This transcript has been edited for clarity.
Sumanta Pal, MD: Hi. My name is Monty Pal. Welcome to InDiscussion. I'm a medical oncologist at the City of Hope Comprehensive Cancer Center, focused on kidney cancer and other genitourinary (GU) malignancies. I'm really delighted to have here today Dr. Martin Voss, from the Memorial Sloan Kettering Cancer Center, who is also an expert in renal cell carcinoma. Martin, welcome.
Martin H. Voss, MD: Hi, Monty, and thanks for the invite.
Pal: Absolutely. You're probably well known to this audience, but if you could just give us a little bit of background … I'm particularly curious about how you got into the field of kidney cancer specifically.
Voss: Sure. As you said, I'm a GU medical oncologist here in New York at Memorial Sloan Kettering Cancer Center. I focus on kidney cancer. My clinical practice is primarily patients with advanced renal cell cancers [RCC]. And my research really revolves around drug development and biomarker discovery, an exploration into biology, epidemiology, and so forth, in this disease. I have been in the kidney cancer space now for over 10 years and started to work in RCC doing clinical research as a clinical research fellow here at Sloan Kettering. I had traveled through the various clinics of solid tumor malignancies as a fellow. During our first year, we get to dip our toes into just about any disease and, interestingly, I had actually not done a single kidney cancer clinic when I decided to work in RCC. At the time, which is a long time ago in the RCC perspective, I became very interested in RCC because targeted therapies were already the lay of the land for renal cell cancer, whereas they really weren't for most other diseases. I was very intrigued by that. And I thought it was so interesting that there was this cancer that had been known to be refractory to just about any cytotoxic chemotherapy regimen. Fifteen to 20 years ago, RCC patients used to be very prominently featured in any phase 1 clinical trial, because there were so few options for these patients. It was a very opportune time because VEGF [vascular endothelial growth factor]-targeted agents and mTOR [mammalian target of rapamycin] inhibitors had been discovered to be effective in this disease based on understanding the biology, which I thought was very interesting. I became interested in RCC because of that and sought out a research opportunity then.
Pal: It is a pretty amazing evolution in the field and, I have to tell you, I got into kidney cancer for a lot of the same reasons that you did, and it's just fascinating to see how things have evolved since then. The field has changed so quickly. We started probably at the time of the advent of targeted treatments for the field, and now it's gone on to doublet therapies in the front-line setting. We've actually done a podcast here at Medscape focused on front-line treatments for renal cell carcinoma. Now it entails combinations of immunotherapy or VEGF-targeted therapy with immunotherapy. And it leaves open the space of second- and third-line treatments for RCC. Can you give us the lay of the land in terms of how we should be approaching that nowadays?
Voss: I think the best way to understand where we're at is with a bit of a historical perspective. You and I both said so much happened several years ago, and targeted therapy took us from a difficult-to-treat disease to something that was obviously very treatable. If we go back a couple of years ago, prior to the advent of immunotherapy, we had things squared away pretty systematically and you would start patients on therapy in the first line, typically with a VEGF-targeted TKI [tyrosine kinase inhibitor]. Once patients progressed on that and you had to treat a patient in the second-line space, we knew which drugs were effective in TKI pre-exposed patients due to the registration studies that were done then. It had become quite apparent that one could sequence kinase inhibitors, TKI after TKI, and some of the drugs that are still FDA labeled in that space got their first registration during that time. For instance, sunitinib and pazopanib used to be standard first-line drugs, and medications like axitinib or cabozantinib at the time were developed as second-line options subsequent to disease progression on a first-line TKI. And those labels still exist. Now what did happen was that over the last five years or so, the front line changed and we now, as you mentioned, are commonly using combinations in the first line, IO [immunotherapy]/TKI combinations like axitinib/pembrolizumab or lenvatinib/pembrolizumab, or double checkpoint inhibitors like ipi/nivo [ipilimumab/nivolumab]. Now we are faced with the fact that the second-line options that have been approved for many years are still here for us to use. But the data that got them approved predates the data that we have in the first line, right? We are learning now how well these perform after patients are treated with doublets upfront.
