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

Dr. 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 the practical nuts and bolts of toxic management, now, as these are sort of rolling out into practice. So Betsy, thanks for joining us. Maybe introduce yourself and you can give us a little bit of your take on toxic 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 a topic the three of us chat about pretty regularly on email and otherwise, and so it’s nice to be able to explore it together. 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 III trials, I would say most patients probably are and should be getting IO-VEGF combinations in the frontline.

Betsy Plimack:
One of the things we’ve been talking about a lot lately is picking the most efficacious regimen-

Betsy Plimack:
[Inaudible 00:01:33] for toxicity, 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, where you’re getting efficacy without too much grind in terms of toxicity. And the dose… [inaudible 00:01:55] of course is the VEGF right now for IO, that’s the standard.

Brian:
Right. So talk about how you do that. I mean, 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 the other as the first step?

Betsy Plimack:
Yeah. Sometimes I do, I try… 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, a trial and error. 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 with a VEGF and then layer in the IO. But for the most part, I do start with the doublet. How about you guys?

Brian:
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 are PS 2, 3, et cetera, that I was worried about the doublet and I’ve started them on IO monotherapy and then layered in the VEGF. It’s pretty rare, I can think of maybe two or three patients in the last few years. But I’m just kind of curious-

Betsy Plimack:
I would say I generally don’t do that, I think if the patient is sick from disease I go for it, I 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:
So I think it’s a rare situation… And this is where the art of oncology comes in, is the patient in front of you and you’re… You know what your drugs are capable of, both advocacy and tox-wise and what they can handle or what risks. But I think generally, if patients are starting with both, the issue that comes up is when tox happens, how do you attribute it? And then how do you manage it? And always in your mind, you’re looking to attribute it and then both of those things in parallel.

Brian:
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, like which IO you’re giving and half an infusion schedule is. So I certainly see them each infusion with axi-pembro, for instance, we do give that 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 patients on it longterm. So I’m seeing them every three weeks. 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 to blisters or before the diarrhea gets to be at 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? When are you saying, “Listen, you need to get back on the phone if this is 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. 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 the appointment in a puddle and you’re like, “Why didn’t you call me? I could’ve helped.” But for the most part, they do call-

Brian:
When does your nurse call them?

Betsy Plimack:
They have a specific regimen, I think, during the first week they’re called. And that’s actually a pharma-

Betsy Plimack:
Sort of around the oral medication. The infusional medications patients are seen so often, and the IO, I think, there’s sort of a constant vigilance you need to 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 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, it’s 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, and I think, [inaudible 00:06:47] VEGF supports that, as does all the other side effects that you just mentioned, Tom. So if something happens at month six, like acute diarrhea, I think that risk… [inaudible 00:07:02] just because why would you get that all of a sudden from your VGEF that you haven’t had diarrhea from before? So I think tempering is really important when you’re thinking about attribution and that parlays into management, the patient who gets profuse diarrhea at month six, you would be much more have a heightened concern for immune-mediated colitis and start steroids potentially earlier. Although, I would argue for, again, the move with VGEF-IO to attribute and manage toxicity-

Betsy Plimack:
[inaudible 00:07:29] 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, but usually if something gets better with just holding, it’s probably the TKI. Do you guys-

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 and you have to get LFTs or whatever in three days, re-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. 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 longterm since these drugs work, the efforts it’s front-loaded. If you put in that effort at the beginning, it’s something that is going to prevent 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.

Brian:
I agree. 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. How are you going to tolerate-”

Betsy Plimack:
[crosstalk 00:08:38].

Brian:
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.

Tom:
I agree.

Betsy Plimack:
Right. That’s really important Brian, because you’re really saying it’s not going to be like this forever, [crosstalk 00:08:51], we’re in it with you, there’s a lot of things. I love that sort of setup.

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. True.

Tom:
So we talked about this exploratory journey at the beginning, let’s say hypothetically, and let’s not specific 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, we need to see you.

Betsy Plimack:
Yeah. I mean, I think hold the drug, don’t take your drugs today and-

Betsy Plimack:
And that sort of does a couple things. One you’re doing your 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-

Betsy Plimack:
You want to get it 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, what [inaudible 00:10:16] liver function there’s a grade one transaminitis, what are you doing with that patient? When are you starting steroids and how long are you prepared to just stop the drug? Let’s start with cabo or lenvatinib because 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. Plus the way you presented the case was sort of sudden onset, which is generally not how TKIs come on in terms of diarrhea. 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 little-

Betsy Plimack:
Brian, do you do that as 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. It depends on if it’s in an 82-year-old with other medical problems and limited reserves, et cetera, and it’s Friday afternoon, I’m just admitting that patient. 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:
Firstly you-

Betsy Plimack:
Mm-hmm (affirmative). Have you found any-

Betsy Plimack:
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 and then [crosstalk 00:11:49] converted them to IV.

