ASCO GU丨龚侃教授&Eric Jonasch教授共话肾癌相关治疗新策略与展望（下篇）

That looks like they're beginning to potentially cause neurological problems or pancreatic neuroendocrine tumors that are approaching three centimeters in size. And in general, if we have a patient that has only one lesion, for example, one spot in the kidney, where an intervention with an ablation or a surgery would allow them to then have a long period of time where they would not need additional interventions, we would not offer Belzutifan to them.

We typically are offering Belzutifan to patients who have multiple lesions that look like they're going to cause problems and would result in them having multiple surgeries. So we start Belzutifan on those individuals, and we then follow them for the toxicities.

The major toxicities include anemia, and the reason they get anemia is because erythropoietin (EPO) is a HIF-2α client gene. So we're basically knocking down transcription of EPO. We, in my practice, typically are using erythropoietin-stimulating agents to bring up the hemoglobin levels.

The second major toxicity is hypoxia, which we don’t see very often in patients with VHL disease when they’re younger, but we do see it in older VHL disease patients and also in patients with advanced kidney cancer.

There, what we do is we will follow. We ask every patient to get a pulse oximeter, we have them watch their oxygen levels. If it goes below 90%, we have them hold the drug, we wait till it goes above 92%, and then have them lower the dose.

The third side effect is fatigue, and that is something that we manage usually with dose reduction.

Yeah, so the approval of Belzutifan in advanced renal cell carcinoma clearly is a great advance for patients with renal cell carcinoma.

This study looked at individuals who had received prior therapy, either with an IO agent plus a TKI. They had to have received both, and the median number of treatments that the patients had received was three.

What we saw with that study was the objective response rate was around 23%. But the other thing that we did see was that the progressive disease as best response was 34%. So clearly, some people are benefiting, but others not.

If patients responded, their responses lasted close to two years, and the treatment is very well tolerated.

So I see the future for Belzutifan in advanced renal cell carcinoma as being a monotherapy in individuals who have received prior treatments.

But the big question is whether or not Belzutifan should be combined with other therapies in earlier lines of treatment.

We have data from LITESPARK-003 that shows that in combination with cabozantinib, there’s an objective response rate of around 70% and a progression-free survival of 30 months in a predominantly favorable-risk population.

So maybe combination with cabozantinib is a good idea.

We have a number of other studies combining Belzutifan with IO therapies and IO/TKIs, and we don’t have information on those yet.

For example, there’s also a study of Belzutifan plus lenvatinib compared to cabozantinib, that’s LITESPARK-011, and we’re waiting for those data.

We do have a few data on Belzutifan with IO therapy. There are the KEYMAKER studies that are being run right now. Very small numbers, but they show that Belzutifan together with immune therapy does not seem to have quite the same progression-free survival as Belzutifan with TKI.

So maybe there is less synergy or additivity between Belzutifan plus immune therapy compared to TKI.

I think we need to keep on working very hard on understanding how to use this drug. It’s clearly helpful, and which combinations are going to be best and in which disease state to use, we will find out in the next few years.