Brian I. Rini, MD

Just to summarize what we’ve said, I think we agree that, right now, an anti-PD1 IO [immuno-oncology] based doublet is standard of care. We’ve sort of talked about nuances of different TKIs [tyrosine kinase inhibitors], and dosing, and different strategies around it. Use of ipilimumab/nivolumab in select populations, and the need to use ipilimumab early. I think we had a lot of good discussion around empowering the patients, and really working with patients to make these more tolerable. To me there’s always a learning curve with a new regimen in the first several dozen patients, whether it’s a given TKI, or a doublet, or maybe triplets in the future. I think working with your team to really get comfortable with using certain regimens is important. We talked a little bit about quality of life, and some of the limitations. I think we, as a field, need to do a better job of measuring it, and measuring it accurately because I know it’s meaningful to patients.

I think the adjuvant space is really going to be interesting. I kind of assumed when the KEYNOTE study was positive, they’d all be positive. Clearly, I was wrong, and we need to see the details.... We also need to be cautious because we’re overtreating a lot of people. The benefit-risk in the adjuvant setting is very different than in the advanced setting. I think we all recognize that and have had those conversations with patients. 

Then where are we going in the future? Triplets. We’re going to see the first data soon, and there’s other trials going on. I think it’s going to generate a lot of discussion, and a lot of debate. And that’s always good. I think we always get smarter when we do that. We haven’t really even touched on novel drugs, and I think we also didn’t touch on biomarkers. But I think we’d all agree that a lot of what we talked about could be addressed with more effective biomarkers. We’ve not done a great job, as a field, of developing those. There are a lot of efforts ongoing, and hopefully when we’re sitting here in a few years we’ll be talking about, “Based on this biomarker I would give a triplet, or I would give adjuvant therapy,” that would be a much more informed discussion.

Thanks to both of you for your time, I really appreciate it. It’s been extremely informative. Thanks to our audience for watching this 

 presentation. We hope you also found it useful and informative. Thank you.

Videos

Closing out their discussion on advanced RCC, expert hematologist/oncologists offer key takeaways from their discussion and look toward future treatment evolution in the first-line setting. 

First-Line Treatment for Advanced Clear Cell RCC: Key Takeaways 

We only have about 5 minutes left. I have about 2 minutes of a summary, so that gives you 1 minute each to talk about the COSMIC-313 press release. COSMIC-313 is ipilimumab/nivolumab/cabozantinib vs ipilimumab/nivolumab. It was recently reported only by press release, the PFS [progression-free survival] was positive, the hazard ratio, if I’m remembering correctly, was 0.74, or in that range. The overall survival [OS] was not significant. It was called immature. I’m pretty sure that’s the only data that was given in that press release. But it’s at least top-level data to say there’s a PFS benefit, which may not be surprising, but no OS.

Monty, maybe we’ll start with you. I know I’m asking you to comment on a press release, but it’s important. It’s the first triple to be reported and there has been other studies ongoing. We’ve alluded to triplets in this broadcast, so what do you think?

Maybe it’s going to sound greedy, but I really want to have as many options available as possible. So even if we don’t see an OS signal, or a huge advantage, I still think that having cabozantinib/nivolumab/ipilimumab at my disposal is going to help in those situations where I really am struggling. I see that young patient, 45 years old, metastatic RCC [renal cell carcinoma], clear cell, and I think to myself, gosh. Then they’ve got really bulky, bad disease. Unfortunately, I think the 3 of us probably see these patients all the time. You just sort of think to yourself, gosh, I want to give them the response rate advantage that I get out of cabozantinib/nivolumab, but on the same note, I want to get them that tail on the curve that you potentially get with ipilimumab/nivolumab. I really want this triplet for those patients. And that’s kind of the picture that I’ve painted in my mind of who I’d offer this regimen to. I know it’s definitely not going to be for the faint of heart. My 85-year-old patient with metastatic disease is not going to be able to tolerate.

So maybe in a select subset of patients that you’ve described. Hans, what do you think?