Pal: That makes perfect sense and I know it's hard to do, but can you summarize the experience using some of these TKIs in the second-line setting post doublets?
Voss: We learned first that all of the TKIs that we used to commonly apply in the second line are still good, effective options. And that includes medications that we commonly integrate into doublet therapy. For instance, two commonly used second-line TKI options are axitinib and cabozantinib. Axitinib was originally FDA approved all the way back in 2011 based on the AXIS trial. Cabozantinib was FDA approved in 2015 based on the METEOR study. And since then, we commonly use IO/TKI combinations in the front line. So, if you treat someone upfront with axitinib/pembrolizumab, in the second line you may choose a different TKI, like cabozantinib. Or if you've treated someone upfront with cabozantinib/nivolumab, then you might seek out a different TKI in the second line such as axitinib, so we can swap things around. Retrospective data suggest that this is effective and all of us have learned that we can do this. And there's a few prospective pieces that are now helping us with some data in that space. I think one of the most commonly used second-line drugs is cabozantinib. More recently, we've learned how it performs in the current era, specifically after the use of checkpoint inhibitors. So there's a study called CANTATA, a randomized study that was recently presented at ASCO [American Society of Clinical Oncology] 2021. Nizar Tannir presented that data; CANTATA was a randomized trial that randomized patients to receive standard cabozantinib [cabo] in the second line versus cabozantinib plus a new drug called telaglenastat, that's a glutaminase inhibitor. And all patients that went on the CANTATA study had to have had one or two prior lines of therapy and, because it was conducted fairly recently, a good proportion of these patients, about 60% of them, had been checkpoint inhibitor pre-exposed. So now we have a data set of patients who are treated with more or less current regimens. And then after they progressed, they go on the CANTATA study and are randomized. Now CANTATA happened to be a negative study, so the addition of that new medication did not add to the efficacy of cabo. But what it did provide was current data on how cabo performs after checkpoint inhibitor–based therapy. The response rate was somewhere in the range of 25%, and the progression-free survival (median PFS) in these patients — again, second- and third-line patients — was about 9 months. So, it's what one would have anticipated, but it's super helpful to us as we try to understand how our patients will do, to choose drugs, and also to plan new efforts to know how these drugs currently perform in the second line.
Pal: I guess there are some other new players in this refractory space, drugs like tivozanib. Can you share with us where you sequence that or where you find it to be most useful clinically?
Voss: Tivozanib is the new kid on the block, at least in the U.S. It's a drug that was just FDA approved last year. It's a VEGF-directed TKI that has a very narrow kinome, so it mostly targets VEGF receptor 2. It was studied and approved based on a phase 3 study called TIVO-3. And I know you were very involved in its development. TIVO-3 was published in 2019, and it was a study that randomized patients who had had two or three prior lines of therapy to receive either tivozanib, this new TKI, or sorafenib, an older medication that's been used for RCC in the past. The primary endpoint was PFS and there was benefit to the new drug. The investigational arm had a median PFS of just under 6 months versus just under 4 months for sorafenib. That met the primary endpoint and the drug got FDA approval. A feature that's nice about tivozanib is it tends to be well tolerated by patients and it did get its FDA label in March of last year, specifically in patients with two or more prior lines of therapy, which is new for us. It's known as the first drug that's specifically developed and approved for heavily pretreated patients. And then secondly, because of when the TIVO-3 study was performed, about a quarter of the patients that went on that trial were checkpoint inhibitor exposed. So again, there is comparatively applicable data in terms of how current the patient population was and how we can apply it. I do use a lot of tivozanib these days. I tend to use it more in more heavily pretreated patients. A lot of my third- or fourth-line patients go on tivozanib, and I do find it a very useful addition to our toolkit.
Pal: It's really interesting. We've touched on a lot of the agents that we tend to use in the refractory setting. We talked about cabo, we talked about axitinib, you've now just mentioned tivozanib. How about lenvatinib and everolimus? Is that something that you're using in your armamentarium much? And if so, what is your dosing strategy with it?
