Ep 79: coBRIM, COMBI-d 5-year follow-up

[Music] Melanoma Matsas is an educational resource and the opinions we express are our own, do not reflect medical advice. If you have questions specific to your own situation, please contact your own clinician. This podcast may be available in both audio and visual, so please check your platform. Hi everybody, welcome to Melanoma Matters, I'm Sutton Fittell. Hello, I'm James Larkin. Hi. We thought we'd do more targeted therapy today. We've done Columbus seven years, so Cobram, which I think was one that you were intimately involved with, how intimately you can share, and then Kombi-D, which was part of the kind of Kombi-V, Kombi-D, amalgamated study. There's some long-term follow-up there. Before we do that, it's so funny now, trying to think of things we don't know about each other or funny things. I guess the question for you, because I'm bearing the lead here a little bit, but have you ever been to a film premiere? No, not that I can remember, but thank you for the question. As it happens, I might be going to, I don't know this yet, it hasn't us, Sutton's my brother that we can this week, on Thursday. So one of my brothers is coming to stay, because he's going to the film premiere, and I said, oh, you'll come to stay. In fact, you know what I haven't told you this, the phone I'm about yesterday, it's not just him coming to stay. So his wife's coming to stay as well, and his friend's coming to stay as well. I think his friend's called Steve, but he'll not tell you. So all these people are coming to stay at a house this Thursday, to go to this film premiere, and I said, oh, good, do you think you can get me to get the film premiere, because you're coming to stay at our house, and that's still up in the air. Anyway, the film's called the Penguin Lessons, and Steve Kugans in it, and it's about, let's book, the Penguin Lessons came back a few years ago, and it's about semi-autobiographical, the author writes under a normal plume, and it's about a teacher in Argentina in the 70s who befriended or took a penguin in, who'd been injured in an oil slick or something like that and brushed up on a beach. And I read the book, and it's a really nice book. And I don't know about the film. I think it's going to be like a feel-good sort of British type film, but there's a nice, if you're in the right mood, and it's black time. I also found that out yesterday when I was talking to my brother. Excellent. So we're not really. Yeah, so we're a penguin. A penguin outfit. So the penguin film. That's cute. So if that ends up happening, I'll get some pictures. But maybe what would be cute is if your brother's wife wears a tuxedo. So they bring out something actually. That's a good look of a woman in a sharp tuxedo outfit. Yeah, that's an interesting question, isn't it? Actually, I haven't really thought about that, but I don't think it's going to happen. So if it does work out, and it's 72 hours from now, so it's not long to find out, I definitely get some pictures. But yeah, some of the stuff about our video watchers, I think they would like to see Larkin in a penguin suit. Yeah, a penguin suit sort of sounds bad, doesn't it? Doesn't, you know, it reminds you of penguin in Batman or something. Okay, well no. Tuxedo, dinner jacket, black time. You know, if you're sealed on me. Plus, I don't wear it very often. So there's always going to be a slight issue when you get your dinner jacket out, right? If you're sealed on me. Even more reason why we want to see the pictures. So, come on. All right. Okay. So let's, let's wait and see. So who's going to start this and what we, what we're going to start with here? Five years from, um, Cobraan? Super. Super. Yeah. So it's five years from Cobraan or what's the Cobraan? It's five years from Conde de Niz. So either one, you choose one, I'll choose the other. Okay, let's do Cobraan. That's probably, um, you don't mind. Um, CCR, uh, October 21st of years, get now Palais, Seattle, is the lead author and then Cron McArthur, uh, senior author. Um, we were certainly involved in this study. Um, and actually Tony Weaver, this was one of the other main people. We said that in the, um, episode we have the Tony fact, we talked about this a little bit, I think. And I remember and you might remember as well, seeing the data for the very first time for Cobraan. We're in probably 2014 and me and Tony were, I think the only academic investigators on the, on the call, and we were actually, I mean, it was striking data on the first saw the PFS, um, benefit for them, KB over KB. So I don't think we need to dwell too much. Honestly, on the trial design and it been reported first in 2014. In fact, I'm in L. E. J. M. And this is, like we said, five year outcomes and maybe just take a little look. Um, at some of the figures and maybe see what we can extract, um, from that. I'm in the overall survival. Um, so this is figure one. Um, you can see that the mediums are quoted. Actually, the hazard ratio isn't quoted. The median hours for them, KB 22.5 months. Um, placebo plus them is 17 months. Curves do come together a little bit actually. Um, at five years and there's a lot of censoring after that. Um, I think if