Yeah. I 100% agree. I don’t think this will be a regimen for everyone. Already now, in the last few years, I’ve been struggling with some of these patients, where I know, I would love to give nivolumab/ipilimumab, but I’m afraid of the tumor burden. I would love to have that option for triple therapy. So I think there’s a real population there, where this could be quite useful, I hope. Coming to the OS, I think we’ve been spoiled with OS. I think they’ve been spoiled with OS. I think it will be much harder moving forward to show OS. I don’t think, for example, even the Merck MK-6482-012, which is Lenvatinib/pembrolizumab vs 2 triple therapies can count an OS benefit. And I would not fault those regimens if they don’t. I think it’s just much harder to show an OS against a very active type of backbone vs VEGF-TKI [tyrosine kinase inhibitor] monotherapy. I think that’s going to be a struggle moving forward. I do feel that we are going to be back for a while into the PFS space, and then we have to see what the long-term outcome is in other markers of utility.

I think I’m a little less bullish than you both. I don’t disagree. It’s OK if there’s just a PFS benefit, but also depends on the magnitude. Can you get that same PFS with a doublet like lenvatinib/pembrolizumab? I kind of doubt the PFS of that triplet is going to be over 23.9 months. I want good therapies as well, but that doesn’t necessarily mean we should just throw the kitchen sink at people because we’re going to hurt some people with toxicity that is potentially life threatening. So, again, we need to see the data. None of us have seen the full data, so it’s a bit premature.

But I do think we’re all, in general, bullish on triplets that can cure more patients. I happen to think those will probably be triplet immune therapy. Hans, you might agree with me on that. I think triplets, of all immune regimens, to me, make a lot more sense. I think we, as a field, would, in some ways, love to get away from TKIs. We’ve been talking about toxicity, and this and that, a lot during this session. So if we could move to reduce our TKI use, whether it’s with HIF [hypoxia inducible factor] inhibitors or all immune regimens, I think, philosophically, that’s sort of where I would put my money.

I totally agree with you. To me, the picture that’s emerging is that the TKIs really don’t synergize with immunotherapy. They’re not going to make somebody a better immunotherapy responder if they weren’t meant to be, anyway. That’s probably also the message, quite frankly, from COSMIC-313 is if you add a TKI, it’s not going to be magic. I think that’s the lesson learned from this one. Triplet therapies, improving immunotherapy, improving that backbone with agents that can truly improve the immune response, I think that’s going to be key here.

I can’t tell you how much I love these sorts of side-by-side tabular depictions you have across studies. I think it’s going to be really hard with the triplet therapy trials to do that. Only because I’m just putting myself in my investigator shoes, and thinking, gosh, it’s a very different patient that I put on CheckKMate9ER vs COSMIC-313. I’d probably be reserving COSMIC-313 for patients that are a little sicker, maybe younger, or a little bit robust. I don’t know what that means in terms of our PFS and response rate expectations. I, personally, think it's going to be very different, the composition of those trials.

Shared insight on the data from the COSMIC-313 trial and the potential for first-line triplet regimens in patients with advanced clear cell renal cell carcinoma. 

Triplet Regimens in Advanced RCC in the Frontline Setting 

I’ve got 2 other big topics to tack on in our last 5 or so minutes. Let’s say you have a patient who got adjuvant pembrolizumab and progresses. And I’m starting to see these patients in my clinic, as I’m sure you are. How are you approaching those patients? And let’s take right now the patient who would walk in the door. I saw a patient who got 6 months of adjuvant pembrolizumab, got the scan for routine restaging, and had progression. So patients are progressing on therapy. I’ve had patients progress years later, which wouldn’t be possible now. Let’s put that aside. But a patient progresses on pembrolizumab and tolerated it. Let’s say they received 6 months of treatment, for the sake of argument, and then they walk in and say, “Hey doctor, what should I do now?” Hans, why don’t you start.

That’s complicated. I think it depends on the tumor burden at the time, how it progresses. If it’s just 1 or 2 nodules, it’s a different scenario than somebody who was not—

It’s moderate. It’s not addressable by local treatment. Let’s say that.

But if it’s smaller…I understand we talked about how ipilimumab works best, I agree with you, early on. But, for example, we had both trials open, and I had a patient progress in the atezolizumab adjuvant trial who was exposed to atezolizumab. I treated them with nivolumab-ipilimumab, and he had, essentially, a very deep response. It’s now been going on for years. So it’s not that it cannot work. I think it depends on in which patient is a 10%, 15% response rate reasonable to consider up front, or not. It will not be many patients, I totally agree with you. A TKI [tyrosine kinase inhibitor] will be important. We’re now learning how important it is, or not, to continue on immune checkpoint inhibition. Some of the CONTACT-03 studies, TiNivo-2, etc., will be important to inform us in that regard. And then for some patients where you want to kind of give both, control the lesions, and then maybe alter CTLA-4 without too much risk, you can then consider triple therapy. So it really depends on that scenario.

