Episode 117: PD1/VEGF adverse event management in renal cancer

Betsy Plimack discusses the tricks of the trade.

 

Brian:
Hey, everyone. Welcome to the next Uromigos Podcast. Tom and I are with Betsy Plimack. And we are going to talk about toxicity management around IO-based doublets in kidney cancer. We’re not going to talk so much about efficacy but kind of the practical nuts and bolts of tox management now as these are sort of rolling out into practice. So, Betsy, thanks for joining us. Maybe introduce yourself and you can sort of give us a little bit of your take on tox management for these doublets broadly.

Betsy Plimack:
Sure. So I’m Betsy Plimack. I’m at Fox Chase Cancer Center in Philadelphia. Tom and Brian, thanks for having me. This is the topic the three of us chat about pretty regularly on email and otherwise, and so it’s nice to be able to kind of explore it together.

Betsy Plimack:
So the VEGF-IO doublets are firmly in the frontline setting. I think for renal cell, there’s probably a role for pure IO therapy. There’s probably a role for observation and for single-agent VEGF. But given the efficacy we’ve seen pretty consistently across multiple phase three trials, I would say most patients probably are and should be getting IO-VEGF combinations in the frontline.

Betsy Plimack:
So one of the things we’ve been talking about a lot lately is picking the most efficacious regimen… and can manage for toxicity, right? Once you start a patient on a regimen, it’s really important to try to keep it manageable for them because they’ll be on it long-term because these drugs work. But also to be able to kind of keep the dose at the sweet spot, right, where you’re getting efficacy without too much grind in terms of toxicity. And the dose we modulate, of course, is the VEGF, right, not the IO. That is standard.

Brian:
Right. So talk about how you do that. I guess maybe talk first about… Are there patients who you think just won’t tolerate a doublet, and do you kind of start them on one and later on the other as the first step?

Betsy Plimack:
So sometimes I do. Since the side effects are pretty random, I don’t know if you agree, but I usually say, “Here’s the long list of side effects you could get with VEGF. Here are all the things that could go wrong with immunotherapy. You’re not going to get all of them. We hope you get very few of them, but let us know what you get, and then we’ll react to it.” So it’s very much in the first month or so, especially with the VEGF, for trial and error.

Betsy Plimack:
So the way I manage it is I try to be aggressive and pick doublets, give doublets, except for the very good risk patient I’ve been observing for years where we’re just getting started. They’re worried about toxicity there. I might start within a VEGF and then layer in the IO. But for the most part, I do start with a doublet. How about you guys?

Brian:
How about are there patients… For me, yes, I agree for the vast majority. But some patients are so sick. I’ve had patients who are just really sick, who just by the time they get to my office, our PS two, three, et cetera…

Betsy Plimack:
Right.

Brian:
… that I was worried about the doublet, and I’ve started them on IO monotherapy and then layered in a VEGF. It’s pretty rare. I can think of maybe two or three patients in the last few years, but I’m just pretty curious.

Betsy Plimack:
I would say I didn’t like don’t do that. I think if the patients sick from disease, I go for it, feel like I have one shot. And if the patient’s sick from other things, then that’s sort of a different conversation where…

Brian:
Yeah.

Betsy Plimack:
… and this is where the art of oncology comes in, right, if patient in front of you and you try… You know what your drugs are capable of, both efficacy and tox-wise and sort of what they can handle or what risk. But I think generally, if patients are starting with both, the issue that comes up is when tox happens, how do you attribute it?

Brian:
Right.

Betsy Plimack:
And then how do you manage it? And always in your mind, you’re looking to attribute it and then both those things sort of in parallel.

Brian:
So how often do you see people on these doublet regimens, you or your nurse practitioner or some provider?

Betsy Plimack:
Right. So we always see them… I mean, it depends on the infusion of like which IO you’re giving and half of the infusion schedule is. So I certainly see them each infusion. With axi-pembro, for instance. We do give the three-week pembro at least to start because we don’t really have data for the six-week, although we have flexed on that for patient on it long-term. So I’m seeing them every three weeks. And when starting anyone in a VEGF, my practice has always been to see them at week three or four, again, to identify quickly what they’re experiencing and be able to intervene quickly before the hand, foot gets the blisters or before the diarrhea gets to be the point where they want to throw their drug in the garbage.

Tom:
Betsy, when you let the patients go home for the first time, what do you tell them about contacting the support team that… When are you saying, “Listen, you need to get back on the phone if what is happening,” and how often do they comply with that?

