Chapters Transcript Video ALK/ROS and Others Back to Symposium All right. So we're gonna jump into Elk first and certainly it has been a lot of progress made in ALC targeted therapies. Um And I've put the three biggest trials here comparing to the first targeted therapy, Crozat Nib. Um So first we have um trials with Elect Nib, then begat Nib and then most recently, La Latin I um where we sound updates from the crown trial. Um and we still had not reached the median PFS for patients that receive first line la Latinum at the five year mark. So that was certainly impressive. Um But these are all the uh later lines, uh later generation Elect and Brigatinib and Laura Latinum are still really good options for patients with tart, with ALK fusions. Um The safety profile of the second generation ALC TKIS does differ a little bit. Um Katin probably having um the most toxicity and the thing that patients complain about the most is usually edema. Um and Ecton Burgain or Latinum have their own kind of a ease of interest um for lectin, perhaps it's myalgia um for Brigatinib rash. Um and some uh lab abnormalities as well as pneumonitis. We think about and then La Latin having some kind of strange um hypercholesterolemia and mood effects um for patients, of course, there are new um ALC TKIS on the horizon. So this is NNVL 655. the alcove one trial, this is open for patients with ALC fusions um who have had prior um second or third generation tkis and also uh could have had prior chemo um or chemo and immunotherapy. Um And this, we got some new data on this um at ESMO, this trial is opening and open and enrolling at Penn. Um So, the first thing that they presented was that this was really a heavily pretreated population of patients with alc fusions. Um So, not only were they heavily pretreated but they had a number of resistance mutations. So, um if you look at the first um circled box, you see that there were compound alc mutations, meaning there were several on target resistance mutations in about 25% of these patients. Um And then there were also, there was also the most common the G 1202 R um also in about 20 to 30% of patients. Um And then looking at the second box that's highlighted these patients had a number of prior treatments. Um Most had um more than one targeted therapy against ALC, most of them have had exposure to elect NIB or begat nib. Um And actually a good percentage, 84 to 85% depending on the cohort actually had seen lower Latin I previously in the, in this cohort that they're reporting. Um and there was preliminary anti tumor activity across uh many of these subgroups. Um So, looking at both the prior lower Latinum and the lower latinum naive in the, in the patients that had seen prior lower latinum, the overall response rate range um from 35 to 54% depending on the type of um alterations they had. And then in the lower Latinum naive, um 53 to 88%. Um So certainly there's anti tumor activity even in this very heavily pretreated population. Um They also showed some really important subgroup analyses and um subgroups of interest. So there was intracranial activity um in patients that had brain metastases at baseline, both in those that had prior lower Latinum and uh lo and who were lower latinum naive. This is super important because these patients frequently have brain metastases and elect burgain and lower Latinum have excellent intracranial response rates. This is really a key for anything that we're developing in this space. Um The safety profile was relatively what we would expect for a targeted therapy in ALC there were certainly abnormalities and LFTs um and then some other um low grade toxicities. So, in conclusion, for NVL 655, we do have uh early data now on the recommended phase two dose. Um the anti tumor activity seems to be across multiple subgroups of heavily pret pret patients. And the safety profile is similar to other drugs in its class shifting now to Ross one. So in Ross one, we also have a number of agents that target Ross one. some of them overlapping certainly with the alc fusion population. Um first and foremost Ryot Nib with a pretty impressive overall response rate of 72% in this very rare subgroup. Um More recently, we um saw in Trek with an overall response over 77%. And importantly, an intracranial response um of about 61% um repo repo tract and it was actually approved recently and is now the first line option with a nice overall response rate of 79%. And an intracranial response, it's quite high although only in eight patients. Um and then at the bottom of my graph, the different TKIS um uh showing that repro track and have really had the most impressive progression free um survival in trials and is our first line option now. But of course, there are new drugs on the horizon. So this is the arrows, one trial, this is open and enrolling at Fox Chase. Um This is NVL 520. Um So this has ROSS one activity. Um It is has AC NS activity and importantly, it was designed to try to avoid some of the trek cross reactivity that some of the other TKIS have. Um So this uh trial is um in patients also that have had prior ross one targeted therapies. Um It was again a heavily pretreated population. Um So these patients had about 50% had a history of CNS metastases, which would be pretty standard for this population that's had um multiple lines of therapy. Many of them had secondary ross one mutations about 40%. And then most of them had received um other ROSS one TKIS such as la Latin repot and tract. Um And again, there was nice anti tumor activity across a variety of subgroups um in patients with prior rec reprotect nib, we saw um a nice waterfall plot and then those that had never had reprotect and it certainly also um activity. Again, we do have intracranial responses over this drug about 50% in a small group. Um and looking a little bit at the preliminary safety data, the edema rates are lower than what we have seen in those with um with cross reactivity for Trek um at about 19%. But certainly we are still seeing it as well as low grade LFT abnormalities. So conclusion for NVL 520 we uh do see anti tumor activity in this heavy, heavily pretreated population with resistance mechanisms. There is intracranial activity and perhaps the safety profile is looking a little bit better than some of our other agents. Sorry, the formatting is a little off on here. It got shifted. Um So, in conclusion for ac um the five year lower latinum crown data is certainly impressive. We haven't even reached the median in five years. It's hard to argue with that. Um But this may come at a cost of quality of life. Um We're starting to learn that dose reductions and in particular, starting at a lower dose may help to mitigate some of these things. But certainly elective elect NIB and begat NIB are still reasonable. First line options to consider in some patients and this is a very patient specific decision for a lot of us. NVL 655 is an exciting new agent in this space and has um efficacy against many resistance mechanisms. So it's definitely something to watch out for in Ross. One rep protractive had recently become the new standard of care. Um but we do have NVL 520 which is another exciting new agent um that has activity and just my last word of caution um is which I haven't addressed directly during this presentation. But ALK and Ross, one alterations are fusions. Um And so these are sometimes difficult to detect, they can be missed on liquid biopsy. Ideally, we're using RN A based assays on tissue biopsies to detect these alterations. Thank you for your time. Created by Related Presenters Melina Elpi Marmarelis, MD Medical Director, Penn Mesothelioma Program,Assistant Professor of Medicine (Hematology-Oncology), Hospital of the University of Pennsylvania