Brian, we should have started with these questions. This is good.

I hear you saying there may be a role for salvage ipilimumab. Let’s call it salvage ipilimumab-nivolumab. In those patients [INAUDIBLE], but they certainly haven’t been exposed to ipilimumab, so that’s reasonable. But would you agree that probably single-agent TKI is the standard in those patients? It’s a very unsatisfying standard, I’ll give you that.

I agree. It’s unsatisfying. On the other hand, I don’t routinely continue an immune checkpoint if somebody progresses on it. So if somebody progresses on nivolumab-ipilimumab, I don’t continue on nivolumab, I don’t continue pembrolizumab. It makes no sense. So those patients will be in the same group, unfortunately.

Monty, what do you think? How are you treating these adjuvant pembrolizumab failures?

It’s such a tough question, Brian. But I do think there’s sort of a red zone and a green zone for further immunotherapy. That red zone for me is kind of like the scenario that you’re stating, where that patient is on adjuvant I/O [immuno-oncology] and they progress during that span of time. Hans, I may be looking at this way overly simplistically, but I view that as being a patient that has sort of exhausted their benefit from I/O. Despite examples like the one you’ve given, if your patient is on adjuvant atezolizumab followed by nivolumab-ipilimumab, I’d probably go with that sort of unsatisfying strategy that Brian suggested of using a TKI alone. I’d probably follow it with TKI monotherapy. The green zone for me, on the other hand, where I’d want to rechallenge that patient, that you kind of alluded to, Brian, where they finish up adjuvant I/O, then a year or 2 passes, then go ahead and start on double. The gray zone is everything in between. I have no idea what we should be doing there.

I was saying to a patient the other day that it’s a totally data-free zone right now, and nobody really knows what to do. I’ve been pretty much recommending single agent TKI, but I also do talk about ipilimumab-nivolumab. I think if I had a younger, healthier patient, I might lean toward that, but we’ll see. I think some of the ongoing trials like TiNivo-3 do allow patients who simply failed adjuvant pembrolizumab. Is that right, Monty?

: So, we’ll start to see trials and data that actually inform this decision, but it’s clearly going to be an emerging patient population.

Panelists identify second-line treatment options they would consider in advanced clear cell RCC if a patient progresses following first-line therapy.

Selecting Treatment for Advanced RCC in Second Line and Beyond

We have a little bit of time left. Maybe we can touch on some sort of newer topics; one would be adjuvant pembrolizumab. I have 2 questions around this. So, we know that the KeyNote data from the adjuvant pembrolizumab was fairly cleanly positive. It has a ratio for disease-free survival in the update that I believe was 0.63, if I have it right. No survival signal yet, but it’s fairly early and the hazard ratio is trending in the right direction. So fairly clean. That was the first study reported. But we’ve gotten wind, at least by press release, of some upcoming negative trials for other adjuvant immune therapies.

My questions to both of you, and I’ll start with Monty because he’s smiling, is: Do you think this is going to change people’s perception of the pembrolizumab data? The opposite happened with TKIs [tyrosine kinase inhibitors]. It was a bunch of negative trials, and then suddenly stuff tracked positive with sunitinib, which I think caught us all off guard. But it definitely colored our perception of those data, among other reasons. So here it’s kind of the opposite, where the first trial is positive, and trials 2, 3, and 4 are negative, and there’s still at least one more out there. Do you think this is going to change people’s perception? Will it change your own perception in practice?

I don’t think so. I’ll tell you why, Brian. I think we’re going to really garner some important information from the setting in which these trials were conducted and the differences in methodology. For instance, among these negative trials that you have mentioned, one of those is PROSPER, which uses a perioperative approach. Maybe the presence of negative data in PROSPER but positive data in KEYNOTE-564 tells us that perioperative therapy isn’t a reasonable strategy. Again, just by way of example I’m using PROSPER, but I think each one of the studies is going to carefully help us distill the setting in which adjuvant I/O [immuno-oncology] may not be helpful. I still think that the benefits seen in KEYNOTE-564 will stand.

