We’re going to end this time. Thank you all for your time and expertise. [Dr Bastos], I’m going to start with you. Tell me, what are you most excited about in kidney cancer [treatments]? [It] could be a drug, it could be an approach, it could be anything.

 Well, I think as we discuss ways to improve immune checkpoint inhibitors, [it] is very important to understand mechanisms of resistance. One thing that’s very interesting for me, and that’s something that we did a few clinical trials with a drug that targets cancer cell metabolism, is for instance in this particular case, FH-deficient [cases]. They tend to have more glycolytic pano, the cancer cells tend to survive more glycolytic pano, and that shift from glycolysis to others, metabolism in cancer cells may lead to apoptosis.

 Metabolism-directed drugs seem [effective], obviously in cases like FH-deficient tumors, but they may also be extended toward the renal cells.

 I think if we take a step back from all these data, it’s kind of amazing how many folks are living beyond 5 years, right? We could not have imagined this, I think, when we started these studies. So that I’m just excited to see, and I think as we cross-compare and decide which is better, they’re all really great compared to where we were before. I am going to pick, as the thing I’m most excited for, trying to understand where the options are for de-escalation. We talked about stopping pembrolizumab, when to do it, who can be sequenced vs combination as we move toward triplets. It’s in way easier to answer that question because you just do the study and load them up up front and then compare, but really [what] you want to know is that overall survival. Can we achieve the same thing with sequence, with less, with breaks, with treatment-free survival? And it’s a hard question to answer, but I hope we can put a lens on that going forward now that we have the luxury.

De-escalation strategy, deintensification strategies. I’m doing like the two-word summary of each of your answers. [Dr Jonasch], what do you think?

 On top of tuning the immune system, I think one of the other things that’s striking, I did my board renewal and I saw that all of the other diseases have antibody-drug conjugates [ADCs] or something where we know we have CA 19-9 [cancer antigen], we have CD70. We need to figure out what is it that we want to deliver, what’s the lethal payload that’s appropriate for renal cell carcinoma? How do we take advantage of this? We now have imaging modalities, the zirconium-89, girentuximab. That tells us we can get stuff there. We need to figure out what it is we want to get there.

 I would say, I think it’s about precision medicine. I think your work, [Dr Rini], that you’re doing with biomarker development and developing signatures, how can we best identify patients for some therapies? And really looking at our trials, getting that blood that our patients gave for the studies, analyzing it and seeing what we can do with that data and really presenting that and trying to find better ways and what we can build upon. Because there are a lot of great studies that are coming out for biomarkers-selected therapy, which a lot of other tumors look at. I think if we can incorporate that, other than the IMDC [International Metastatic RCC Database Consortium] risk, that would be really important.

Thank you. These are all great answers. Really good answers.

I would say, yeah, biomarkers of course, but I might say, I think we’re about to see a wave of novel immune drugs, novel non PD-1, PD-L1 base, be it LAG-3 or TIGIT or novel CTLA-4, those novel CTLA-4 drugs. And I think we’re going to start to see those develop, see them combined in the front line, and I think we’re going to cure more patients. On that note, thanks again to our panel, this was great. And thanks to our viewing audience. Thanks for joining us. We hope you found this 

 discussion to be useful and valuable for the treatment of your patients with advanced kidney cancer.

Videos

Shared insight on the evolving state of renal cell carcinoma management and hope for future growth in the treatment landscape.  

Renal Cell Carcinoma: Future Evolutions in Care

In the interest of time, I’m going to move on to our second case, and we’re going to talk briefly about non-clear cell [cancer].