you look at the, um, the forest plot, um, pretty much all the subgroups are benefiting, um, from them, KB. Um, if you look at, um, if you other sort of subgroup type analyses, this is still all in figure one. So you've got L. D. H. Normal versus L. D. H. Elevated, for example, really big difference there, which is pretty, I think that comes out of all these studies that have now been analysed for that over the years that, um, if you've got a normal L. D. H. You're based on you really do a lot better. Uh, which I think stands for the natural history of the disease and also pretty much all our treatments as well. There's one of these analyses by CR versus PR versus no response. This is figure one D. Uh, and again, predictably in my view, you're really seen pretty significant variation. Figure two is all about splitting out Tumorburden, L. D. H. Um, unequal performance status and it sort of figured two H. H. As you have that was done, but you're trying to pull out these, these different groups and so the best one in blue, this is OS, is normal L. D. H. Some of, um, tumor diameters is less than 45 millimeters and predictably once you start kind of getting more Tumorburden and you get a higher L. D. H. then you're really getting very poor outcomes again, which exactly I think mirrors, um, what we see in clinic. Um, same sort of analysis of involvement of organ sites through more organ sites in metastasis. And again, I think that's quite a lot of work on this now. Um, and I think it really confirms validates if you like what we see in clinic. Um, figure three is PF. As, uh, and again, you can see a pretty clear difference, which we knew about already. Same for L. D. H. And then the same sort of quality of response. Um, safety, I don't think there were really any late safety signals here that sort of hadn't been reported previously. So, I mean, I think it's good to see those five year data. I think they're relatively consistent with the other trial data sets. Um, and you're probably going to quiz me at length about how much does Mac and E. B. Sian out? I'll pause there. Then you can say something. I wouldn't do that to you. Not with that. Um, did you tell it in table one or did you mention what percentage of the study was D600E versus D600K? No, I didn't. Um, but if you could, I think it's far away. I don't know if I see it either. It may be in the original report and not here. Let me just check the report. Yeah. I'll call you. I'll call remember. Sorry. Go on. No, it's okay. I bring it up because of our Combe A D study. And when we discuss that study, 9% of this study had B600K. And as a result, now that's an adjuvant trial, of course, but as a result, it looks like they missed their hazard ratio for OS significance. And it was simply due to that 9% being B600K. If you did subgroup analysis with just D600E, it looks to have a fairly tight confidence interval on the good side of one. So just curious in this metastatic setting. Yeah, I've got that. Now it can just pull it out from from the figure. So, E, in the control arm, is 174 patients versus 32, so that's a ratio of around 6 to 1, that kind of ballpark. And then if you do the same thing, just using crude figures, again, in the experimental arm, the numbers are 170 versus 24, so it's a slightly different ratio actually, but it's the same sort of ballpark. So I guess you're saying 15 or 7, and then if you look at efficacy, I'm sorry. So, yeah, that's about 1 out of 6, 1 out of 5.5 in the control arm, but 1 out of 7 in the experimental arm. Correct. And that is subtle enough difference, but there is just enough fewer, by the way, is that the right term, just enough fewer, I was going to say less, just enough fewer, be 600 to 1, and say, patients in the experimental arm, that it could push the signal in favor. Now, that's not what's happening here, that's not what I'm trying to say, but it's just worth noting that there might be ever so slightly imbalance of the proportion of patients, of K in the control and in the experimental. Yeah, I mean, also the hazard ratio is a pretty similar, I would just say as well, for the, this is OS as well, remember, for the E and K, and obviously wider confidence, of course, for K. I mean, I don't, a dot on K, if you will, I see the bar, but I don't see the dot. Yeah, and you're right about that as well. So, I'm assuming that the dots are in the middle, I've closed the middle, but you know, first off. Yeah. Sorry. It's a microsite. That's a very small dot. Yeah, not much we do about that. Okay, so, yeah, I'm too much else to say here, I'm not really sure, actually. What do you think? No, I think that's good. So, let's talk about Kambi D then. So, Kambi D is de-braphanib-tremetinib compared to, this is confusing because the five year update of de-braphanib-tremetinib is a combination of Kambi D and Kambi D. Kambi D is de-braphanib-tremetinib versus de-braphanib-tremetinib versus demuraphanib. But essentially the same theme, which is combination versus monotherapy-braphanib-tremetinib. And he's zoom in a little bit here. So, 563 patients, assigned to receive de-braphanib-tremetinib. They give us PFS rates here, but maybe what we really want to look at is the five year