Betsy Plimack:
Until you converted to IV.

Brian:
Yeah. Yeah. I wouldn’t say [crosstalk 00:11:53]

Betsy Plimack:
[crosstalk 00:11:53] to keep in mind that if the steroids aren’t working, if they’re oral to try the IV route, because-

Betsy Plimack:
Reversed from colitis in my experience, but little power.

Brian:
[crosstalk 00:12:06] what do you do about, I’ve come into this in the last couple of weeks, steroid dosing. So not even just diarrhea, but rash or LFTs or whatever, 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.” Do you do that or?

Betsy Plimack:
I do. The one mil per kg, if you have someone who’s really large, I had someone the other day with colitis and ended up being like 150 milligrams of prednisone-

Brian:
That’s a lot.

Betsy Plimack:
And I was always taught there is… The curve of efficacy flattens out for the oral steroids, so above 60 or 80, you’re probably not getting that much of an advantage, you’re only getting toxicity. So I tend to try really hard not to go above 60 in general, but I do tend to not… If I’m going to start, I usually start at 60, Brian, and-

Betsy Plimack:
Inch of the taper quickly, the bottom range of the taper, I have been-

Betsy Plimack:
I go really slow under 20 milligrams.

Brian:
Yeah, I agree.

Betsy Plimack:
Like super slow.

Tom:
Let’s move to this individual, let’s say a week on day four now, he’s obviously on both drugs because he’s not having another infusion and things settle on day four, the transaminitis sort of settles a bit, 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 them steroids? I forgot.

Tom:
Yes we did, so he’s had 60 milligrams of pred. To restart the VEGF-TKI if possible, 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-day symptom-free.

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

Brian:
You would keep him off the TKI?

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 them to 40th pred and restart as TKI. Although, I think the thing to remember, there’s not an urgency to restart the TKI. I mean, unless the disease is pressuring, let’s say it’s high volume symptomatic disease.

Tom:
Brian, my take on it is while they’re on steroids my preference is not to restart the 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 [inaudible 00:14:47] the VEGF will knock all of the adverse events, I think hypertension is an exception. But the transaminitis, for example, has a component. I suspect the transaminitis generated by VEGF-TKI has an immune component to it, even as a single agent. And therefore the principle of saying, well, it’s either… 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.

Tom:
So my temptation is actually to keep the patients off active therapy until they are a couple of… At least a week or two stable. And Betsy, I-

Tom:
That’s right earlier is that my [inaudible 00:15:39] is to always start a little bit longer, rather than a little bit shorter. [inaudible 00:15:45] doctors told me, “Hey, I’ve [inaudible 00:15:47]” It might have been James Lakin, who said, “If you’re giving steroids, give an extra week and it’ll always help you.” So I kind of tend to give a little-

Betsy Plimack:
Especially the lower ends, it’s the taper to eight milligrams, four milligrams to off where I find the flares tend to happen. And at that low dose, it’s lower, you’re usually restarting whatever therapy it’s a little bit low.

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 restarted it. I will say, in some of these patients we get CRs, 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. Maybe you can be in that treatment for your survival-

Betsy Plimack:
[inaudible 00:16:40] to respond. That’s a very individualized decision, but…

Brian:
I was going to say it usually happens early on. So somebody in month two or four, maybe they’re responding, they’re not out on the tail of the curve [crosstalk 00:16:52]-

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

Brian:
Right. So how do you decide when to restart TKI? I think one important point is you should restart TKI, and I think we would all agree that just dropping it is a mistake.

Betsy Plimack:
Yes.

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? Or is the-

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

Brian:
Itchy. No-

Tom:
Yeah, I agree. So 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 for a couple of weeks. But there does come a 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.

Betsy Plimack:
Mm-hmm (affirmative). And remember with the VEGF-TKIs in the package insert, you can hit liver tox, pause, let it get better and safely restart. 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 are… The drugs, what proportion of drugs that you interrupt… Sorry, what portion 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:
Yep, okay.

Betsy Plimack:
Yep.