This is a 42-year-old woman who presents to clinic with new onset gross hematuria, fatigue, and flank pain. Past medical history is just well-controlled hypertension and occasional smoking for her social history. On CT scan imaging, she has a nearly 8-cm infiltrated left renal mass and some small nonpathologically enlarged retroperitoneal nodes. [She has] normal labs and a performance status of one. This patient undergoes a left radial nephrectomy, which confirms renal cell carcinoma [RCC], but it’s a fumarate hydratase or FH-deficient tumor. So non-clear cell, a relatively rare tumor. It’s grade 3, no sarcomatoid features, pathologic stage T3aN0. And she’s referred appropriately for genetic testing given her age and her histology, and is actually found to have a germline pathogenic variant, which is then confirmed to be present in family members. So, unfortunately, [this patient doesn’t] get adjuvant therapy; this is non-clear cell disease, this patient undergoes imaging post nephrectomy 6 months and has, unfortunately, recurrent metastatic disease, mediastinal lymph nodes, and hepatic metastasis. So [Dr Jonasch], I’m going to start with you, FH-deficient kidney cancer. Do you see a lot of this? I don’t.

I have several, I have a number of cases, and my go-to treatment for these patients is bevacizumab-erlotinib, based on the NCI [National Cancer Institute] data. And I’ve had some pretty dramatic and sustained responses with that combination.

[Dr Berg], any experience here? Maybe just [with] non-clear cell in general. We’re talking about germline variant, so I don’t want to get too down the rabbit hole here. But either this or just non-clear cell, a papillary patient who comes in, which is obviously far more common.

 Variant histology is always challenging. The [PAPMET] data that [Sumanta “Monty” K. Pal, MD] started through SWOG was, I think it did establish cabozantinib...for papillary was the best. And we know about chromophobe not really reacting to immunotherapy, medullary cancer. We know it doesn’t really react in normal kidney cancer types. But I think it is something where I’m a go-to of cabozantinib for a lot of the variants. And sometimes now we have a lot of doublets that I’ve been looking at for pap.

That was going to be my next question. There are some phase 2 data of IO-TKI [immuno-oncology/tyrosine kinase inhibitor] combinations. Some presented at ASCO [American Society of Clinical Oncology annual meeting] and if people know numbers, feel free to chime in, but there’s clear activity to IO-TKI combinations. To me it looks like more activity than TKI monotherapy, separate trials of course. Do you give TKI monotherapy or IO-TKI or both, or how do you decide?

 Since with everything coming out now, I’ve switched to just treating [non-clear cell] like a clear cell to actually giving a doublet therapy.

 Yes. FH-deficient [cancer] obviously is very rare, and I agree with the bevacizumab [plus] erlotinib, but I think there’s that proper classification, once we know it’s a variant histology, is so important, and getting pathology review and getting second opinions, sequencing, things like that are giving us what these unclassifieds used to be and giving us an in to them. Because I think, we always see these trials, like what are these unclassifieds? What does that even mean anymore? We really need to start defining these, and there’s even, in the WHO [World Health Organization] classification, there are new entities that are coming out that have different variants.

They seem to come out with another 12 classifications.

 Yes, exactly. So having that pathology is really important.

Academic center pathology review, hugely important. You mentioned genetics and genomics in these, and I couldn’t agree more. [Dr Plimack], what’s your approach? You can either comment on this or just on non-clear stuff in general.

 My comment on this is kudos to whoever picked up the FH deficiency, because it’s not necessarily apparent on pathology. You do need to send them for germline testing. I think the teaching point here is that any papillary that’s young, it’s a good idea to send them because [of] that match to bevacizumab [plus] erlotinib. I have a handful of patients too, and some of the best responses of any of my patients have occurred with that combination in these FH-deficient patients. So that’s something. And then to [Dr Berg’s] point, I think there’s chromophobe, which is treated one way, and papillary, that’s treated another. I tend to go to [lenvatinib plus pembrolizumab] based on the data at ESMO [European Society for Medical Oncology] that Laurence Albiges [MD, PhD] presented. And then there’s medullary, which is a chemotherapy-treated disease. If you can just separate those three out and consider them completely separate, that would be great. Unfortunately, the trials don’t do that for us, so we’re sort of subsetting those data.

 [A patient with] typical metastatic papillary [cancer] who comes in, what do you give them?

