to the scalp as well because of the scalp folliculitis that can arise with antimab. And what they saw is that if you did this enhanced dermatologic regimen starting with cycle 1 day 1, you saw significantly reduced dermatologic toxicity. So up here we can see the grade 2 or greater dermatologic adverse events, specifically then broken down by skin or perreychia, and you can see particularly the skin toxicities are significantly diminished when you use this prophylactic regimen. Maybe not quite as much difference in peronychia but some decrease, um, and then the scalp, I, and I, I, in my own practice, I think the scalp irritation can be really problematic with Amivantumab, so it's really nice to see that these regimens do, I lost my pointer, but, um, do decrease the rates of, of dermatologic adverse events involving the scalp and face. These are very important for patient quality of life and so I think this has really been a very successful strategy. Um, they also did a separate study looking at ways to prevent infusion-related reactions. And what we saw in that study was that the use of oral dexamethasone prior to the first dose of amivantumab, specifically 8 mg twice daily given for 2 days before that first infusion of amiantumab, decreases the risk of infusion-related reactions substantially from about 66% to about 22%. So in our clinic, that's now become a standard of care in whatever context patients are getting amiantumab, whether for classic mutations or Exxon 20. Um, you can see that, you know, not only were the overall IRR is reduced, but also all of the symptoms that go along with it. So they only need this high, high dose of dexamethasone with that first exposure to amiantumab. Or the other sort of tip I'll give you is that if you, if patients have been off of ammiantumab for toxicities for a longer period, I think it's after about 4 to 6 weeks, we start to think about the risk of infusion-related reactions going up again. And so often I'll think about giving them that the premedications again. Um, the, we, I touched on this during the last talk, but I think in when we think about infusion-related reactions, my hope is in the future, this is something we'll spend a lot less time talking and thinking about with the subcutaneous formulation of Amiantumab. We do see that subcu formulation of amiantumab really decreases and close to eliminates the risk of infusion-related reactions. There can still be a low rate of what they've sort of termed now ARRs, administrative administration-related reactions, but these tend to be much less severe and sort of less problematic. A lot less chair time is needed, and, and so I think this is quite promising. Um, the other intriguing thing with the subQ formulation, and I didn't go into the efficacy data, but one, they saw some interesting efficacy signals that maybe subQ will be a little bit better in terms of even overall survival than IV. I'm not sure we can quite understand why that would be, but we'll stay tuned. And we also saw lower rates of VTE. And so if you look at patients who got subQM antumab and prophylactic anticoagulation, the rates of VTE are quite low, um, less than 10%. So, you know, I think this is really quite encouraging. But again, um, VTE prophylaxis is really important for these patients, particularly when they're getting, um, amivantumab plus a TKI. Uh, I will just highlight that with the subcutaneous formulation of Amiantumab, unfortunately though, we don't see any difference in the rates of dermatologic toxicities. So this will help with the sort of initial infusion-related reactions, but all of the issues related to the cocoon regimen and dermatologic prophylaxis are something that we have to really kind of develop pathways for in our clinic because I think that's here to stay no matter what the route of administration is. Um, so this I thought was a nice slide that just sort of summarizes, puts us all together into one, table. I'll, I'll, um, I'll say this is from a presentation from the cocoon study from ELCC earlier this year, and I find this very helpful because it kind of puts it all together as to all the different things that we have to be thinking about. So again, dermatologic, sorry, uh, infusion related prophylaxis with steroids before for 2 days before the first infusion, before cycle 1 day 1. Um, VTE prophylaxis. So we put our patients on Epixaban 2.5, but any sort of prophylactic dose, um, uh, anticoagulant is required for at least the 1st 4 months of treatment. Another thing that I, we've sort of been talking about is when patients discontinue aivantumab, how long do you need to keep them on the blood thinner? I think that's an open question. Our pharmacists have advised that based on the half-life and everything, probably at least a month, um, after discontinuation of aivantumab, we did, you know, have, uh, we've had at least one patient who developed a thrombosis after discontinuing amiantumab, and of course that could be for just because of their cancer, but I think it is important to sort of keep these patients on. Um, even after the Amiantumab has been discontinued, if, if they've had a good exposure to it. Um, and then the dermatologic prophylaxis. So again, here we're talking about 12 weeks of oral antibiotics, doxycycline or minocycline, 100 mg BID. After those 12 weeks, if they're not having skin toxicities, you can stop the antibiotics, but continue with the, um, with the topicals, clindamycin lotion to the skin, um, and on the scalp in particular that I have patients start doing from the beginning. It's tricky, I think, you know, to, to put a lotion in your scalp, but it does really help, and these can be very kind of quality of life impacting. Um, keeping the nails short and clean, um, using chlorhexidine as sort of a ster, um, uh, antiseptic around the nails can help prevent perychia. I also advise patients to avoid sort of pedicures and manicures and things like that just because of the risk of irritation, um, and then aggressive moisturizers and not listed here but skin sun protection. So, you know, sunscreen and, and sun protection is also really important. So all of this to say, you know, I think these are this is takes a lot of time. I think this really requires, um, kind of close communication with our nursing staff who are doing a lot of the both teaching, um, you know, the teaching session for patients really clear handouts for patients to be able to follow at home. We get a lot of calls saying wait which one. Am I supposed to take? When should I start these? So being very clear on those points and then also knowing what side effects to be aware of when patients call in and are saying, you know, I'm having this or that problem, I think is really, really critical, but it does help improve the quality of life and help us deliver these regimens more effectively. So, thank you very much.
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