OS. So, the overall survival rates were 37% at four years and 34% at five years in the combination arm. And then this LDH story comes out here as well. So, maybe I should go back and make the citation. This is Carolyn Rober in Georgina Long, a senior author, Carolyn Rober is first author, doing Lundjornal Medicine, and this is in 2019. Five year outcomes with de-braphanib-tremetinib and metastatic melanoma. And then if you look at their five year, they have a PFS, supporting to LDH level. That's in figure 1B. And then OS here, similar, they do an OS by LDH. Guess what? It's the same as in CobraM, normal LDH is doing better. And maybe it's just worth saying what proportion of our patients here are normal LDH in these studies. Did you mention it in your CobraM? Yeah, there we go. You forgot it. Yeah, it's normal versus elevated. It's about 359 normal versus 192 elevated. So a little less than 2 to 1. So mostly normal, which they're saying that when we look at our metastatic trials, what's the proportion of patients with an elevated LDH? Is it a third of patients or so? Here it's a little more than a third. I don't know. Honestly, I don't know. I think it just really depends. And then are we using a cutoff of just any value over upper limit? Are we talking about 1.5, 2X? We see it all across the board. And I think as we've often said, makes it challenging to interpret when everybody uses a little bit of a different definition. Bottom line here is majority of patients had a normal LDH. Yeah, I mean, it might be fun to say something about table 1 here. LDH is very close to my heart, as you know. And so this is multi-barit analysis of baseline factors associated with PFAS and OS. And I don't know if you've got it open there or not, but if you look at the PFAS and you just look down those hazard ratios, what's the strongest hazard ratio there? LDH. 0.5. And then you look at a few other things, a type of B ref mutation, for example. So that's E versus K or E and it's 0.65, something like that. And then the disease stage, gender, age, even E.Cog, performance status, 0 versus 1.68. So it's an organ metastasis, that's very popular amongst some people, but that's 0.72. Number. Or is it safe? Yeah, no, no, no, less than three versus more than three. 0.72 and then some of lesion diameters above and below medium 0.97. That was a PFAS just to be really clear rather than OS. And then if I'm going to do OS as well, obviously. But I will actually. I will just for a second, as you go through this multi-barit, all of these things are falling out age via 10-year increments, sex, disease stage. But the sex thing is really interesting because there's some work on the Androgen receptor conferring kind of a worse outcome in male patients to both targeted and perhaps even in checkpoint inhibitor. And so would male patients benefit from Androgen receptor blockade to improve the use of targeted therapy? That was not a question we were asking back then, but interesting that you see that this hazard ratio for us plot also suggests that the female gender is doing better both in terms of the PF on the OS. I have to say, and clinical, I don't know what you think as well, that for my very long term, survival patients who are still on treatment, okay, so not the people who've had checkpoints inhibitors in their stock treatment and they've got a chance of being cured. It feels like the bulk of them, the female, they're probably, you know, a discussion in the same right. And that's just sort of me making an observation in clinic. But yeah, and then if we just, for completeness, I just took that OS in this table as well. You know, what's the winner? LDH, hazard ratio, point 4, 7, PS, point 4, 9. So that comes out more strongly, PS, for OS than it does with PFS. And then actually, organ sites are then probably coming in next 0.58. And then actually gender sex, whatever your preferred, the make literature is, is the next thing of 0.68. So, you know, I think it's quite an interesting table. So that was table one. Back to you. Yeah, maybe the last point to make on this is overall survival in patients with a normal LDH and less than three organ sites of metastasis. So kind of putting together a couple of those things that fell out of multivariate. Those patients are doing very well. And the OS curve for them at five years is better than 50%. So 55% overall survival, if you have a normal LDH less than three sites and you take combination of Raffinib, Trabatineb in some version of kind of quote unquote first line metastatic area. Interesting. So that just crashed altogether for me. I said, lost internet connection. I got kicked out. Just look back in. And then you were saying, okay, so the last point I was just making is that figure three. This is progression free survival and overall survival by best response. And just worth noting for the New England Journal of Medicine, these are invalid graphs and analyses. You cannot graph survival with starting from randomization. So they start this from time zero and they're graphing by best response. But best response is not a time zero factor. You don't know it at time zero. You can only graph it from the time it happens. So you can graph this starting