Emerging Therapies for Relapsed/Refractory mRCC

Martin H. Voss, MD: It’s much easier for all of us to leave the real-world oncology decision space with a lack of data and think a little about trials that are coming and the data we might be excited about. There’s nothing easier than to talk about trials that we don’t have the data for. We can just talk to the mechanism of action and how interested we are in these new strategies.

In pretreated patients, there’s an endless list of strategies being explored, especially in the very early stages of drug development. If we were to touch base upon some of them, we need to talk a little about HIF inhibitors that entered the space in pretreated patients and are now also starting to emerge in the front line. Amishi, maybe you can talk a little about the HIF2 alpha inhibitor data, your thoughts regarding how that data looks, and where it might fit the trials that are coming.

Amishi Y. Shah, MD: Absolutely. Belzutifan HIF2 inhibition has been a very interesting drug to follow over the last couple of meetings. We have data for it specifically in patients with renal cell, which is a rare situation. Those are very impressive data in that patient population. We now have data looking at later-line patients who have failed multiple prior TKIs [tyrosine kinase inhibitor], yet we’re seeing responses that are more proximal in the pathway activity. Overall, it’s a relatively well-tolerated drug. Major areas of note are you need to follow a patient’s hemoglobin very closely because this drug does cause anemia, as well as some events with hypoxia. It’s something to monitor very closely.

Belzutifan is moving into a lot of combination strategies. There’s an ongoing cabozantinib-plus-belzutifan trial as well as some other combination strategies. This will be an important mechanism that comes out in our field. Later line is probably where it would be most helpful, as it stands. As we talk about sequencing, I wanted to go back to 1 point that Tom made about whether we continue I/O [immuno-oncology]. We don’t have a lot of randomized trials, but there are a few interesting pieces of information to keep in mind as we go forward. We have 3 trials, with TITAN, OMNIVORE, and HCRN GU16-260, that showed that late-line addition of ipilimumab after progression on nivolumab doesn’t add much robust benefit. There’s a chance to get ipilimumab in early. It doesn’t seem to do much later in the disease course, so maybe early modification is key.

The other interesting data that we have are with lenvatinib-pembrolizumab in I/O-pretreated patients. These were patients who had frontline I/O therapy—somewhat dealer’s choice: nivolumab-ipilimumab, axitinib-pembrolizumab, cabozantinib-nivolumab—and then on progression went on to lenvatinib and pembrolizumab. There were some really robust responses with that combination, higher than would be expected to be driven by lenvatinib alone. To me, the jury is still out on this question. There may be something going forward to keeping your immune checkpoint inhibition on board as you cycle through different TKIs. I completely agree with Tom’s point that giving the TKI well and managing toxicity is an important key in all this.

Transcript Edited for Clarity