First of all, I think it’s still unclear, to be honest with you, if you need to be [INAUDIBLE] immune checkpoints in the adjuvant space. That space was developed with cytotoxic chemotherapy where it was clear you could not cure anyone once you had microscopic recurrence of cancer¼breast cancer, for example. Cures in the adjuvant setting don’t mean cures in the microscopic recurrence setting. That was the primary rationale, and that’s why the space is heavily an adjuvant space. For immune checkpoints, I cure patients routinely who have overt recurrent microscopic disease. So it’s not clear yet, to be honest with you, that they cure more patients in the adjuvant setting. I think what we do is, we do expose more patients who don’t need it to therapy, and with it, to toxicity and death. So that’s something to keep in mind. Patient selection is critical in that setting, and we do cause a lot of irreversible side effects. Nobody died on that study, but we all know that, clearly, this is not an innocent drug.

The other thing with overall survival [OS] that we need to keep in mind is that this study was not perfectly designed in terms of access to subsequent immunotherapy in certain areas of the world. One-third of patients will probably never get access to immunotherapy. Versus the melanoma trial, also from Merck, Keytruda (pembrolizumab), was perfectly designed because it guaranteed everybody access to pembrolizumab if they progressed. And interestingly, with years ahead, there’s still no OS benefit. Now they use it more avidly. Why? Because recurrent melanoma is a devastating process. It’s just a very fast, devastating occurrence typically for patients with metastases widespread in the brain and everywhere else. So I think, in that disease setting, it may make more sense. But again, there is no OS benefit so far.

I would say, right now, that patients will select themselves. They’re nervous, they want to do it, I give it to them. I also tell them I don’t think you’re going to make a major mistake by just being under the microscope and being watched. And I think that is supported by the negative trials. Not as a reason against it, but as one where I think it’s clear that it’s not a no-brainer to give with adjuvant therapy. It’s a complicated discussion. We need to study the data carefully. But it’s not like, here’s the data, and now we all need to rush into the adjuvant space, and everybody should have it. That is certainly not the case, and I think the negative trials give us enough warning.

You got me, Brian. I was not going to answer that question. I was going to plead the Fifth. No matter how many times I was asked, I was going to plead the Fifth until after ESMO [European Society for Medical Oncology’s annual meeting]. Even if they asked 440 times, I was still going to plead the Fifth.

I think that was well stated. And again, in fairness, we haven’t seen all the data. There’s a whole lot of differences in detail, but I think it’s the beginning of the conversation. Certainly not the end.

Expert hematologist/oncologists consider the potential role for adjuvant immunotherapy in patients with advanced clear cell renal cell carcinoma.

Adjuvant Immunotherapy in Advanced Renal Cell Carcinoma 

Let’s turn to some patient subsets. We haven’t talked about bone metastases, brain metastases, or liver metastases. We talked a little about high-volume symptomatic [patients] and how I/O [immuno-oncology]–TKI [tyrosine kinase inhibitor] regimens are preferred from a disease-control standpoint. Let’s take bone metastases. Cabozantinib has had this halo of having more of an effect in bone. Hans, we’ll start with you this time. Do you believe it? Does a metastasis in a particular organ drive your choice of therapy, bone or otherwise?

I don’t think so, to be honest. I don’t see the data. For me, immunotherapy can work in any of these pieces. Immunotherapy for me is the most important component. If you see sclerosis and bone formation in these areas all of a sudden, it’s a very satisfying view because that means you have a nice treatment effect in these views.

The 1 advantage that cabozantinib has is the indirect effect on bone turnover. I don’t know how aggressive you guys are with bone-targeted therapy in terms of zoledronic acid—for example, bisphosphonates and others. This is obviously a widely debated topic in kidney cancer too. But the 1 advantage it has, if you will, is the suppression of bone turnover already built in. That’s 1 of the advantages it might have.

You have a higher rate of osteonecrosis of the jaw with cabozantinib than with some of the other agents, and it’s probably related to that. We all remember probably these mystery bone scans that became negative on cabozantinib in prostate cancer. If patients are worried about being on bone-targeted therapy, the advantage is you can probably have a 2 for 1.

Monty, how about you? Do you use the site of metastasis to drive your decision-making?

