Examining TKI Combinations in Advanced RCC - Episode 8

Using TKI/IO Combinations in Patients With mRCC

April 29, 2021
Robert J. Motzer, MD

Toni K. Choueiri, MD

Thomas E. Hutson, DO, PharmD

Both nivolumab + ipilimumab and lenvatinib + pembrolizumab TKI/IO combinations are discussed, with patient selection and appropriate use being the focus.

Toni K. Choueiri, MD: I use both in my practice. I try to keep nivolumab-ipilimumab in the approved indication: intermediate and poor. I don’t use it in good risk. I don’t think it’s a mistake, because of the CR [complete response] rate, but I do not. That’s 1. In patients with sarcomatoid histology, it is the combo that should be the best standard because of the complete responses of 19% from CheckMate 214. That’s the second 1. The third 1, in patient with tumors that are not progressing rapidly, it was significant disease volume. Although we’ve seen responses with nivolumab-ipilimumab, I lean toward VEGF–TKI [tyrosine kinase inhibitor] rather than nivolumab-ipilimumab.

Thomas E. Hutson, DO, PharmD: That’s an area where you’re going to get different opinions from all our friends and colleagues. I still think there’s an advantage. Especially with CRh [CR with partial hematologic recovery] and I/O [immuno-oncology] TKIs, the degree of shrinkage and the clinical benefit rates are excellent. You can always carve out patients that could be treated with just a single-agent TKI. I do have some of these patients in my practice, but the standard should be the default, should be I/O–TKI vs the other way around. Go into a favorable-risk situation if you made the decision to treat and not just monitor. The majority of people will make the decision to go forward with treatment that an I/O–TKI should be your default. Then you can carve out from them a smaller group that may benefit with just the TKI.

For instance, patients I just saw 2 types of patients today in clinic. One was an organ transplant patient. Obviously with a favorable-risk patient, you’re going to avoid your checkpoint inhibitor. Giving a single-agent TKI is reasonable. Another group that I’m leaning on, that we have the most data in the setting, is patients whose disease is predominantly in the remaining kidney. They’ve had a renal cell. They’ve lost a kidney from that. They have 1 kidney remaining, and it has tumors. And you’re channeling them like a patient with VHL [von Hippel–Lindau], and you’re trying to be careful and preserve kidney function. But sometimes we end up having to put them on a systemic therapy with the hope of making tumors they have smaller to allow a percutaneous intervention or just to stabilize things.

I’ve had patients on a single-agent VEGF TKI, and most of us are aware of the data coming out of Houston, Texas, in the past where that was somewhat instrumental. They’ve done a lot of that work on looking at the degree of shrinkage in the tumor from the TKIs. I’m sure I/O–TKIs do that at some level too. I’m just not as familiar with that degree of shrinkage. I’ll have those patients on a single agent. But that’s the minority. The default for me, mostly is I/O–TKI. If a select group seems to be ideally suited for just a single-agent VEGF inhibitor, then I would consider using traditional sunitinib or pazopanib.

I see a role for that, especially for the follow-up, and we understand the CLEAR data better. Right now, the agent with the longest follow-up and the most attractive 1 is the durability of the response that exists with the I/O–I/O. What drives that, the ipilimumab or not, no one knows. There are triplet studies planned that add ipilimumab into an I/O–TKI regimen. It will be interesting to see the benefits. I completely agree with Toni. I usually agree with Toni on most things. But the way he unpacked that is a reasonable approach, where you are using both. You can look at the way that the patient is presenting. Do they have time? The difference is the I/O–I/O combination is going to work in less people.

The clinical benefit rate is less. Do you have a patient who can afford to have I/O–I/O not work? As the volume of disease sets, it would allow that. If you have someone on the other end of the spectrum, where you really need to have an insured a rapid response, we see the data, and we didn’t talk about it at the time to response for lenvatinib-pembrolizumab. The cabozantinib-nivolumab is probably pretty quick. You can get these really symptomatic patients under control quickly.

The other thing that we also didn’t mention is expanding understanding about stopping it. How do you go about stopping an I/O–TKI vs the I/O–I/O? Some people would say it’s a disadvantage to be on an I/O–TKI and try to stop. Other people would say it’s an advantage because you could go off the I/O or the TKI and do it that way. There’s a lot that we have to understand about these drugs. If I was predicting that CLEAR study on the CheckMate 9ER trials to continue to evolve, where there’s evidence of durability of response, the more durable those responses are, the less I’d be inclined to use an I/O–I/O in those setting. But we don’t know that yet.

This transcript was edited for clarity.