[Dr Bastos], what do you think, either this case or just more broadly, non-clear cell, papillary being the most common when [a case] comes in, what are you reaching to?

 I have a patient also with FH deficiency, and the erlotinib [plus] bevacizumab is the treatment that I’m using for this patient. They are responding very well, and there is a family history, but there is also some interesting discussion about how this was picked up, because there are data in undeveloped countries that don’t have access to NGS [next generation sequencing]. How to train the pathologist, how to triage which pathology cases: you should refer to NGS. They’re using AI [artificial intelligence] also on this pathology, to help this pathologist to triage better the NGS. That’s very important because as you see, there are two family members, and there is a 15% to 20% risk of developing RCC in this patient population. They need to be monitored very closely. So that’s very important. And then if it’s not a genetic-related tumor like this one, I think I’m tending to treat more like a clear cell now, with IO-TKI because just a TKI by itself [is] obsolete right now, and we should incorporate better strategies on this, definitely.

So it seems like in non-clear cell we go back and forth between, oh, we want special treatments [and] oh, we’ll just treat them like clear cell. They want special treatments, we treat them like clear cell. But I agree, I tend to do IO-TKI in your average papillary, whether it’s a cabozantinib [plus] nivolumab or lenvatinib [plus] pembrolizumab based on some recent ASCO data. Again, I think it’s the same as our discussion in clear cell, pick your favorite.

Focusing their discussion on a real-world patient scenario, expert panelists discuss treatment options in the setting of advanced non-clear cell renal cell carcinoma.

Selecting Optimal Therapy for Advanced Non-Clear Cell RCC

Just to continue on toxicity—Stephanie, maybe I’ll ask you. I know you were more of an ipilimumab-nivolumab user, but you do give some IO-TKI [immuno-oncology–tyrosine kinase inhibitor therapy]?

When you do, are you choosing based on the TKI? I like axitinib with a short half-life better, or I like lenvatinib because it’s more potent? What’s making your choice? And then if, kind of the related question, I’m going to ask everybody this for lenvatinib-pembrolizumab, which I think everybody gives a bit. Are you starting at 20 mg?

 I always start at 20 [mg] at lenvatinib. I try to follow that. I know a lot of the dosing is also different among tumors, of lenvatinib of 18 mg or 20 mg. The toxicity is so challenging because we know they’re all overlapping, and trying to decide among that with the different TKIs. I do recognize the half-life of cabozantinib now that they have a newer version coming out, which I cannot pronounce, that has a shorter half-life. Dose reductions are hard because, I shouldn’t say hard, but when you interrupt a dose, it doesn’t just go away in a couple days. It lasts for maybe a week to a week and a half. Then I do like axitinib for that shorter half-life. Lenvatinib, though, still also has a pretty long half-life as well, but not as long as cabozantinib. It’s almost upwards of, cabozantinib is 99 hours, and then the lenvatinib is…they’re just both long.

They’re long. I may have missed this, but when you choose IO-TKI, it sounds like you’re going more lenvatinib-pembrolizumab, or…?

 I do choose more of the lenvatinib-pembrolizumab. Correct. Yes.

Bruno, let me pick on you. When you’re choosing IO-TKI—and it sounds like you use more of that than ipilimumab-nivolumab—what are you choosing as why, and also the lenvatinib dosing question?