Betsy Plimack:
Yeah. So we’re really regimented about that. We’ve really mapped out. We have a care plan. We give it to them in writing. We have a sheet with phone numbers. We have a wallet card for them to put in their wallet. And we do teaching both on our end and then our RN comes in and does more. Then we have a system where the nurse calls them, right? Just whether or not they call, they get a phone call saying, “How are you doing on your therapy?” I mean, I hope we emphasize this enough. Sometimes patients, occasionally, they’ll come to their appointment like in a puddle, and you’re like, “Why didn’t you call me? I could’ve helped.”

Brian:
When do you call them?

Betsy Plimack:
But for the most part, they do call…

Brian:
When does your nurse call them?

Betsy Plimack:
They have a specific regiment. I think during the first week, they’re called.

Brian:
Okay.

Betsy Plimack:
And that’s actually… the oral medication. The infusional medications, patients are seen so often in the IO, I think, in sort of a constant vigilance, you need to sort of impart on the patient. But in the first few weeks, it’s important.

Tom:
We’ve talked pretty much exclusively about VEGF-TKI immune combinations. Let’s keep going with that. So when patients are coming in with these drugs, when can they expect to get their sort of maximum toxicity? When does the toxicity start to occur? And we know that there’s a lot of variability, particularly with immune related toxicity. But we are seeing fatigue, we are seeing stomatitis, we are seeing diarrhea, and obviously, hand and foot syndrome with these drugs. Are they happening at the same time with the VEGF-targeted therapy and the same severity, or do you see it as being slightly different?

Betsy Plimack:
So I think that is a clue to attribution that you just mentioned is the timeframe. So I tell patients whatever you’re going to experience with VEGF, we’re going to see a hint of it in the first month usually, right? And I think sort of [inaudible 00:06:49] supports that as all the other side effects that you just mentioned, Tom, right?

Betsy Plimack:
So if something happens at month six, like acute diarrhea, I think… why would you get that all of a sudden from your VEGF that you haven’t had diarrhea from before. So I think timeframe is really important when you’re thinking about attribution and that parlays into management, right? The patient who gets profuse diarrhea at month six, you would be much more have the heightened concern for immune-mediated colitis and start steroid potentially earlier. Although I would argue for, again, the move with VEGF-IO to attribute and manage… wait a few days and see what happens. And then, of course, the half-lives of the VEGF we’re talking about today are variable so that plays in.

Brian:
Right.

Betsy Plimack:
But usually, if something gets better with just holding, it’s probably the TKI. Do you guys do that?

Brian:
Yeah, no, I agree. I think some of the challenge in a community setting is it takes a fair amount of effort because you have to assess the patient, you have to get LFTs or whatever in three days, or assess them again in three days on a provider staff on a nursing staff. I think it’s certainly more intense…

Betsy Plimack:
It’s a lot.

Brian:
… as opposed to just starting them on steroids, right? That’s sort of the easier answer. But I totally agree with you.

Tom:
So Brian-

Betsy Plimack:
Although Brian, I would argue that in the long term since these drugs work, the efforts at the… It’s front-loaded, right? If you put in that effort at the beginning, it’s something that is going to prevent sort of further episodes down the road. And I think all three of us have patients cruising now on whatever dose that they’re on, that then I think pays back later and sort of after.

Brian:
I agree. And I would emphasize. And I emphasize this to patients. I say, “Listen, give me a couple months to sort of figure out how to dose you…

Betsy Plimack:
I love that. I love that.

Brian:
… how are you going to tolerate.” There’s an adjustment period for me and the patient in the first six to eight weeks. And if we can get through that, then patients tend to cruise. I agree.

Betsy Plimack:
Right. That’s really important, Brian, because you’re really saying, “It’s not going to be like this forever…

Brian:
Right.

Betsy Plimack:
… this is… part. We’re in it with you.” Right? There’s a lot of things that… I love that, that sort of set up.

Brian:
Well, and we give everybody the same dose. Guess what? It’s not going to be the right dose for everybody.

Betsy Plimack:
Exactly. Right.

Tom:
So we talked about this exploratory journey at the beginning. Let’s say hypothetically, and let’s not specify which regime to start with, that the individual phones your nurse or our nurse at week four having just started the second infusion saying that, “I suddenly got diarrhea. It’s happening four or five times a day. I’m losing control of it. My hands are a bit sore.” What advice should that patient receive that’s phoned up asking for that?