from first assessment. You graph Kaplan-Miracurves like this from randomization or from time zero based on factors that are known at the time of randomization. So gender is known at the time of randomization. Number of organ sites, LDH is known. How tall somebody is. What hair color they have. All of that stuff is known. What they eat for breakfast that day. All of that is known at the time of randomization. Their best response to therapy is something that happens emerges after exposure to therapy. So that's not something you can graph. I'm just surprised this made it past a statistical review because these are just not the types of graphs you can show. And it shows what you're supposed to have. The best responding patients do best. The next best responding patients do next best. The least responding patients do the worst. That's not a feature that is present at randomization. So it's just a little misleading to graph things like this. It's just not a valid way to graph this stuff. So that's my soapbox. That's it. I don't think there's much more to say about combination target therapy. I mean, maybe what we can do if we're going to do a fact check for this episode is we can just contextualize this where this sits in line with the Columbus data. Columbus is giving us seven year data. But maybe we can back up to five years. Are there any plateaus forming in targeted therapy? In immunotherapy, we think they start to form around the three year mark. Do we see any plateaus forming with targeted therapy? And are these three combinations roughly equivalent in their PFS and OS at five years and maybe beyond? Or do we have a clear numerical above and beyond the combination that we should mention? Is that some fair? - Yeah, I mean, I just make a couple of extra comments but we close if I may. First one is that, I mean, I've certainly got some patients in clinic who've never had checkpoints inhibitors and they've been on B-Rap talk did therapy for metastatic disease for over 10 years? And quite a lot over five years. So is there a tail on that curve? I think the answer is yes, how big is it? I don't really know. Are those people who've had some sort of immun activation somewhere along the way, as well as their target therapy? I think mine have never had a immunotherapy. That's a question that's certainly in my mind. Never mind how long should they be on treatment? What do you do? How do you monitor the muscles and all that stuff? But these are all people leading normal lives with minimal side effects. The other point I just want to make here is that sometimes in clinic, you know, there's some negativity about targeted therapy because we know that often it won't have durable benefit. But you know, there's patients in clinic with autoimmune disease, for example, who actually might not be that safe to give checkpoint inhibitors to. You might not choose to do it first slide, for a dream seek. Can you get durable benefits with targeted therapy? Yes, you can sometimes. So I think it's actually that message is a reasonably important one to get out there. And then maybe when we do the fact that we can. Well, you've got the face, which says, those who are watching this or video, you've got the face that says you want to say something else. But what I was going to say is that we can pick up some of those other things in fact check. I think that'd be nice. But go on. Yeah, I mean, the only thing that's going to mention is because you brought it up. Is there immune activation in these patients? You've received targeted therapy, never seen immune therapy? Anyway, it's the whole idea of what is the role of mech inhibitor when it comes to immune activation? So there was early suspicion that mech inhibitors were detrimental to an immune response then maybe they sort of perpetuated an immune response. And where are we now? And maybe that comes into a fact check or maybe that's just an entirely separate discussion. But I like all of those points that you made. Yeah, okay, cool. So we're done. Good. Yeah, thanks for targeted therapy. Long term follow us. Cheers. Cheers. Hi everybody, and welcome to Melon Hover Matters. Wait, I don't need to do that, but because this is just a fact check. Yeah, it doesn't matter. We're pretty relaxed about this. We're pretty out of practice. We haven't done a fact check in a minute. But this is a fact check on a B-Raff targeted therapy episode we did where we talked about five years from Cobra and Kombi, essentially the Kombi D study. But there's some Kombi V baked in there. And then some things that came up that we wanted to talk about. So, but maybe if we were fact checking, we were just having a private conversation about the color of your t shirt there. This wanted to point out some dumbbell scuff marks on the shoulders. And you said, and I said, but you can't see it because your t shirt is black. And you're claiming the color of your shirt is. I mean, your eyes are blue. So I'm looking for something that's the color of your eyes. And I that is a gray shirt. Nothing we can fix in post. We probably could. There must be a way of doing that, but it probably be time to do it. Okay, so one of the things we talked about was, where did Columbus