The earlier discussion we had around the broader questions of dosing, quality of life, etc., probably come to the fore more often. They’re going to drive that initial treatment choice. Site of metastasis rarely comes into play these days because I can use those overriding clinical factors to tease apart the different regiments. It’s hard. Right, Brian? When you tease apart the different subsets within these trials of patients with bone metastases, you see activity with all the regimens. The regimen with cabozantinib with nivolumab is good, maybe not markedly distinct from what we see from the other regimens.

Having said that, I think there are some biologically compelling reasons to consider it in that context. Years ago, Bernard Escudier’s team presented some data at ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium] about metastases expression. It actually seems as though whereas in metastases expression primary tumors are robust, you see it to an even greater extent in brain metastatic sites and bone metastatic sites. It might lend some credibility to this hypothesis that cabozantinib might have this preferential activity in patients with those metastatic sites.

I tend not to pick a regimen based on site. As you said, Monty, there are bigger considerations rather than using regimen A for bone and B for liver. It gets too confusing. I’m not sure I’d be doing anything or helping anybody with that approach.

Let me ask both of you: would you give any TKI-based regimens to untreated brain metastases? My practice is that all brain metastases would get local therapy first, usually SBRT [stereotactic body radiation therapy]. Then I put them on whatever regimen is best. But I’ve heard of others. There are data out there about certain activity in untreated brain metastases. That makes me very uncomfortable. I’m wondering what you guys think.

I always insist on primary treatment first for brain metastases. If I really feel a patient is super-symptomatic and needs to get on therapy right away, they’re getting nivolumab-ipilimumab first and their brain metastases treated simultaneously. But I always want to treat before using a TKI.

Same here, certainly. SBRT has completely changed the way we approach brain metastases. I avoid whole-brain radiation. It should never be done in patients before stereotactic radiation. It’s probably safe to use a TKI. For some of these larger trials, even with sunitinib, with a phase 3 trial or with some of the excess trials, we didn’t necessarily screen for brain metastases. If you look back, they’re probably reasonably safe. But if I know that the patient has brain metastatic disease, I absolutely use local control first and start the TKI. Sometimes the problem in the brain is this almost-profound edema that you see. A lot of patients are on the non steroids, for example. In that setting, immunotherapy isn’t going to work because there are going to be multiples of prednisone equivalents way above the limit. I tend to radiate and then use a TKI. Sometimes I start a TKI before I start immunotherapy until they come down with the steroids, and then I go in with immunotherapy.

That’s fair. Talk about whether your consideration of what you might use second line affects your frontline consideration. I tend to use a lot of cabozantinib in the second-line setting, so I don’t use a lot of cabozantinib-nivolumab up front. That’s at least 1 of the reasons. Do you think about the whole sequence of therapies up front or no? Hans, you can go first.

There was a time when I thought about it more, but we have so many pills at our disposal that that thinking is somewhat falling away. It’s much more important to make sure the initial treatment is well chosen for the patient to make sure they’re going to do well. I can see using both cabozantinib and lenvatinib in the first line without feeling guilty about it. I’m coming from the original salvage therapy thinking: I’d use up a salvage agent early on. I don’t have that feeling anymore. I’m like you. I love both agents; they’re both great. If somebody starts with cabozantinib, then I’d certainly go with lenvatinib [after] and vice versa. There are great opportunities for patients with both agents.

I don’t have a lot to add, but I still think we’re just notoriously bad at picking who those patients with primary PD are going to be. Sometimes you can try to tease that out from their clinical phenotype. If they’ve got big, raging, quickly-growing metastases, that might be that patient who’s going to quickly go on to second-line treatment. Having said that, I think it’s always best to put our best foot forward in this setting and use whatever regimen we feel is going to benefit the patient most, rather than saving stuff for later.

Focused discussion on the selection of first-line therapy for advanced clear cell renal cell carcinoma based on sites of metastasis.

First-Line Treatment in Advanced RCC: Sequencing Therapy   

Let me turn to Monty. You brought up quality of life. This is a big topic and kind of a thorny topic. We all agree that quality of life is important. We’d all agree—correct me if I’m wrong—that as you alluded to, the way we measure it is imperfect at best. My question is: how reliable are these data? For practitioners, should they be looking at this to compare regimens? I put up a table comparing response rates. You could argue that that’s not fair, but we do it anyway. With quality of life, how should we be using the data? What’s the value when you boil it down in terms of deciding on 1 regimen over another or just inherently on the quality of a given regimen? We’ll start with you, Monty, then go to Hans.