Brian:
Come in, come in. We need to see you. Yeah. Right.

Betsy Plimack:
Yeah. I mean, I think hold the drug. Don’t take your drug today… and that sort of does a couple of things. One, you’re doing your sort of hold intervention, which is diagnostic and potentially therapeutic. And two, you’re really emphasizing the partnership around management of this, again, in that early period whereas Brian says… you want to get right.

Tom:
And let’s say that patient comes in and they hold the drug. And after four… days, they’ve still got diarrhea four times a day. And… liver function, there’s a grade one transaminitis, what are you doing with that patient… use starting steroids, and how long are you prepared to just stop the drug? Let’s start with cabo or lenvatinib… to their half life is a little bit longer.

Brian:
I think it depends a little bit on how sick the patient looks. I mean, if I’m getting to day four and five, even with cabo or lenva, I’m starting to worry about immune-mediated toxicity more than TKI. And plus the way you presented the case was sort of sudden onset, which is generally not how TKIs come on in terms of diarrhea.

Betsy Plimack:
Right.

Brian:
So I’d have a lower threshold of steroids in that patient, or at least, getting them in and evaluating them. And that’d be a little [crosstalk 00:11:00].

Betsy Plimack:
And Brian, do you do that in inpatient, or do you give patients oral steroids? How do you do that?

Brian:
Depends how sick they look. I try to keep them out.

Betsy Plimack:
Yeah.

Brian:
It depends on if it’s an 82-year-old with other medical problems and limited reserves, et cetera, and it’s Friday afternoon.

Betsy Plimack:
Right.

Brian:
I’m just admitting that patient, right?

Betsy Plimack:
Yeah. Right, right.

Brian:
If it’s a 52-year-old with good support system and et cetera, et cetera, and they’re close to the medical center, then I’m going to try to manage them as an outpatient. So I think that’s just the variability.

Tom:
Well, let’s say you’ve given-

Betsy Plimack:
Have you found any… Oh, sorry. Go ahead, Tom.

Tom:
No, Betsy, you go. I apologize.

Betsy Plimack:
I was going to say, have either of you found any issues with absorption of oral steroids with the GI toxicities like diarrhea, or IV actually works better?

Brian:
I’m sure. I can’t think of specific cases necessarily, but there definitely been people we’ve started on oral steroids who’ve not gotten better.

Betsy Plimack:
Until you switched to IV.

Brian:
And then, obviously, convert them to IV. Yeah, yeah. I wouldn’t say, Betsy, [crosstalk 00:11:53].

Betsy Plimack:
So I think.. could keep in mind that if the steroids aren’t working if they’re oral to try the IV route… reverse some colitis in my experience but [crosstalk 00:12:05].

Brian:
What do you do about… I’ve come into this in the last couple weeks sort of steroid dosing. So not even just diarrhea but rash or LFTs or whatever.

Betsy Plimack:
Yeah.

Brian:
I don’t like to give everybody a milligram per kilogram or 60 of prednisone. I don’t like to start everybody. And so sometimes, I’ll sort of finesse it and say, “Well, let’s try 40. Let’s try 20 for a few days and see what happens.”

Betsy Plimack:
Yeah.

Brian:
I mean, do you do that?

Betsy Plimack:
I do. I mean, the one [inaudible 00:12:29] if you have someone who’s really large, I had someone the other day with colitis and end up being like 150.

Brian:
Yeah. That’s a lot.

Betsy Plimack:
And I was always taught like there is like the curve of efficacy flattens out for the oral steroids, right? So above 60 or 80, you’re probably not getting that much of an advantage.

Brian:
Yeah.

Betsy Plimack:
You’re only getting toxicity. So I tend to not try really hard not to go above 60 in general but I do tend to not… I mean, if I’m going to start, I usually start at 60, Brian, and…

Brian:
Okay.

Betsy Plimack:
… range of the taper quickly. The bottom range of the taper, I have been… like a really slow under 20 milligram.

Brian:
Yeah. I agree.

Betsy Plimack:
Like super slow.

Tom:
Let’s move to this individual. Let’s say on day four now, he’s obviously off both drugs because we see he’s not having another infusion. And things settle on day four, the transaminitis sort of settles a bit or let’s say day four. And then he comes back to see you on day seven and said, “Actually, I’ve been going pretty well now for three days. No problems. Thank you.”

Brian:
Did we give him steroids? I forgot.

Tom:
Yes, we did. So he’s at 60 milligram of pred.