stack up at five years? Because we did a Columbus seven year episode where we might have mentioned Tom Newsom Davis for the first time on that episode if I'm not mistaken. I think that's the episode where you talk about how you got into medicine. Hang on, I'm just going to change my microphone here because I realized I'm on the wrong microphone. Oh, I can't. Okay. Anyway, you talk about, yeah, why you got, how you got into oncology specifically and how you were sitting at the Jeremy Bentham. Yes. Yeah. So that was our Columbus seven year episode. But we, because the Commbee and Cobram are five year updates, we wanted to just for benchmarking purposes, where did Columbus pan out at five years? So I have the numbers. I made a table that's not going to show well to the viewer, but obviously if you listen, you can make your own table. KFS and OS, Cobram, Commbee D, and then Columbus study. So we're just going to talk about the combination, really, arms here, because the monotherapy is pretty consistent. But the PFS in Cobram at five years was 14%. In Commbee, it was 19%. And in Columbus, it's 23%. Columbus has been running around sort of marketing themselves as best in class. Based on what hard to say, but these numbers sort of suggest numerically, they have a higher five year PFS. We also probably got better at managing the Raph Mach and keeping people on the treatment between the evolution of Vencobee and Anca Raph and Abinni metmit. So that we have to take into consideration. The OS at five years, 31% with Cobram, 34% Commbee D, 35% Columbus. I grew up. So pretty similar there as far as OS. We asked if we thought there was a plateau forming. With immunotherapy, we often think there's a plateau at about three years, and for currants, there's a pretty rare after three years. So when I went through the graphs here, you know, let's say for Cobram, for example, I could see a 6% drop in PFS and OS between three years and five years. So it's really hard for me to say that that's a plateau. If there's another 6% to 8% drop between these studies, Cobram, Commbee. Though I guess our feeling is maybe not so much a tail or a plateau, but obviously lesser recurrences the later you get, but not certain it's as low as zero to 1% difference. Over time, let's see. Yeah. And you just did something when we were sort of planning this fact, like you just said something and I was like, let's hit record, because that's a gem. No, no, no, no, no, I mean, so what I was wondering is that we accept, I think, that adjuvant targeted therapy, pure after targeted therapy is associated with cure. And no idea when that came. So that's not kind of interest. That is not a reflection of those feelings. Redo, we can cut that if we need. Yeah, well, I can we do it. But I think I think that's I'm controversial to say that we think that there are people who are being cured as a consequence of adjuvant talk. Did therapy with de-brafalib and tremesonib, a year of treatment. And we think the reason for that is the eradication of micrometastatic disease in the sensitive patients. So then what I was wondering about is the sort of numerical threshold for eradication of disease with targeted therapy, meaning, well, I think you've got it, right? And so again, if you're picking out these patients that do really well, who've got stage four disease I'm talking about now, and I guess a few with unreceptable stage three for the record as well in these trials. So let's just say that in more. And then we know the ones who do well, the ones with low LTH, low disease, dirt and et cetera, et cetera, et cetera. And we know that we've got the patients in clinic are actually over 10 years now. And so then I am wondering if some of those are potentially cured stochastically, is probably the right word to use in terms of the disease volume for some of those patients. Maybe it's not that far off. Some of the patients with what you might call bad stage three, who again, maybe we're curing as well. So maybe there's a bit of an overlap there and maybe there's a sort of a ceiling if you want to call it that for what targeted therapy can do on it. So bearing in mind though that you know, you might get some immune reconstitution reactivation. And then we talked about that before. Have a moment. And that, you know, this is a disease where there is a tail on the curve as well before we had any treatment we knew that. And we also know that spontaneous regression is occasionally happened as well. So difficult difficulties this apart, although we were just saying, I'm not aware anyone's really systematically gone and looked at all the patients who got to three years to ask the sort of the thing we talk about with checkpoints inhibitors a lot, which is to say that relapses beyond three years for people who've responded are really rare. I'm not even sure we have a figure for that. I don't have one. Gone. Well, I would love in the episode you do talk about all the different kind of hazard ratios by these kind of uni variant. categories, so low LDH versus normal LDH versus elevated, number of organ sites, so less than three organ sites versus greater than, and by the way, those unresectable stage three C's that you were