Optimizing Dosing of First-Line IO-TKI Therapy in Advanced RCC


Shared insight on optimal dosing strategies with first-line tyrosine kinase inhibitor and immunotherapy combinations for patients with advanced clear cell renal cell carcinoma.

Brian Rini, MD:
There are a couple of big topics that you both alluded to, so I thought we’d discuss a little more. Clearly dosing of TKIs [tyrosine kinase inhibitors] is a big topic. What’s interesting to me about the 3 I/O [immuno-oncology]–TKI trials is that they all took a very different approach. Axitinib-pembrolizumab is axitinib dosed in the middle titrated up or down, cabozantinib-nivolumab took a step down from monotherapy, and lenvatinib-pembrolizumab gave the highest dose of lenvatinib that had ever been given in a cancer trial to my knowledge. I don’t know what the right answer is. I was initially in favor of a more nuanced approach with axitinib that I had worked a lot with. If you look at the data, you’d say, “Lenvatinib 20 mg is too much for most people.” But it also has the most robust data if we look at absolute numbers, and I understand all the limitations of that.

Monty, I’ll ask you first because you just mentioned this. When I do community oncologist roundtables, nobody is starting at 20 mg. They all say, “We had this experience in endometrial cancer, which is toxic, so we’re starting lower.” It’s hard to argue. I totally take your point. I do the same thing. I start at 20 mg and go down. Help me reconcile that. There’s what you should do on paper and then there’s real-life experience. Do we know the right dose? Maybe that’s the question. How do we reconcile that?

Sumanta Pal, MD, FASCO: For a situation like endometrial cancer, my understanding is that lenvatinib-pembrolizumab is it on the treatment landscape, so it makes sense to play around and tinker with the dosing strategies. I did a talk with Don Dizon a couple of weeks ago. He works with endometrial [cancer] at Brown [University], and he was alluding to this very topic. I almost raised my hand, but then I put it down when I realized that in endometrial cancer, that’s all that they’ve got. In renal cell carcinoma, you’ve got more options. Rather than starting with an attenuated dose, why not go with something that’s been established in a frontline trial? If you think that patient can’t get away with 20 mg of lenvatinib, then maybe they can get away with 5 mg twice a day of axitinib or 40 mg a day of cabozantinib. I’d rather the folks in the community consider that approach rather than tinkering with the dosing strategy.

If they’re tethered to using lenvatinib-pembrolizumab in the frontline setting, I tell them to give that patient instructions on dose modification. I tell them to give the patient counsel that it comes as 10 mg, 4 mg, and 4 mg. It couldn’t be easier to do this dose reduction on an individual basis. If they start running into trouble at 20 mg, have them pull back. See if they can scale back initially to 14 mg, or see if they can scale further down to 10 mg on their own. It’s a little complicated with lenvatinib 20 mg because I guess you’re getting two 10-mg tablets. But anything they can do to interrupt dosing early and get that patient dose reduced is going to help them mitigate toxicity in that first month or 2.

Brian Rini, MD: Thanks. I appreciate it. Hans, what do you think about this lenvatinib dosing question? This is clearly active but also clearly toxic. In a community setting, they may not have the resources that you or I do in an academic setting or just the sheer volume of patients [they see]. What do you think about starting everybody at 20 mg and going down vs maybe a more nuanced approach, understanding it hasn’t been well studied?

Hans Hammers, MD, PhD: I really like what Monty just said. We need preparation. No. 1 is if you have somebody in your clinic and their blood pressure is already 150/91 mmHg, if your blood pressure isn’t already primarily well controlled, it’s going to go sky high on lenvatinib 20 mg. Make sure the patient is already set up to do well with 1 of the earliest adverse effects that they would call you up with, which is hypertension. With the two 10-mg tablets, that dosing form is not ideal. I wish there would have been a 10-4-4-2-mg option, so we have patients who quickly could go to a lower dose and you don’t have to reorder the lenvatinib.

To be honest, I typically pursue a strategy in which I’d rather dose interrupt than dose reduce. I’d rather work with interruption schedules. It’s not uncommon for a patient to be on it for 2 weeks and then take a few days off once the adverse effects come. I give my patients a lot of autonomy. As they’re taking it, I try to maximize the effects on the receptors and then build in shorter breaks. That tends to work reasonably well because we have a shorter half-life with that agent. That’s roughly the way I approach it.

It’s also important to initially follow up these patients early. That becomes a bit harder in the community setting, with the understanding that I’m not good at predicting who’s going to do well on 20 mg and not. You’re sometimes surprised who tolerates it well and who falls apart on these agents. Actually, across the different TKIs, I’m unable to predict. Even a 400-pound Texan man can be hurt hard by even lower doses.

You will find out fairly early on, within a month or 2 at the latest, roughly what the schedule and dose should be. It’s an initial investment. Talking to the patient about the expectations and how to manage them, contact us, or work with a nurse practitioner or nurses to address some of these adverse effects and management is absolutely key. It’s patient education, it’s preparation, identifying problems early on. Also, tell the patient if they feel really bad and their blood pressure is out of control, to stop the pill. Let us know, and we’ll develop a strategy based on it.

Brian Rini, MD: I agree with all those points. I often tell patients it’s going to take a couple of months for us to figure this out. We dose everybody the same, in essence. We’d all agree that’s not going to be the right strategy. We don’t have a more nuanced way of doing it, so all those points you made are good ones.

Transcript edited for clarity.

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