Brian:
Yeah.

Tom:
To restart the VEGF-TK, if possible, what are you… And he’s currently on pred 60. And in fact, he’s relatively asymptomatic, let’s call grade one fatigue. What are you saying to this patient now who wants to get back on his treatment dose of his drug? He’s on 60 milligrams of pred, and he’s been three days symptom-free.

Betsy Plimack:
I usually give it longer unless the disease is pressuring me otherwise. Brian, I don’t know what you do.

Brian:
You would keep him off the…

Betsy Plimack:
Yeah.

Brian:
I’d be tempted to restart because we’re saying it’s probably immune-mediated, given the response to steroids and the time course. I’d probably drop him to 40 of pred and restart his TKI.

Betsy Plimack:
Yep.

Brian:
Although, I think the thing to remember, there’s not an urgency to restart the TKI.

Betsy Plimack:
Right.

Brian:
I mean, unless the disease is pressuring, right? Unless it’s high-volume symptomatic disease.

Tom:
I mean, Brian, my take on it is if as while they’re on steroids, my preference is not to… drug because inevitably, the VEGF-TKI, the immune drug is still kicking around in the background. I think there probably is some synergistic interaction between some of the adverse events. I don’t believe the adverse events are either VEGF or not all of the adverse events. I think hypertension is an exception.

Brian:
Yeah.

Tom:
But the transaminitis, for example, has a component. I suspect the transaminitis is generated by VEGF-TKKI has an immune component to it, even as a single agent. And therefore, the principle of saying, well, it’s either… And actually, when we did the trials, it’s frustrating because we had to say, is it VEGF or is it immune related? And if it was immune related, we had to treat differently from VEGF related where I think a lot of the adverse events actually overlap to some extent, diarrhea and transaminitis being the commonest two of those. And so my temptation is actually to keep the patients off active therapy until they’re a couple of, at least a week or two, on stable. And Betsy… that’s right, earlier, is that my… is to always steroids that little bit longer rather than that little bit shorter. And the doctor taught me, I think of Dave [inaudible 00:15:47]. It might have been James Larkin who said, “If you’re giving steroids, give extra week, and it’ll always help you.” So I kind of tend to give-

Betsy Plimack:
Especially at the lower end, right? It’s the taper to eight milligrams, four milligrams to off where I find the flares tend to happen.

Brian:
Right.

Betsy Plimack:
And at that low dose, it’s lower… You’re usually restarting whatever therapies a little bit…

Brian:
So how do you decide when to restart TKI?

Betsy Plimack:
I think if someone’s been really good for a while and especially if their disease is pressuring me to, I restart it. I will say in some of these patients, we get CRs, right? We get deep responses less than 80%, down to 80%. If I have a patient in that category who hits tox, I sometimes take it as an opportunity to see if they need more therapy, right? Maybe you can be in that treatment for your survival… if you got to need to start to respond. So that’s a very individualized decision.

Brian:
I was going to say, it usually happens early on. So somebody in months two or four, maybe they’re have responding.

Betsy Plimack:
Right.

Brian:
So they’re not out on the tail to occur and to restart.

Betsy Plimack:
Yeah. Then we don’t. Right.

Brian:
Right. So how do you decide when to restart… I think one important point is you should restart TKI.

Betsy Plimack:
Correct.

Brian:
I think we would all agree that just dropping it as a mistake.

Betsy Plimack:
Yeah.

Brian:
So how do you decide when to restart? Is it X amount of time on steroids? Is it X amount of time clinically symptom-free? Or is it just-

Betsy Plimack:
I think both those things. … down below 40 or ideally even down to the 20. But if that’s taking too long, I restart. After about a month off, I get itchy to restart.

Brian:
Itchy.

Tom:
Yeah. I agree. As for a successful taper asymptomatic, I think those two issues are important.

Brian:
Asymptomatic for how long, just asymptomatic?

Tom:
I’d like to be asymptomatic for a couple of weeks. I’d like things to settle down…

Brian:
A couple of weeks.

Tom:
… couple of weeks. Yeah.

Brian:
Okay.

Tom:
But there does come time with a grade one transaminitis or occasional diarrhea where, as Betsy said, sometimes you just need to get back in and see what happens. Yeah.