Voss: That's a combination of a VEGF TKI, lenvatinib, together with an oral mTOR inhibitor, everolimus. And it has been on the maps since about 2015. It was FDA approved based on a phase 2 randomized study that compared lenvatinib versus everolimus versus the combination, so a three-arm trial testing each drug individually versus a combination. And again, this was done prior to us heavily depending on checkpoint inhibition. In that trial, most patients had one TKI previously. And, essentially, what was seen was that the TKI lenvatinib was more effective than the mTOR inhibitor everolimus, but the most effective was the combination of the two, with a high response rate in pretreated patients of about 40% and a very low failure rate, which I always emphasize for that regimen. Less than 10% on that arm had primary failure. It does come at a price. You can imagine when giving two medications together, there are overlapping toxicities, specifically in the GI tract, which can be difficult. And then you brought up that point … dose modifications become more challenging when you're giving two oral medications at the same time. So, one has to figure out which drug is causing the stomatitis, which drug is causing the rash, and which drug is causing the diarrhea, all of which is manageable but it's work. So, I use the medication in patients with aggressive disease that need aggressive therapy to regain control of the situation. That's probably the most commonly used scenario in my clinic.
Pal: That's interesting. I tend to set it in that same setting in my practice as well. You've done a great job of outlining for us comprehensively the second- and third-line landscape for renal cell. But clearly there are patients who need more, and I think maybe the most exciting part of our conversation is going to be this next one. Martin, you're really at the forefront of a lot of early phase studies. What's on the horizon for renal cell? What do you think we might look forward to in the years to come?
Voss: I think conceptually the biggest question right now is whether we can go from combination to combination. In the front line, a lot of efforts in recent years have demonstrated that comparing a two-drug combination to single-agent therapy benefits the majority of patients. We have learned that two is better than one in the front line for many patients. And the de facto standard in the front line is doublet therapy for the majority of RCC patients. Subsequent to that, the textbook would say most patients are to be treated with monotherapy; that's the FDA label we have currently. And I think the field is interested to know whether we can bring that paradigm of "two is better than one" into the next line of therapy also. Should we, after a patient fails a doublet, consider another doublet and try to get at the cancer from two different angles? There are a couple of studies that are exploring this already, including some phase 3 trials that are ongoing.
Pal: Maybe you can outline some of those phase 3 studies for us. I was quite curious about their design, and I think that might be helpful for the audience here.
Voss: There is a study called CONTACT-03 that, at this point, has fully accrued its goal of bringing on about 500 patients. CONTACT-03 is a trial that enrolled patients previously exposed to progressive checkpoint inhibitor therapies plus or minus other therapies, with a maximum of two lines of therapy. And patients were randomized to receive either standard cabozantinib or a combination of cabozantinib plus atezolizumab, which is a PD-L1 [programmed death-ligand 1] inhibitor. Here, most patients, one would expect, would have received doublet therapy in the front line. And now we are trying to see whether two are better than one: cabo alone versus cabo plus PD-L1 inhibition. The core primary endpoints are overall survival and progression-free survival. And that study is fully accrued. There's a very similar trial called the TiNivo study, which goes back again to one of the drugs we've discussed previously, tivozanib. That's a smaller trial of about 300 plus patients, again with one or two prior lines of therapy in the metastatic setting. All patients must be checkpoint inhibitor pretreated, which in the United States would mean that most of them would have had a doublet before. Patients are now randomized to receive either tivozanib alone, which we discussed previously, or the combination of tivozanib plus nivolumab, so PD-1 [programmed death-1] inhibition plus tivo. The primary endpoint here is progression-free survival. And that study is currently still enrolling. So, these two trials, you can see, are conceptually very similar and both getting to the same point: they are registration trials that are challenging the current standard of care.
Pal: We see this a lot in clinical practice … patients getting second-line, third-line continuation of their immune checkpoint inhibitors. And I've always wondered about the utility of that. I'm hoping these studies add a little evidence base to that approach, if at all. I guess what I wanted to close on are the cutting-edge treatments that might be hitting the RCC clinics within the next 3 or 4 years or so. Any perspectives on that? Drugs that you're excited about that might ultimately translate in the RCC clinic?