Tom:
Betsy, [inaudible 00:18:32] ?

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 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 the IO in that circumstance or does it depend on severity?

Betsy Plimack:
I’m going to say never. I’ve done it, but I have to really see, I usually wait until there’s some progression, to make sure they need it, to be honest. Yeah, if it’s a bad [inaudible 00:19:13]

Brian:
It sounds like I tend to restart VEGF sooner and restart IO more, because I tend to just-

Betsy Plimack:
It sounds that way.

Brian:
Yeah.

Betsy Plimack:
Let’s go.

Tom:
So I probably… I suspect to have slightly more cautious in terms of the time to restarting, but I agree, Brian, I try. And even for those individuals who’ve 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 when we got even grade three toxicity sometimes we could re-challenge with the drugs successfully. Good example of that was transaminitis where often it was worse during the first 12 weeks of their therapy and then settle down. 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 a second time is something that needs careful consideration.

Brian:
But remember, Tom, the four to six liver toxicity manuscript that just came out, the majority of people who are re-challenged did just fine. So I think that’s important 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 re-challenge. And I think the other piece here is the context of, are you in the first two to three months or are you out of 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, but 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 in the patients as possible. [crosstalk 00:21:08]

Betsy Plimack:
Great, and I think what you’re bringing up. Brian, is that the type of toxicity matters, like pneumonitis versus hepatitis versus colitis, the timeframe matters and the urgency that the disease is putting pressure on us matters. So there’s 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 can go. It’s all about how clinically sick they look, we’ve all been doing this a long time and sat in front of people where you’re just like, “This patient doesn’t look right, they look toxic.” Those people are definitely getting admitted for IV steroids, and/or older patients with less organ reserve, where I’m worried that a little bit of dehydration is going to tip them off into something. So those are the people that I would give… That I would lower my threshold for IV steroids. I don’t think it’s wrong to give them, 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 save them the hospital admission. 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 haven’t used it in a while, but obviously for steroid refractory.

Betsy Plimack:
Right. I would say I tend to admit pneumonitis and colitis pretty… So even if they look sick but sometimes even if they don’t, first of all, I’d like to get the diagnostics done quickly, so colonoscopy or [inaudible 00:22:46] with biopsy, especially if it impacts our future treatment decisions for the patient. And. [Inaudible 00:22:54] 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. Elevated LFTs [inaudible 00:23:05] that we lean on for that. 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 that scenario.

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, they don’t want to stop a drug that’s helping them. But then they come back and they say, “Gee, I took three days off and I felt great for the next two to three weeks.” Do you guys do that?

Betsy Plimack:
Yeah, definitely a good thing, for sure. Usually I call it… And this is again, [inaudible 00:23:53], these drugs work so they’re on them for a long time. So you got to make it… Just like we all need vacation, they need drug holidays [inaudible 00:24:03] maintain momentum. So I agree.

Tom:
And Betsy, anything specific for… [inaudible 00:24:10] or axitinib, any… I think more similarities than differences between the drugs, any specific advice for any one of those drugs?

Speaker 5:
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… Is easier. Dosing of lenvatinib and Cabo is clunkier. Axi comes in one milligram doses, we’ve done all kinds of creative dose… [inaudible 00:24:43] dose. 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 you… 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, 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:
[crosstalk 00:25:19] 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, [inaudible 00:25:30] in the future, and I think being able to learn new drugs is part of our core skillset. So I love [crosstalk 00:25:37], 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. So I don’t-

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. I don’t know. If the data changes [crosstalk 00:25:57]

Tom:
It sounds like a slightly different debate [crosstalk 00:25:59] about-

Betsy Plimack:
It is [crosstalk 00:26:01].

Tom:
But we might have to do that another… I think my take on this issue for what it’s worth is I 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 [inaudible 00:26:27] but, Brian, that [inaudible 00:26:32] it looks like… My biggest concern at the moment is that I think that we’re seeing quite a lot of patients stopping drugs very early, irrespective of the regime we choose because of [inaudible 00:26:42] 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 Ipi/Nivo conversation 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 does that sound?

Brian:
Sounds good.

Brian:
Yeah, sounds good. It’s a good discussion.

Betsy Plimack:
We’d like that.

Brian:
Thanks, Betsy, appreciate it.

Tom:
[crosstalk 00:27:03] great to hear from you.

Betsy Plimack:
Thank you both.

Tom:
See you soon.

Betsy Plimack:
All right, bye-bye.