Those are very good points, I agree. Like I said, I’m in the community practice. We tend to see patients going [to] different hospitals and things like that, sometimes outside the network. You sometimes get phone calls of patients to be admitted. Now [the patient is] going to have emergency surgeries and things like that, and how to manage it. So, because of that, I tend to choose a little bit more the axitinib combination because the [with] the shorter half-life, it’s much easier to manage in situations like this when patients require either a major dental surgery, which sometimes happens, or patients in the outside doing procedures. So even our staff feels more comfortable with that because we don’t like to get surprised [if a] patient requiring a major operation [is] in a long half-life VEGF-TKI [vascular endothelial growth factor–tyrosine kinase inhibitor]. The IO-IO toxicity, we see it. I tend to be a little bit less concerned when we are dealing with advanced disease, and as was mentioned here, I think we are either learning how to do it better or maybe less afraid of steroids. It doesn’t seem to be a major deal, the use of steroids. Obviously, in the real-world scenario as opposed to in a clinical trial, I was part of the COSMIC-313 [trial; NCT03937219], they have strict guidelines [on] how to use steroids. Sometimes I feel it’s a little bit too much that you really need it in clinical practice because it’s one size fits all. In a clinic you can maybe do 0.75 mg, 0.6 mg/kg of prednisone equivalent. So I tend to feel that these high-dose steroids would go down a little bit. But obviously we are concerned about the toxicity. Like I said, I get a little bit more nervous. I don’t know if we’re going to have a chance to talk about the adjuvant, but I tend to get a little bit more concerned about the IO [adverse] effects in the adjuvant setting, because those are the patients who really could be chosen to go for observation as one standard treatment and then they may get severe IO-related toxicity, which I’ve seen. It’s something that it’s difficult to manage, and how to relate the patients to the team when patients have a more severe toxicity.

Yeah. We’re not going to get to the adjuvant setting, but clearly the benefit risk is different because many of your patients don’t have cancer, so it’s very different. All right. Betsy, your turn.

 So, really quick, you asked if I start at 20 [mg]?

 I start at 12 mg because I get 4-mg pills. I just can’t get good tolerability at 20 [mg], and 16 [mg] even is hard. What I love about axitinib is the nimbleness. You can order 3-mg pills and do whatever crazy dosing you want to do within that realm. With lenvatinib, you’re ordering 10s or you’re ordering 4s and you’re combining them. So I start at 12 [mg], then I have 4-mg pills and I move with those until I hit the right dose.

 Three 4-mg [pills], and then quickly you have them take a fourth 4-mg [pill] if they’re doing well.

I see. I didn’t think there’d be any math on this panel

 I know. It’s off-label. It’s outside the data. That’s why I’m a little sheepish about it. But I find that’s how I can most quickly find the dose that matches that’s tolerable long-term. They do so well that they’re on long-term.

I can tell you do a lot of roundtables with community doctors, and nobody starts at 20 [mg]. They all started either at 8 [mg] or 10[mg] or 14 [mg]. It’s all over the map, and it’s fascinating to me. Two decades later, we [are] still not sure how to dose drugs right. We’ve been doing this literally for 2 decades. Not lenvatinib, but similar drugs, and we still all have our little quirks and ways to do it.

: Yeah. I mean, it’d be great if we can get higher doses into people, and they feel great and are living their lives. It’s harder to do with lenvatinib than axitinib.

Agreed. I do tend to start at 20 [mg], but with an extremely low threshold to go down, and my nurses are calling [the patient] every week. So it does take more.

 So we probably get to the same place, you and I, from different directions.

: I think so. Sure. You would assume in a given patient you’re going to end up at that same place. Hopefully, that sweet spot of just enough but not too much.

 I mean, it depends on the patient population that I see to have a lot of uncontrolled hypertension. So when we see this patient population, you get a little concern with VEGF-TKI. Maybe when you’re in academic setting, maybe in different centers, patients have more access or they’re more strict with their blood pressure. But in my current practice, I tend to see a lot of patients with hypertension at baseline.

Panelists consider best practices in dosing while managing patients on first-line therapy for advanced clear cell renal cell carcinoma. 

Dosing Strategies With First-Line Therapy in Advanced Clear Cell RCC

Let’s talk about toxicity of these regimens. They each have their toxicity, and as I mentioned, one of the reasons that maybe I don’t give more ipilimumab-nivolumab is that fear of ipilimumab toxicity. Because if you have a bad TKI [tyrosine kinase inhibitor]-based toxicity, that might be like bad diarrhea and anorexia, and you stop, and it gets better. Transaminitis, and you stop, and it generally gets better within days, maybe weeks. If you have a bad ipilimumab toxicity, that can be life-threatening. We’re all scarred by our worst experiences somewhat. I guess maybe the question, Betsy, I’ll start with you, is are you not giving more ipilimumab-nivolumab for the reasons that I may be alluding to, that I’m a little scared of that up-front toxicity and actually shortening a patient’s life instead of lengthening it?