Betsy Plimack:
And remember with the VEGF-TKIs and the package insert, you can hit liver tox, pause, let it get better and safely restart, right? This is a paradigm we are used to. And so having that confidence, I think, is important. So to that end, yeah. They do have to get…

Tom:
My next really important question because this is a concern of mine is if we … the drugs, what proportion of drugs that you interrupt? Sorry. What proportion of patients who you interrupt their drugs can you get back on to some form of therapy or combination therapy?

Brian:
Get back on both drugs?

Tom:
Yes. So this patient here, we’ve been-

Brian:
I think it’s the vast majority.

Tom:
Yeah.

Betsy Plimack:
Yep.

Tom:
Betsy, do you agree, Betsy?

Betsy Plimack:
Yeah. Sorry. I dropped out for a second. Yeah. I think the vast majority do end up definitely back on the VEGF-TKI for IO. If it’s severe, we’re requiring IV steroids. I tend to not restart. I know some colleagues do, but I tend to go on the paradigm that, look, they hit tox. They’ve gotten the maximum benefit we can afford to have them be off therapy. And I restart the VEGF and then continue. That’s usually my-

Brian:
So do you ever restart that IO in that circumstance, or does it…

Betsy Plimack:
I’m not going to say never…

Brian:
… depend on severity of the tox?

Betsy Plimack:
I’ve done it, but I have to really see. I usually wait until some progression to make sure they need it, to be honest, yeah, if it’s a bad toxicity.

Brian:
It sounds like I tend to restart VEGF sooner and restart IO more.

Betsy Plimack:
Yeah. It’s that way.

Brian:
Yeah.

Betsy Plimack:
Let’s go.

Tom:
I’m slightly more cautious in terms of the time to restarting. But I agree, Brian. I try. And even for those individuals who required IV steroids, it wouldn’t be unusual for me to have potentially another go. But if we were going to do that, I would keep really close observation under those circumstances. We did learn a little bit. I know it’s very different. We did learn a bit from the VEGF-TKI era where we got even grade three toxicity… we could rechallenge with the drugs successfully. And that good example of that was transaminitis where often it was worse during the first 12 weeks of their therapy…

Brian:
Right.

Tom:
… and then settled down. But I think that’s obviously not for the faint-hearted. And I think you need to be keeping a very close eye on patients that have clearly come into harm’s way to do that second time is something that needs careful consideration.

Brian:
But remember time that a 426 liver toxicity manuscript that just came out, the majority of people who were rechallenged, they’re just fine.

Betsy Plimack:
Right.

Brian:
So I think that’s important certain data that took forever to get out in manuscript form. But I think it’s important to realize that most people will do just fine with rechallenge. And I think the other piece here is the context of, are you in the first two to three months, or are you out at month 18? And the patient has a 70% response, and they’re doing well. Those are, to me, different conversations. If I’m farther out, then I’m like you, Betsy. Well, let’s see if I can get away with no therapy. Because the patient’s disease is under control. They’ve had an immune response. I’m feeling much more comfortable than on week six where it’s kind of on and we need to… I’m a believer. We need to get as much therapy into patients as possible.

Tom:
Brian…

Betsy Plimack:
Right. And I think what you’re bringing up, Brian, is that the type of toxicity matters like pneumonitis versus hepatitis versus colitis, right? The timeframe matters and the urgency that the disease is putting pressure on us matters, right? So there is an art to it. It’s nice to be able to put some pearls out there for management, but it’s a difficult and tricky scenario to manage.

Tom:
We’ve got a couple of minutes. And before we finish, I’d just like you to ask, when are you definitely diving in with IV steroids admitting, and which patients are getting infliximab?

Brian:
I mean, I can go… It’s all about how clinically sick they look, right? We’ve all been doing this a long time and sat in front of people. You’re just like this patient doesn’t look right. They look toxic, right? Those people are definitely getting admitted for IV steroids and/or older patients with less reserve, right, less organ reserve, where I’m worried that a little bit of dehydration’s going to tip them off into something. So those are the people that I would lower my threshold for IV steroids. I don’t think it’s wrong to give them. And we can also just give a dose as an outpatient in the clinic. Give two or three doses as an outpatient if they’re close and can come back and just, say, on the hospital admission.

Betsy Plimack:
Right.

Brian:
And then infliximab, I haven’t used in a while, maybe because I’m giving less Ipi/Nivo now and more IO/TKI. But I don’t haven’t used it in a while, but obviously for steroid refractory.

