Robert Motzer, MD: So, I think in terms of with the TKI-IO combinations, there's really three to choose from, lenvatinib, pembrolizumab, cabozantinib, nivolumab, and axitinib + pembrolizumab. So, Dr Ornstein, how do you pick one over the other? What goes into your factor for your choice for a given patient?

Moshe Ornstein, MD: It's a great question. I'm not convinced that there is a specific feature that can drive someone to pick one of the IO/TKI regimens versus another one. For me in general, my first decision in clinic is choosing between an IO/IO with ipilimumab-nivolumab or one of the IO/TKI regimens. And certainly, for patients who have a higher burden of disease, those with liver metastases and bone metastases patients I'm concerned that if they progress rapidly through the front line, I won't be able to salvage them with a subsequent therapy. Certainly, that patient population I treat with an IO/TKA regimen because of the higher response rates up front, there are nuanced differences between the regimens, whether it's toxicity-based, dosing-based, and just general familiarity with the TKI. The IO component is fairly similar among them, but I think what’s most important is the ability to appropriately manage the toxicities that come with the combinations as a whole. So I often talk to community physicians, and I tell them, if you're comfortable with a specific regimen, being able to tease out what's causing the diarrhea, if it's the cabozantinib or the nivolumab, what's causing the elevated LFTs, the axitinib or the pembrolizumab, understanding how to manage these patients is probably more important than which specific combination you're choosing. In my practice, I tend to lean more towards cabozantinib and nivolumab or lenvatinib and pembrolizumab simply because recognizing the cross-trial limitations, they have really high response rates and strong PFS. And again, if I'm picking one of these regimens for that upfront response, I'm going to try to pick the one that to me has a high efficacy upfront. So, I think, again, they're all appropriate to use. Learning how to manage the toxicities is the most important part of that, but I would choose the one that's most comfortable for a group practice where they might not be seeing 25 metastatic kidney cancer patients a month, but in my practice, I lean more towards cabozantinib-nivolumab or lenvatinib-pembrolizumab.

Robert Motzer, MD: And how about you, Dr Rini? How do you differentiate, who would you say you may choose? What sort of patient would you choose one versus another for?

Brian Rini, MD: I have a similar initial algorithm to Moshe. Is this patient in ipilimumab-nivolumab candidate? For me that'd be younger, healthier, limited volume, sarcomatoid changes in their tumor. There's some, albeit subset, I think good data from CheckMate 214 that the sarcomatoid population does extremely well. Response rates were 60%. CRA was something like 25%. So that histologic variant, if you will, tends to be more immune responsive, and so I would definitely treat those patients with ipilimumab-nivolumab. But for most of my patients, I would say it's a good 30, 40% of patients who walk in who just aren't going tolerate ipilimumab. I'm just worried that it's going to be too much. And then I certainly give IO/TKI to those patients, and I tend to either give axitinib + pembrolizumab or lenvatinib + pembrolizumab. Maybe not surprisingly, I was a big axitinib pembro user when it came out. cabo nivolumab data seems similar, so I didn't really switch. But lenvatinib + pembrolizumab, as we've referred to, at least ostensibly has highertumor shrinkage effects. I think there's two reasons for that. One is the dose is relatively the highest. It's 20 milligrams, which is a high dose and a tough dose for many patients, and it's also more multitargeted than axitinib. And so maybe for one or both of those reasons, you're getting higher response rates. But also, lenvatinib + pembrolizumab can have a share of toxicity. So, there'll be patients I'm just a little worried about the toxicity of lenvatinib + pembrolizumab, and so I'm happy to give them axitinib + pembrolizumab. So that's my general algorithm.

Robert Motzer, MD: Those are all good points. I don't think there's one clear winner here. And we make choices based on certainly the published data, but also the relative toxicity profile for these programs seems to be driven by the tyrosine kinase inhibitor and they all have slightly different profile, although they're the same class in terms of expressing toxicities. And so, one TKI may fit in better with comorbidities of a patient's or a patient's need than another's, and also familiarity with the regimen, making sure you use it well. Those are all extremely good points in terms of picking one program that you feel comfortable with for giving to each patient.

Moshe Ornstein, MD: I would just jump in and add two more quick points. One is I definitely find that I'm using axitinib and pembrolizumab in those patients who are a little bit older and a little bit frailer because of the short half-life of axitinib. I know that the toxicity management, at least for me and my group, is a little bit more manageable. And then the other thing I would add is that when it comes to using IO/TKIs, one of the reasons is we don't want patients to have disease progression as their best response, otherwise known as primary PD. And when you look at those primary PD numbers for both lenvatinib, pembrolizumab, and cabo nivolumab, they're single digits, around 5%. So, another reason to use one of those regimens as the patient is unlikely to progress as a primary response or as their best response to the combination upfront therapy.