I definitely wouldn’t look at the quality-of-life data in isolation. They do add some general credibility to the story that we’re building for particular regimens. For instance, in quality of life with nivolumab-ipilimumab, without question you see the patients, particularly those who might be on extended holidays or deriving substantial benefit across these various metrics that we’re using. Intuitively, that makes sense.

As you look across, and I’ll use the comparison of lenvatinib-pembrolizumab vs cabozantinib-nivolumab, in my opinion it tells the same story as the toxicity and discontinuation data. When you look at the rates of discontinuation, dose reduction, and so forth of lenvatinib-pembrolizumab, it’s substantially higher than what you see in the context of cabozantinib-nivolumab. It aligns with the quality-of-life data, and you see this modest separation between cabozantinib-nivolumab and sunitinib. But across the metrics that have been presented—it’s what’s out there—for lenvatinib-pembrolizumab, everything is overlapping. I can’t really tease those curves apart. It tells a portion of the story that’s in sync with the remainder, so it’s something we can potentially factor in, although it’s not the be-all and end-all.

I totally agree. It’s part of the story. My personal opinion is that you need to titrate any TKI [tyrosine kinase inhibitor] that you use in any setting. The truth is, we sometimes feel 1 TKI is better tolerated than another until the patient complains about the 1 you thought is better tolerated. It varies quite a bit. I can’t predict who’s going to like which 1 better, even comparing across or looking at their treatment history.

The fair thing to say to a patient is to give us a little time, and we’ll find the right dosing schedule for you. That’s true for any agent that you use. You can adjust that, and you can find it. For some of the agents, it’s easier to find simply because you started at a lower dose. With cabozantinib-nivolumab, you start at a dose that most patients end up at anyway if you started them on 60 mg. It’s a regimen where you don’t have to work as hard to find the sweet spot vs lenvatinib, where you’re starting high. You’re starting with the goal to get things to shrink, and then you’re going to probably do a little more work to find the right dosing schedule for the patient.

I’ll reinforce something you had mentioned previously about dose interruption. Patients are reluctant to stop their cancer pill, and you need to empower them that taking a pill every day isn’t the goal and that if they feel bad, they should stop. I’ve found over many years that those 3-day breaks or whatever recharges the batteries. They make the regimen much more tolerable. It’s not something you can study. It’s hard to point to data, but I don’t know what you guys think. In my clinical practice, pretty much everybody on a TKI long term takes breaks every month, every 2 months, or maybe more frequently.

I agree 100%. I also give my patients the autonomy to almost schedule their breaks. If there’s a certain family event coming up, like July 4, or whatever you think about, the holidays are often sought-after moments with family. They want to minimize the toxicity.

So, they get a lot of leeway. Now, patients run into the knife initially. I would say, as you said, patients are highly motivated. They still have to understand that this is a marathon and not a sprint, and so I would say most patients initially make the mistake of going a touch too far in their toxicity exposure, but they learn quickly.

Yeah, I agree. I usually tell patients, “When you start to feel like you think you might need a break, take it.” For most patients, and it’s usually the spouse who’s saying, “You should take a break.” The patient is like, “I’m going to push 5 more days, 7 more days.” And I say, “You’re not helping yourself.” So 

Yeah, and it’s also the spouse. It’s the support system. I work a lot with the spouses. Remember, two-thirds of our patients are men, and they don’t tend to listen too much to themselves or their bodies. Getting the spouses early on into the picture and encouraging the spouse to take a break is absolutely key.

Expert panelists consider the importance of quality of life when selecting first-line treatment regimens for patients with advanced clear cell renal cell carcinoma.

Brian I. Rini, MD | Authors

Articles

First-Line Treatment for Advanced Clear Cell RCC: Key Takeaways

Triplet Regimens in Advanced RCC in the Frontline Setting

Selecting Treatment for Advanced RCC in Second Line and Beyond

Adjuvant Immunotherapy in Advanced Renal Cell Carcinoma

First-Line Treatment in Advanced RCC: Sequencing Therapy

First-Line Treatment in Advanced RCC: Quality of Life Considerations