Betsy Plimack:
Right. I mean, I would say I tend to admit pneumonitis and colitis pretty… certainly if they look sick but sometimes, even if they don’t. First of all, I like to get the diagnostics done quickly. So colonoscopy or… big with biopsy, especially if it impacts like our future treatment decisions for the patient. And… colitis, we do that… sometimes now. Our team tends to like that. There’s some data on that. But it’s important. Infliximab is not the drug of choice for hepatitis, right? Elevated LFTs [inaudible 00:23:05] or CellCept that we lean on for that.

Brian:
Yeah.

Betsy Plimack:
And so there is nuance to sort of what immune modulators beyond steroids we use. And that’s where at least talking to a specialized center, I think, is critical in this matter.

Brian:
Can I ask both of you? Maybe my final question is, I do a whole lot, especially as patients get beyond month, two or three of telling them to take little holidays from their TKI, three days, four days, five days. Again, we have disease control at that point. We’ve managed toxicity. We’re kind of settled in. And I find it just really recharges the batteries. And you often have to talk patients into it. Right.

Betsy Plimack:
Yeah.

Brian:
They don’t want to stop a drug that’s helping them. Then they come back and they say, “Gee, I took three days off, and I felt great for the next two to three weeks.”

Betsy Plimack:
Yeah.

Brian:
Do you guys do that?

Betsy Plimack:
That’s really important thing, for sure. Usually… I mean, this is, again, these drugs work, so they’re on them for a long time, right? So you got to make it… Just like we all need vacation. They need drug holidays to really maintain momentum, right? So I agree.

Tom:
And, Betsy, anything specific for… or axitinib. I mean, more similarities than differences between the drug. Any specific advice for any one of those drugs?

Betsy Plimack:
Well, I think I can speak more theoretically. Obviously, I’ve given a lot of axi, pembro, and less of the other two, but the longer half-life of lenvatinib and cabozantinib has to be taken into account when you do the hold and see if it resolves trick…

Tom:
Yeah.

Betsy Plimack:
… make it easier. Dosing of lenvatinib and cabo is clunkier. Axi, it comes in one milligram doses. We’ve done all kinds of creative… therapeutic with all of those. So those I think are the nuances, but those are secondary to efficacy. I think the efficacy with len-pembro is really compelling and again, treat for efficacy and then manage for tolerability, quality of life, and tox.

Tom:
Anything from your… before we call it a day?

Brian:
I think it’s just like we talked about a decade ago, it’s more about learning the drug, how to give it, when to hold the nuances of dosing and titration, that understanding a drug or in this case a regimen is the most important thing. So pick your favorite and figure out how to give it.

Betsy Plimack:
I know you say that, and I’m just going to push back. I don’t think in oncology, we have the luxury of getting comfortable because it’s going to change. For all we know, it’s going to be belzutifan-avelumab in the future. And I think being able to learn new drugs is part of our core skillset. So I love axi-pembro. I’m comfortable with it. If you’re going to tell me to pick my favorite, that’s my favorite. But boy, the len-pembro data is compelling. I’m going to use it next chance I get because of the data.

Brian:
That’s fine but you also see a ton of kidney cancer, right? If you’re seeing four or five patients a year, you probably shouldn’t give four or five different regimens, I guess, is my point.

Betsy Plimack:
I guess.

Brian:
Right.

Betsy Plimack:
I don’t know.

Brian:
All right.

Betsy Plimack:
If data change that fast, [crosstalk 00:25:57]…

Tom:
It sounds like a slightly different debates excited about.

Betsy Plimack:
[crosstalk 00:26:00].

Tom:
But we might have to do that… I think my take on this issue for what it’s worth is do genuinely think the way we give these drugs and support structure the patients have while they have them is probably more important, the regime that we give. I do take Betsy’s point where with new drug development, you want to try the… But, Brian, that community, it looks like… My biggest concern at the moment is that I think that we are seeing quite a lot of patients stopping drugs very early, irrespective the regime we choose…

Brian:
Agree.

Tom:
… in the toxicity management. And I’d like to address that issue first, before we talk about the subtle differences between these regimes. We’ve not talked about Ipi/Nivo. The… is actually, I think, for a different day because the profile is very different. But we’re going to perhaps do that another time. How that sounds?

Brian:
Sounds good. Yeah. Sounds good.

Betsy Plimack:
Would love to.

Brian:
Good discussion.

Betsy Plimack:
Yeah.

Brian:
Thanks, Betsy. Appreciate it. Have fun.

Tom:
It’s great to hear from you.

Betsy Plimack:
Thank you both.

Brian:
See you soon. All right. Bye-bye.

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