talking about that we lumped into this trial, perhaps by definition end up in that less than three organ sites just by kind of definition. And of course, I just asked you since you were a co-author, does less than three organ sites mean just that? So liver, lung, spleen, is three or less organ sites? Or do we, I don't know if it's less than three or three or less, but do we mean that or do we mean two tumors in the liver is less than three organ sites of the houses? You know what I mean? I'm sure you probably mean like anatomic organ sites, but I think there's it, as we know, there's a difference between a liver that has a solitary met and a liver that has multiple, you know, eight or 10 tumors. And they may not exactly be the same tempo of disease, despite maybe both of those being less than three organ sites. When you go through all those univariate, even things like gender fall out, but really when we get to the bottom of it, like you said, everybody probably has somebody they've kept on targeted therapy, well passed a complete response, a quote unquote cure, just because as you make the point, well, they're tolerating it well, not likely to develop any kind of like long term immunologic side effects. It's still getting reimbursed, and so then it just sort of turns into there. So then what does that curfew like? What are the characteristics of those patients? Did they start out with normal LDH? Did they have this low tumor burden less than three organ sites, you know, or however we want to define it? I think that is interesting. And you had just mentioned you were in a task one of your intrepid fellows with maybe. Intrepid. Check it. Did you say. Did you say "trapid"? Well, that's how I described Andrea Schmidt, a couple of years ago, remember? Andrea's absolutely wasnies intrepid. No, no, no, they're all intrepid to be fair. Now I've already sent an email, so I'm gonna take care of that tomorrow. I like it. I don't think that's. It is, and you'd say on the app, you may point because I sort of said something like. Whether it's mood or not, because now we've got immunotherapy, and you said, "Yeah, yeah, but of course immunotherapy, you can't treat everybody all a dream see." But it's worth thinking about you have somebody progressing off a frontline, and yeah, you've got other things to use, but do they fit in this category where had they been treated in the frontline and targeted therapy, they would have an excellent outcome. Normal LDH, low tumor burden, maybe could you come in with your targeted therapy? Anyway, I like the project. You know, contribute and read it, so. - Yeah, and today's what's the 29th of December, isn't it? - Why do you always do that? You always do this on our podcast. You say the date, and then we don't publish these episodes for like six months and we look silly. - So I could be 29th of December. - A lot of times. - But I was just trying to think and the fallows is a deadline to sort of, you know, have the manuscript ready. What do you think? - Out of it. - Years eve. I mean, they're not gonna be busy, are they for the next two days? What? - You're not throwing a New Year's Eve party for that? What a, what a preceptor you are. - They've already had a Christmas party. You know, they'll be getting greedy. You know, treat me, treat me and keep 'em keen. That's what I say. - Oh boy, oh boy. So you think of anything, you just said something that relevant. Our last little fact to check, you know, you said something about immune activation and what do we know about MECH and immune activation? Mainly because MECH inhibition for a minute was kind of controversial for us in melanoma. You know, it was, do you combine it with targeted with immunotherapy? Is it immune-suppressive? Is it immune-promissive when you block MECH inhibitors? And it's not that straightforward as it turns out, right? So maybe I'll just bottom line it here that MECH inhibitor will have mixed results when you combine it with immune checkpoint inhibitors. Here we go. It impairs naive CD8 T cell priming and tumor bearing mice and then potentially in the periphery, but in the actual tumors, it can protect the till that are there and it can actually lead to increase and affector T cells in the tumors. So it's like got a variable result. So kind of like we probably knew it's not a binary answer here. You don't just use a MECH inhibitor and get it better or worse in immune response, you're augmenting the entire system and so it's complicated. - Yeah, I agree. And it would be surprising if it wasn't. I was gonna say, I'd be surprising if it wasn't complicated and messy and heterogeneous because, you know, you're gonna be inhibiting MECH in every cell, cancer cell or normal cell and guess what, you know, there isn't really gonna be it in my opinion anyway. You know, a uniform outcome from that, which is kind of what we just said. - Oh, that's a really insightful comment because unlike a B-Raff inhibitor, it's not just targeting a mutant NICIP form. It's inhibiting broadly. So yeah, good point. - Yeah. Okay. So we don't know, is there anything else on the laundry list? No. - Mm-hmm. - Yeah, I think we're good. - Okay. Okay, thank you. - Okay, thank you. - Bye. - Bye.