Voss: I think there are lots of studies that are exploring novel mechanisms of action, and some of them are opening entirely new fields to kidney cancer patients. I do think there's an unprecedented amount of opportunity here for patients and treating physicians. There are so many things that we could talk about. I am very excited about cellular therapies. Reprogrammed T cells, which are being explored for kidney cancer, CAR [chimeric antigen receptor] T-cell trials, with both off-the-shelf products and patient-derived samples that are being engineered in the lab before they are re-infused. And while we have not seen data yet, it is exciting to see that some of these studies are open. I know you are having some of these efforts open at City of Hope and so are we, here at MSK. There are some novel immune therapies that are going beyond the simple targeting of PD1, PD-L1, and CTLA-4 [cytotoxic T lymphocyte-associated antigen], that we have tested in various reiterations, either exploring ways to target several of these at the same time, so there are bispecific antibodies out there that are trying to block signaling of PD-1 and CTLA-4 through the same molecule and on the same cells. And then there are so-called T-cell engagers, which seek out targets expressed on the surface of kidney cancer cells and use them as anchor points to redirect an immune response toward those cells. There are medications that are binding the kidney cancer cells and a T cell at the same time to lead to a localized immune effect. I think all of these are tremendously exciting because they are so different from what we've done successfully up until now. It's just intriguing to me to think of new ways to get at the cancer, because my hope is that we might prove it is effective in even heavily pretreated patients.
Pal: I couldn't agree with you more. Think about the different approaches we have now in the clinic. They're really divided in these two buckets of VEGF inhibitors and checkpoint inhibitors. Maybe we'll have drugs like belzutifan in the clinic in the relatively near future. But with all these other agents, I definitely feel that the horizon is just jam-packed with possibilities. Martin, before we close out, I wanted to get your perspective. You're a guy who I feel has been just amazingly successful as an RCC investigator. And you're at a place where you have tons of aspiring fellows hoping to get into the field. Certainly, we have a similar batch of really outstanding candidates at City of Hope and at other academic centers. What's your advice to folks getting into the field now in 2022?
Voss: I do think, speaking specifically about the RCC field, there are a lot of ways to get engaged. It's easy for you and I to say that, because we're obviously in a place where we have broad exposure and opportunity. But I do think that the kidney cancer field is very friendly and open to new faces. There are conferences that are specifically geared toward kidney cancer investigations, and some of these are smaller, and so, the poster sessions are smaller. It's easier to interact one on one. The Kidney Cancer Association has an annual symposium in the U.S. and there is one that they lead in Europe also, which I think is a wonderful venue to learn about kidney cancer but also to meet people. And typically, it leaves room for junior investigators on the podium, which is not always the case at ASCO, ESMO [European Society for Medical Oncology], ASCO GU, and so forth. For the more laboratory science–inclined investigators who have an interest in kidney, there is the KCRS meeting. That is a younger meeting, now also annual, and again a small, tight-knit corps of investigators, with lots of room for young folks to showcase their work but also to learn about the opportunities there. So, these are meetings that focus on kidney cancer, typically 2-day events. And given what we've seen over the last 2 or 3 years, a lot of these have hybrid opportunities to participate and learn about science.
Pal: I love that great idea. We actually haven't highlighted some of those disease-specific meetings in kidney cancer, but they really do offer outstanding opportunities for junior faculty. Martin, thank you so much. I really enjoyed having you on the program today. And to our audience, thank you for joining us today for Medscape InDiscussion.
Resources
Renal Cell Carcinoma Treatment & Management
Cabozantinib Versus Everolimus in Advanced Renal-Cell Carcinoma
FDA Approves Tivozanib for Relapsed or Refractory Advanced Renal Cell Carcinoma
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Cite this: Second-Line Treatment of Renal Cell Carcinoma - Medscape - Jan 05, 2023.
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