Eric Jonasch, MD: We have the data that point to this. We have nivolumab vs everolimus. The primary [focus] of this study was overall survival, and the objective response rate was 25%, and PFS [progression-free survival] was 4.6 months. We had the cabozantinib-vs-everolimus METEOR study, in which objective response rate for cabozantinib was 17% and PFS was 7.4 months. Lenvatinib plus everolimus vs lenvatinib or everolimus was a small study, which wasn’t designed to be a registrational study but was so good that it ended up becoming 1. These are the investigator-reviewed data. You saw a PFS of 14.6 months for the experimental arm. Those are reasonable numbers. An overall survival at 25, 21.4, and 25.5 months, and these were all statistically significant. But as I said, these are data that were not generated with individuals who progressed on 1 of these I/O [immuno-oncology]–TKI [tyrosine kinase inhibitor] and I/O–I/O combinations.

Robert Motzer, MD: In terms of the patients who are progressing, like this 1 on pembrolizumab plus axitinib or pembrolizumab plus lenvatinib, or nivolumab plus cabozantinib, what do you offer your patients? Let’s take pembrolizumab plus axitinib and this patient who progressed on that. Tom, what would you offer this patient as a second-line therapy outside a clinical trial?

Tom Hutson, DO, PharmD: It would be definitely cabozantinib. That would be my second line, and I can even go on a limb and say my third line is lenvatinib-everolimus.

Robert Motzer, MD: OK. Bradley?

Bradley McGregor, MD: I agree 100%, and if this patient progresses on a non-cabozantinib regimen in the front line, I’m going to use cabozantinib my second line and then lenvatinib-everolimus as my third-line option.

Robert Motzer, MD: Eric, what would be your go-to program for this patient?

Eric Jonasch, MD: I agree with my colleagues. Cabozantinib would be a great choice.

Robert Motzer, MD: Is there a role for continued I/O therapy in these patients after a progression on a first-line I/O program? In terms of the patient who progresses on, say, nivolumab plus ipilimumab, [would you use] standard-management TKI alone? Would you consider giving that person cabozantinib alone or cabozantinib plus nivolumab? What’s your take on that, Eric?

Eric Jonasch, MD: We do have some data. There are phase 2 data that point to the fact that, for example, lenvatinib and pembrolizumab after patients progress on an I/O-containing regimen in a small study that your group was involved in, where there was a high objective response rate of greater than 50% and a progression-free survival of around 12 months. We have some data that speak to this, but these are not level 1 data. Bob, intellectually, it doesn’t make sense to discontinue a PD-1 blocking agent. Why would PD-1 blocking agents suddenly not remain important in the second- and subsequent-line settings? But we just don’t have the data to conclusively say that we should. I want to see those data, and there are a number of clinical trials underway that are testing the hypothesis that an I/O–TKI vs a TKI in the second-line setting is a superior approach. We don’t have those data yet.

Robert Motzer, MD: Let’s follow up with this patient. This patient was given lenvatinib plus everolimus as a treatment. In terms of lenvatinib-everolimus, my colleagues have mentioned that that probably would be a third line in their practice a third line. What’s been your experience, Bradley, with giving lenvatinib-everolimus in this setting a third-line therapy? Is it well tolerated? Is it effective?

Bradley McGregor, MD: In the majority of patients, they tolerate it. There’s a minority of patients who I start this on, and they don’t feel well. Despite dose reductions, it’s not something they can get along with. But the majority of patients tolerate this well because you’re starting with a lower dose of both. Everolimus is 5 mg daily. Lenvatinib monotherapy is 24 mg—you’re starting at 18 mg, go down to 14 mg, then down to 10 mg. Similar to what we talked about, this can be an active regimen. It’s a matter of finding that right dose. Data by Monty [Sumanta Pal] has shown that starting with an 18-mg dose is the best, then do dose reductions as necessary for toxicity, as opposed to trying to start low and going up if you’re doing OK.

I’ve had patients who may have had...response to nivolumab-ipilimumab-cabozantinib, and then you get lenvatinib-everolimus and it can work well. It’s a highly active regimen. I like the idea that you’re attacking on multiple mechanisms of action—the mTOR inhibition and the VEGF [vascular endothelial growth factor] —and hope for some synergy or added depth between those 2 options. It’s a highly active regimen. Counsel the patients that there are risks for adverse effects, and it’s going to be important that you stay in constant communication, especially that first month to find that optimal dosing strategy for them.

Robert Motzer, MD: That’s great. Have you seen responses with lenvatinib-everolimus in the third line? Is it more or less stable disease for a time period?

Bradley McGregor, MD: I’ve seen great responses. I’ve seen responses on the first scan. We get a scan at 8 weeks, and they’re seeing over 30% shrinkage.

Robert Motzer, MD: Oh, wow.

Bradley McGregor, MD: I’ve seen activity with lenvatinib-everolimus in later-line therapy.

Robert Motzer, MD: Tom, what’s been your experience with efficacy for lenvatinib-everolimus, either in second- or in third-line therapy?

Tom Hutson, DO, PharmD: I echo what Brad said. It’s definitely a strong agent. The nuance of whether you give it second or third to me doesn’t matter. Both agents are excellent salvage therapies. Also, I agree with Brad that you can see differential benefits. Someone can progress, for instance, through cabozantinib and have this profound benefit with lenvatinib-everolimus, and I’ve had several patients who have just done super well and had meaningful life longevity with their disease.

Transcript edited for clarity.