 For sure. I think a large percentage of patients who get ipilimumab-nivolumab had to be admitted for high-dose steroids and then usually have to stop treatment. Then they’re on to just TKI alone. So that scenario is pretty common with ipilimumab and nivolumab. So it is one of the deterrents for me. Honestly, the reason I don’t turn to it more is because I truly believe the long-term data with the IO [immune-oncology]-TKI combinations is going to match that with ipilimumab-nivolumab when looked at appropriately. I don’t think, it’s not as durable and that’s colored by my clinical experience. We’ve done a lot with these drugs over the years. So toxicity and the fact that I don’t think you give up efficacy by steering away from ipilimumab and nivolumab.

Let me channel some of our colleagues now. So ipilimumab-nivolumab has a 30% tail to PFS [progression-free survival] curves.

Axitinib-pembrolizumab, presented today, was 18.4% or something.

I know we’re comparing subsets and all the caveats and statistics, and luckily there are no statisticians on the panel, but that’s going to happen. Those ipilimumab-nivolumab folks can say, “Wait a minute, it’s 30%, not 20%.”

 But the 30% is an estimate with an awful lot of censoring. Those curves are frozen in time. So the ipilimumab-nivolumab data, there’s 7-plus years of follow-up for the last patient enrolled on that study. That estimate will never change. With the axitinib and pembrolizumab, we’re seeing constant change because they’re actually continuing to collect data on these patients.

You think it’s a bit of a, I don’t want to say, methodologic issue?

 I do. I think that’s why that curve is flat, flat, flat and will be forever, because they’ve lost those patients to follow-up. You can look at the numbers at the bottom and how quickly they drop off; we can’t confirm those patients are alive and progression-free. The other thing is the survival, which is a little easier to track, those curves continue to go down. What are people dying of if they’re not progressing but they’re still dying? My guess is it is uncaptured progression. It’s a guess, but it’s filling in a gap of missing data. And related to having participated in all these studies and understanding how the data collection was different. So it’s nuanced.

I think, and maybe the larger point is, long-term follow-up of trials is super important.

We get all excited about initial results and ASCO [the American Society of Clinical Oncology meeting], plenary [sessions], and all these impact publications, which is great, but in the clinic it’s really important to know how to follow people and how long.

 We’re making decisions based on those at the front line, based on data that we anticipate for that patient in front of us 5, 10 years from now. So yes, it’s important.

How much ipilimumab-nivolumab do you use?

 I use it probably in [approximately] one-third of my patients.

 No. Because I don’t think it’s appropriate for most favorable risk patients, I don’t think it‘s appropriate. Then there‘s the intermediate poor risk groups where I think they need to have a faster response. But for us, obviously the toxicities are things that we have learned to deal with, and we still see a small percentage of individuals who have the very worrisome toxicities, like the myocarditis, the myositis, the myasthenia gravis type symptomatology. We see those, they‘re relatively rare, but even there we usually manage to get patients through those. So I‘m a little less afraid of the toxicity, but it clearly requires a team. [Those] within the department know how to take care of it. All of our subspecialists really have developed subject matter expertise. So that gives me some confidence that we can get our patients through it.

I think when the initial ipilimumab/nivolumab data was presented, I think it was a 35% high dose steroid. It was like, whoa, that’s a lot. Now, I don’t know, we’re not that afraid of high dose steroids, but we’re afraid of the sequelae of irAEs [immune-related adverse events] and needing to use infliximab and needing to use all these other things. If you put somebody on high-dose steroids and they get better, great. I don’t think that’s a problem, in general. But when they don’t get better, require the things are obviously fatal outcomes, that’s…I’m just trying to get a sense of how much that toxicity is.

