Treatment Approaches for Relapsed/Refractory mRCC

Martin H. Voss, MD: Let’s talk a little about patients who have metastatic disease and were previously treated. We spent a great deal of time helping our audience understand options in the first-line space. We’ve seen that most of these are now combinatorial approaches. It’s relevant to keep in mind that the majority of patients will ultimately progress on such therapy. The question is what to do next. There’s a long list of drugs that are approved in this space, but there’s the difficulty we’re facing in the data that led to their approval. For the most part, they predate the data of approving our first-line combinations. Amishi, maybe you can speak a little to that point and the conundrum it poses for us in our clinics.

Amishi Y. Shah, MD: As you pointed out, we’ve had an embarrassment of riches in frontline trials in the recent years. I guess the trillion-dollar question for all of us is, what do we do? How do we optimally sequence therapy? We know that we have excellent efficacy data on TKIs [tyrosine kinase inhibitors], such as cabozantinib and lenvatinib-everolimus, in later-line settings. These are dirtier TKIs. We often see a response, even in patients who maybe progress prior to I/O [immuno-oncology]. But as you pointed out, this work was done primarily before the era of frontline immunotherapy-based combination strategy.

Now we’re going to discuss several important trials that have come out in later-line settings. We had a few updates at ASCO [American Society of Clinical Oncology Annual Meeting] on this note. The CANTATA trial was reported as negative. The CANTATA trial compared CB-839, or telaglenastat, plus cabozantinib vs cabozantinib alone. This was a negative trial. The combination didn’t improve outcomes over cabozantinib alone. So far, single-agent cabozantinib would still be the go-to in the later-line setting for a patient who hasn’t received it in the front line.

Martin H. Voss, MD: Amishi, since you mentioned CANTATA, how did cabozantinib perform in this more contemporary population of patients previously treated for the most part with immuno-oncology drugs?

Amishi Y. Shah, MD: That’s a very good question. It’s still an active agent. What we’ve seen with cabozantinib data in METEOR, CABOSUN, and CheckMate 9ER all held true in terms of its overall efficacy as a drug. The hope was that adding this novel mechanism with telaglenastat would improve it, but it really didn’t have the synergy we were hoping for.

Martin H. Voss, MD: What about tivozanib? Here’s a drug that recently hit the market based on a phase 3 randomized trial that was also conducted, at least in part, in patients who were treated more recently and had access to immuno-oncology drugs. It wasn’t all of them, but at least some of them. Can you speak to those data a little?

Amishi Y. Shah, MD: Tivozanib was very recently approved. The trial that led to its approval showed a 23% response rate. As you pointed out, this was a fairly heavily pretreated population. Most patients were in second-, third-, and fourth-line therapy. Now it’s another TKI in our tool kit. It’s the exact same conundrum I mentioned a moment ago in the sense that many of these patients were not necessarily ones who had cabozantinib or lenvatinib in the front line. As a TKI, we know it hits VEGF1, VEGF2, and VEGF3. Does it overcome resistance from these dirtier TKIs in an earlier-line setting? That is to be determined. I have just started using it in my practice. I have 3 people on it, so I’m eagerly waiting to see how they do as well. It’s a nice tool, but it’s not studied in the exact scenario we’re facing.

Martin H. Voss, MD: Same here. We’re all interested to try it out a little more. Bob, maybe you can speak to this. The combination of lenvatinib-everolimus has been on the market for several years. I wonder if the whole extravaganza and common notion that combinations in the first-line are the way to go has persuaded treating oncologists to be more open to using a combination in pretreated patients also. Do you see the use of lenvatinib-everolimus on the rise, or do you see it fading away following the CLEAR data?

Robert S. Alter, MD: That’s a great question. When we talk about sequencing, we’re always stuck with the conundrum of second line or third line being all based on what they receive first line. Now that we’ve gone away from single-agent TKIs and use I/O as a second-line therapy, and that goes back 3 or 4 years already, when we started making I/O–I/O as a first-line therapy, it became very easy to know that second-line therapy would be a TKI. But what happens now that you’ve exhausted 2 grades’ mechanisms in first-line therapy and are stuck with healthier patients who are in second-line therapy? If you asked 10 oncologists, you’d probably have 20 answers in regard to how they would treat their patients.

They base it on many factors. First, it’s the patients. You have to know the patient’s functional performance status. You have to know how much volume of disease they have. You have to know how their tolerance was to first-line therapy and how durable that therapy was. Can you reduce that therapy as a second- or third-line therapy in combination, almost like what PDIGREE has? Can you add a TKI to a patient on I/O as a second-line therapy because they don’t have enough of a robust response? If we go by the package insert, lenvatinib-everolimus is a second-line TKI therapy, so if it comes down to patients being treated with an I/O-TKI, whether it’s lenvatinib-pembrolizumab or cabozantinib-nivolumab, lenvatinib-everolimus offers an excellent option. You have to recognize that you’re adding a back-to-back TKI, which some patients have difficult intolerance to.

In the community, we have cost issues. Patients sometimes cannot handle the financial aspect of the therapy as a first-line TKI. Suddenly, you’re hitting them with a dual back-to-back financial toxicity as well. We have used lenvatinib-everolimus in clinic for the last 2 years, since the first study came out. It’s quite impressive how it attacks the tumor in very aggressive fashion. The numbers in regard to PFS [progression-free survival] and response rate were true, which was not a surprise when CLEAR came out, but it does add some toxicity. The tolerance has to be similar to what we see with CLEAR. The dosage may be adjusted a little with the lenvatinib. But for the most part, I’m quite impressed with how patients not only tolerate the therapy, but how effective the therapies are.

There’s this thought, “What is lenvatinib?” when it comes down to all the other TKIs we have. When people start using lenvatinib-pembrolizumab, they’re going to start getting a little more familiar with Lenvima and they’re going to start using lenvatinib-everolimus. I’ve had patients come to me with very bad, aggressive disease, second- and third-line, and lenvatinib-everolimus has been an amazing relief. It’s almost as if you kept your best relief pitcher in the bullpen and you just bring it out. These patients can tolerate the therapy well. You have to recognize issues when it comes to second- and third-line therapies. Now is the summertime, so people can travel a lot, but in the wintertime, people canceled pills. Oral therapies can sometimes be well tolerated, so lenvatinib-everolimus offers that as well.

Ultimately it comes down to sequencing in our head. I don’t think we have to think about third-line therapy when we think about our first-line therapy. When we’re thinking about second- and third-line therapy, we have to think about whether these patients are going to be treated for fourth- and fifth-line therapy. The IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] had that most patients don’t get second- or third-line therapies. In the clinic these days, our patients are going much deeper. Lenvatinib-everolimus is going to play an active role for our patients in the second and third lines depending on what they receive first line.

Transcript Edited for Clarity