Brian I. Rini, MD:Just to continue on toxicity—Stephanie, maybe I’ll ask you. I know you were more of an ipilimumab-nivolumab user, but you do give some IO-TKI [immuno-oncology–tyrosine kinase inhibitor therapy]?

Stephanie A. Berg, DO: I do.

Brian I. Rini, MD:When you do, are you choosing based on the TKI? I like axitinib with a short half-life better, or I like lenvatinib because it’s more potent? What’s making your choice? And then if, kind of the related question, I’m going to ask everybody this for lenvatinib-pembrolizumab, which I think everybody gives a bit. Are you starting at 20 mg?

Stephanie A. Berg, DO: I always start at 20 [mg] at lenvatinib. I try to follow that. I know a lot of the dosing is also different among tumors, of lenvatinib of 18 mg or 20 mg. The toxicity is so challenging because we know they’re all overlapping, and trying to decide among that with the different TKIs. I do recognize the half-life of cabozantinib now that they have a newer version coming out, which I cannot pronounce, that has a shorter half-life. Dose reductions are hard because, I shouldn’t say hard, but when you interrupt a dose, it doesn’t just go away in a couple days. It lasts for maybe a week to a week and a half. Then I do like axitinib for that shorter half-life. Lenvatinib, though, still also has a pretty long half-life as well, but not as long as cabozantinib. It’s almost upwards of, cabozantinib is 99 hours, and then the lenvatinib is…they’re just both long.

Brian I. Rini, MD:They’re long. I may have missed this, but when you choose IO-TKI, it sounds like you’re going more lenvatinib-pembrolizumab, or…?

Stephanie A. Berg, DO: I do choose more of the lenvatinib-pembrolizumab. Correct. Yes.

Brian I. Rini, MD:Bruno, let me pick on you. When you’re choosing IO-TKI—and it sounds like you use more of that than ipilimumab-nivolumab—what are you choosing as why, and also the lenvatinib dosing question?

Bruno R. Bastos, MD: Those are very good points, I agree. Like I said, I’m in the community practice. We tend to see patients going [to] different hospitals and things like that, sometimes outside the network. You sometimes get phone calls of patients to be admitted. Now [the patient is] going to have emergency surgeries and things like that, and how to manage it. So, because of that, I tend to choose a little bit more the axitinib combination because the [with] the shorter half-life, it’s much easier to manage in situations like this when patients require either a major dental surgery, which sometimes happens, or patients in the outside doing procedures. So even our staff feels more comfortable with that because we don’t like to get surprised [if a] patient requiring a major operation [is] in a long half-life VEGF-TKI [vascular endothelial growth factor–tyrosine kinase inhibitor]. The IO-IO toxicity, we see it. I tend to be a little bit less concerned when we are dealing with advanced disease, and as was mentioned here, I think we are either learning how to do it better or maybe less afraid of steroids. It doesn’t seem to be a major deal, the use of steroids. Obviously, in the real-world scenario as opposed to in a clinical trial, I was part of the COSMIC-313 [trial; NCT03937219], they have strict guidelines [on] how to use steroids. Sometimes I feel it’s a little bit too much that you really need it in clinical practice because it’s one size fits all. In a clinic you can maybe do 0.75 mg, 0.6 mg/kg of prednisone equivalent. So I tend to feel that these high-dose steroids would go down a little bit. But obviously we are concerned about the toxicity. Like I said, I get a little bit more nervous. I don’t know if we’re going to have a chance to talk about the adjuvant, but I tend to get a little bit more concerned about the IO [adverse] effects in the adjuvant setting, because those are the patients who really could be chosen to go for observation as one standard treatment and then they may get severe IO-related toxicity, which I’ve seen. It’s something that it’s difficult to manage, and how to relate the patients to the team when patients have a more severe toxicity.

Brian I. Rini, MD:Yeah. We’re not going to get to the adjuvant setting, but clearly the benefit risk is different because many of your patients don’t have cancer, so it’s very different. All right. Betsy, your turn.

Stephanie A. Berg, DO: So, really quick, you asked if I start at 20 [mg]?

Brian I. Rini, MD: Yes.

Stephanie A. Berg, DO: I don’t.

Brian I. Rini, MD:OK.

Stephanie A. Berg, DO: I start at 12 mg because I get 4-mg pills. I just can’t get good tolerability at 20 [mg], and 16 [mg] even is hard. What I love about axitinib is the nimbleness. You can order 3-mg pills and do whatever crazy dosing you want to do within that realm. With lenvatinib, you’re ordering 10s or you’re ordering 4s and you’re combining them. So I start at 12 [mg], then I have 4-mg pills and I move with those until I hit the right dose.

Brian I. Rini, MD:Start at 12 [mg]?

Stephanie A. Berg, DO: Yeah.

Brian I. Rini, MD:How?

Stephanie A. Berg, DO: Fours.

Brian I. Rini, MD:Oh, three 4-mg [pills].

Stephanie A. Berg, DO: Three 4-mg [pills], and then quickly you have them take a fourth 4-mg [pill] if they’re doing well.

Brian I. Rini, MD:I see. I didn’t think there’d be any math on this panel.

Stephanie A. Berg, DO: I know. It’s off-label. It’s outside the data. That’s why I’m a little sheepish about it. But I find that’s how I can most quickly find the dose that matches that’s tolerable long-term. They do so well that they’re on long-term.

Brian I. Rini, MD:I can tell you do a lot of roundtables with community doctors, and nobody starts at 20 [mg]. They all started either at 8 [mg] or 10[mg] or 14 [mg]. It’s all over the map, and it’s fascinating to me. Two decades later, we [are] still not sure how to dose drugs right. We’ve been doing this literally for 2 decades. Not lenvatinib, but similar drugs, and we still all have our little quirks and ways to do it.

Stephanie A. Berg, DO:: Yeah. I mean, it’d be great if we can get higher doses into people, and they feel great and are living their lives. It’s harder to do with lenvatinib than axitinib.

Brian I. Rini, MD:Agreed. I do tend to start at 20 [mg], but with an extremely low threshold to go down, and my nurses are calling [the patient] every week. So it does take more.

Stephanie A. Berg, DO: So we probably get to the same place, you and I, from different directions.

Brian I. Rini, MD: I think so. Sure. You would assume in a given patient you’re going to end up at that same place. Hopefully, that sweet spot of just enough but not too much.

Bruno R. Bastos, MD: I mean, it depends on the patient population that I see to have a lot of uncontrolled hypertension. So when we see this patient population, you get a little concern with VEGF-TKI. Maybe when you’re in academic setting, maybe in different centers, patients have more access or they’re more strict with their blood pressure. But in my current practice, I tend to see a lot of patients with hypertension at baseline.

Transcript edited for clarity.