Pedro Barata, MD, MSc: We talked a little bit about the cabozantinib data, and we talked a little bit about the lenvatinib and everolimus, but I'm curious because it's perhaps the newer kid on the block, and I think we could spend 2 seconds here talking a little bit about tivozanib. Dr Garmezy, can you summarize for us how the TIVO-3 data was relevant in establishing tivozanib as a solid alternative for patients who progressed previously on systemic therapies? Are you using tivozanib in clinical practice based on TIVO-3 data?

Benjamin Garmezy, MD: That's a great lead into something that many folks are less familiar with who are watching this video right now. I try to bucket the TKIs [tyrosine kinase inhibitors] about what has my patient seen and what does my patient need to see for the most benefit? I categorize them, so, cabozantinib and lenvatinib are less VEGF-selective; those are more multi-kinase targets, including TAM kinase receptors, etc. Then you look at axitinib and tivozanib, those are more VEGF-selective TKIs, which have more of a punch, more of an effect on that VEGF receptor, which can be helpful when you start thinking about, and I think you were subconsciously alluding to that when you were discussing, if your patient got pembrolizumab-lenvatinib, you might switch over to axitinib or tivozanib, right? Because it has a slightly different effect on the VEGF receptor.

With tivozanib being the new kid on the block, TIVO-3 was a study that randomized patients between tivozanib and sorafenib in the third- and fourth-line setting. So, not technically in that second-line setting, but they had to have failed at least 2 prior TKI regimens, and they could have failed 3, and then they were treated until progression. The primary analysis of PFS [progression free survival] suggested a benefit of tivozanib compared with sorafenib with median PFS of 5.6 vs 3.9 months meeting significance with a hazard ratio of 0.73. I think a more critical part of this is that these patients are very refractory. This is third- and fourth-line setting, so getting response rates is already difficult. That's not stable disease, that's response rates. Let's look at landmark PFS or long-term PFS at 36 months. We still see 12% of patients who are treated with tivozanib on this study at 36 months, and we see 7.6% at 48 months, and that's compared to 2.4% or less than 1% per sorafenib at those 2 different time points. It shows that if a patient responds to tivozanib in this refractory setting, then those patients still have a chance to do well. What are your thoughts about this data and how are you using this data in practice?

Pedro Barata, MD, MSc: Great summary. One of the things I like about TIVO-3 is that enrolled patients are treated differently. Before, it required at least 2 systemic therapies, at least 1 TKI. So some folks would argue 2 systemic therapies, and you can get them in frontline, but now you've combined an IO with a TKI. I like that some patients who were enrolled in TIVO-3 had a prior TKI-TKI, other folks got IO and TKI, others got an IO or other agents such as interference for example. I like that because it reflects what we're doing today in clinical practice. That's relevant because you have the breakdown of the efficacy data based on the prior therapies, and you see the benefit across the board favoring tivozanib vs sorafenib. That's reassuring. The other piece of the story is, and it's quite interesting that you never see the PFS curves dropping down to 0 for tivozanib as compared with sorafenib. There's something about some of the patients enrolled in the TIVO-3 that remain on tivozanib without progression for a long period of time. I think that's interesting and important.

The final point, and perhaps one of the most important points, is the quality-of-life data. The safety profile of tivozanib is favorable. High blood pressure is perhaps the most common adverse event and it's manageable. Also, some of the safety concerns that we have with TKIs as a class of therapies—hand-and-foot syndrome, diarrhea, mucositis, etc—are not as relevant with tivozanib. It's a very selective TKI with a newer agent, such as axitinib. I think those different components from the TIVO-3 provide that data and that comfort to me in clinic. I have used it quite a bit in the refractory setting in my clinics, and my experience with tivozanib is completely in line with what I've seen from TIVO-3 data, so I'll keep using it for that reason.

Benjamin Garmezy, MD: Yes, I couldn't agree more. When you start talking about the toxicity profiles of these various TKI agents, because of the VEGF selectivity, hypertension rises to the top with tivozanib and you see the hand-and-foot syndrome and some of these other things go down in how common those toxicities are. For patients who were “beat up” on a less selective TKI, and who are wary, or maybe the provider's wary of providing a subsequent TKI, tivozanib is a great point because the toxicity profile is different; it’s unique. The most recent patients that I've treated in the clinic are easily managed by having them buy a blood pressure cuff at a local pharmacy and bringing in a log to check, and [they] call in if they go outside of those parameters that I've set for them in clinic to help manage their hypertension. It’s an easy TKI to use and an attractive one as far as data in a subsequent-line setting showing a PFS advantage. As far as that other combination that I may have alluded to earlier, lenvatinib-everolimus, how do you compare a patient for that combination vs a patient for single agent tivozanib?

Pedro Barata, MD, MSc: That's a great question. We're talking about the setting where the goal of the game is to preserve the quality of life as much as possible while we control the disease. We're not looking for responses, but for patients without progressing on cancer while they're on treatment, and hopefully they'll tolerate treatment well and are able to remain on it for a long period of time. I don't know whether lenvatinib and everolimus are more or less effective than tivozanib. We don't have head-to-head studies to compare. I know that they require dose reduction often, dose modifications, sometimes holding drug, and is the reason why the FDA mandated a noninferiority study with a lower dose of lenvatinib with everolimus at a 14 vs 18 mg because it's unclear whether we need that much of a TKI in that particular setting. I try to balance quality of life with efficacy. That's why I often end up offering tivozanib to my patients.

Transcript edited for clarity.