Dosing and Tolerability of First-line Treatment Options in Clinical Practice

EP: 1.Overview of Advanced Renal Cell Carcinoma

EP: 2.First-Line Combination Options in Advanced Renal Cell Carcinoma

EP: 3.4-Year Follow-Up Results of Lenvatinib Plus Pembrolizumab in Frontline aRCC

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EP: 4.Dosing and Tolerability of First-line Treatment Options in Clinical Practice

EP: 5.Insights from the Community: Optimizing Care for Patients with aRCC

EP: 6.Novel Doublet Combination Regimens in Frontline Advanced RCC

EP: 7.Novel Triplet Combination Regimens in Frontline RCC

EP: 8.Unmet Needs and Future Outlook in aRCC Treatment

Dr. Robert Motzer: You've had a lot of experience with axi pembro and Lenvatinib pembro and probably cabo nivo as well. What's- what has been kind of your take in terms of the use of these combinations in your practice and how you choose one or another? And what's been your experience?

Dr. Elizabeth Plimack: Thank you. So I am an ipi nivo skeptic, just because the short term outcomes I think are important. And in fact, I think with METEOR being presented, I was actually disappointed to see that-. And METEOR, of course is cabo atezo after prior doublet, that ipi nivo patients didn't then get more benefit from continuing immunotherapy with a TKI. So sort of framed it, someone said at one of the meetings, you have one shot on goal and that's your first line treatment. So I worry with ipi nivo that the short- lower response rate, higher primary progression rate burn through that line of therapy a little too soon for some patients. And conversely, as Brian said, we are stopping pembro at two years, and sometimes also either the axi or the len or the cabo and similar. Nivo is a little different, but speaking with the pembro regimens and I tell patients, the goal is to have you treatment free doing well with your cancer controlled. We want to give you a chance to show that you can do that. And so we take the chance together. And just as Brian said, I've had a similar experience where I'm comfortable now doing that. I feel that we can kind of salvage if we do see some growth with either TKI or IO or both, again or other treatments. And it's really nice to have a group of patients in your practice coming back off treatment.

Dr. Robert Motzer: So do you, in terms of choosing one or the other, Betsy, do you have- how do you- for the TKI IO combinations, how do you choose- what factors do you use in terms of choosing one or the other?

Dr. Elizabeth Plimack: Sure, I can share my practice. I will just caveat that probably all three of us do it a little differently. And as Brian said, they're- and as you said, they're very similar outcomes. They're sort of very similar, great results long term. But I usually, if I think someone's going to be on treatment long term, like a favorable risk patient, I usually do pembro with axi, because axi's a little gentler. I can dose it very nimbly and dose reduce it. And for someone who really needs a response with aggressive disease, I do pembro Lenvatinib and I'm comfortable with both regimens. So it's just a matter of trying and then adjusting, adjusting usually the TKI dose to get that sort of long term good quality of life and disease control. Which takes us to the Lenvatinib dosing question, which I know we talk about a lot. So this study starts at a pretty high dose, at 20. A lot of my colleagues will start there. I think I've shared before, my little trick is to start at 12, because that forces the pharmacy to give me four milligram tablets, and then quickly go up to 16. And if that's tolerable, usually get a scan. If it's working, maybe we stay there. If it's not working, maybe we go up. But it's very much in my practice, a sliding scale and I tend to start a little lower just to get people started and not sort of shocked with treatment, and then go up. But Brian, I know you do it a little differently. And Bob, I'm eager to hear how you dose Lenvatinib.

Dr. Brian Rini: I tend to start at 20, understanding that the flaw in that- The good news is or the reason I do it is that's the level of evidence that supports the benefit. The flaw is that 80% of people have to go down, so you're going to beat up more most people at 20, although I was in clinic yesterday, I saw a couple people on 20 and just cruising right at 12, 18 months. It's amazing. And I'm like, "Are you sure you're taking the drug?" I'm always surprised. But I do have a low threshold to go down and I also have a great team of APPs and nurses who can call patients and really, really keep on top of them and I have a very low threshold to go down. I think I mentioned this at ASCO, it amazes me 20 years later, we're still not sure how to dose TKIs. You start low and go high, I start high and go low, and there is a dose effect at least for some patients. And so we're still sort of battling this somewhat silliness of, I don't know what the right dose is for each patient. We have no way to determine it, but empirically, like you say, give a little, see what happens. Give a little more, get a scan, give a little less. And that's fine. And it seems so imprecise in this era of precision medicine. But anyway, I start at 20.

Dr. Robert Motzer: And if the patient is fit, I start with a 20 because of the efficacy data. And there was some other suggestion that high doses of Lenvatinib early on are probably more effective. I think that was largely from preclinical data, however. But one of the things I found is that one of the major toxicities with Lenvatinib is hypertension. And so I've also had an experience, if somebody has hypertension to begin with and they're on a couple of blood pressure medicines, that it really becomes an issue in the very first week or two that I treat patients where we immediately get a call that their blood pressure's sky high. So I individualize the dosing based on the comorbidities of the patient, particularly the status as to whether they have hypertension or not. And for those patients, that I'm either afraid they're going to tolerate because they have other conditions of particularly hypertension, then I also start out at a lower dose of 14 milligrams. And then I escalate with the next refill or so in a month when I know that things are safely being managed as far as their hypertension. I've found that many of my patients, because of the frequent dose reductions that are on Lenvatinib Pembro, wind up on a dose of about 10 milligrams. But just as Brian mentioned, there's others that we go with the full dose of 20 and they're on it for a really prolonged time. So it's really unpredictable. But I do think the three of us are in agreement that it's important to individually dose the patients. It's nice to give the 20, but you also have to do what you think is safe for the patient and carefully manage toxicities. You can always dose escalate if the patient's tolerating the regimen.

Dr. Brian Rini: I will say, this whole titration of TKIs, which I spent a lot of time thinking about is it's challenging. And Pfizer built it into axi's development program, which I think was great, but also very complicated to roll out in practice. And I think at axi pembro been done at 7 BID or 8 BID as a standard dose. You probably see some different numbers albeit with different toxicity. I think one of the take home points, Bob, I think you made is a really good one, is about hypertension early on with lenva and making sure patients are controlled upfront, plugged into cardiology if needed. Understand to call you or message your office if there's problems, know how to take their blood pressure, all that good stuff, because they can get into trouble. And I had the experience early on where, when patients get into trouble in that first week or so, they come back and they say, "Hey doc, I'm not taking that pill ever again." And you're like, "Oh no, I can dose reduce you." And they just look at you and they say, "Nope, I'm sorry, I'm just not doing it." So there is a danger to my approach of losing some patients, if you will, who could probably tolerate 14 or 10 fine and maybe need the TKI component, but you've sort of burned that bridge. So I think it's a cautionary tail and it requires a fair amount of upfront investment, which again, I think we can make at academic centers with resources, but maybe not everybody can make.

Dr. Elizabeth Plimack: I would love to see more dosing studies that help us optimize this for patients. Brian, one of your early works, it was a slide burned into my brain as a fellow where you dosed axiom measured serum levels and it was related to hypertension as a potential biomarker. And so what I take from that is that every patient may be swallowing the same dose, but the amount that's bioavailable differs quite greatly.

Dr. Brian Rini: For sure.

Dr. Elizabeth Plimack: I extrapolate that's the other TKIs, although that work hasn't been done. So I think that underscores what we see clinically and what we're describing as the art of dosing these, but studies would be great.