 That risk exists with all the doublets because there’s IO. So it’s more with ipilimumab-nivolumab.

 But we’re always vigilant for all that.

 I think if you look at COSMIC-313 [NCT03937219]and you look at the discontinuation rates and the toxicity rates and the steroid use for the ipilimumab-nivolumab arm in that study, it is somewhat lower than it was with CheckMate 214 [NCT02231749]. I think this is all part of our learning how to use these agents over time [that’s] really has de-risked that somewhat.

I think that’s fair. We’re going to get to triplets a little bit later.

Expert perspectives on the adverse event profiles of first-line combination therapies in the advanced clear cell renal cell carcinoma space.

Advanced Clear Cell RCC: AE Profile of First-Line Combination Therapies  

I think as you heard, we’ve mentioned every single regimen. That [is] sort of the state of the field, as we all have our different biases. I tend to be an IO-TKI [immuno-oncology–tyrosine kinase inhibitor] person because of disease control, ease to give, low primary progression, all the reasons mentioned. I give ipilimumab-nivolumab to anybody with sarcomatoid, as you all know, there’s really good data that [it] has an especially high and durable response rate in that population. Tends to be that young, healthier patient. Sort of the first note of the algorithm is, is this patient eligible for ipilimumab? Because if they’re not, and a lot of people who walk into my clinic aren’t, then I pick my favorite IO-TKI. I was giving a lot of axitinib-pembrolizumab. I’ve certainly given a little more lenvatinib-pembrolizumab, but, and I want to get to toxicity in a second, the toxicity is limiting as well. So I think, of the 4 regimens, 4 doublets shown to increase survival, I could probably stand up in a debate and take any one of them.

I think all of us could do that. So it just shows you that it’s not a right or wrong choice. As others have said, I think familiarity with the regimen and knowing half-life of drug and dosing. The TKIs took totally different dosing strategies in these trials for a number of reasons. Familiarity is really sort of key. The data at ASCO [the American Society of Clinical Oncology meeting], for me, I think the rising hazard ratios are a reflection of more patients getting subsequent therapy. To your point about when the trials were conducted and availability, I don’t actually know the number of patients in [CheckMate] 214 who randomized to sunitinib who got nivolumab. I don’t know if you know that number.

 No. I don’t think they were able to capture a lot of it that well. Again, this was an early trial, and it wasn’t expected to do as well as it did.

I’m not sure I’ve ever seen that number. Maybe that’s why, to your earlier point. I don’t think the data are going to radically change. None of us said they were going to radically change, and I don’t think on a community practice level or other level that there’s going to be a lot of people who radically change based on it. I think the rising hazard ratios reflect therapy, but I will, in defense of ipilimumab-nivolumab a little bit, [say] those responses are really durable. Which is immune therapy. That’s everything that’s great about immune therapy, these durable responses. So I can see the argument that, I have this patient who wants a durable response of course, and leaning toward ipilimumab-nivolumab, and if you were there for the discussion, there was a nice, heated exchange from people about this. So I think we’re in for a lot of discussion around this topic, and that’s good. That’s what we should be doing, is sort of discussing. I wanted to cover, Stephanie, because you brought up bone metastasis. So it sounds like in a patient with bone metastases, you might lean more toward cabozantinib-nivolumab for the reasons you mentioned. So anybody else want to dive in and say, “I choose this regimen for these organ-specific metastases?” I didn’t hear anybody else say that?

 Cabozantinib just has this link to bone, kind of from history and from the prostate cancer studies. I think we kind of gravitate to that and want to believe that. For a really bad bone metastasis, I still think lenvatinib-pembrolizumab is going to give you the best overall response. I don’t parse by where they are. I agree with Eric.

 Right. Liver’s bad, and a lot of metastases are bad. Those are things that turn you to the regimen with the highest response rate and the lowest primary progression rate. But I don’t pick an organ-specific [regimen].

 No. I agree in principle with that. I don’t think we have the same granularity with lenvatinib-pembrolizumab as we do with cabozantinib-nivolumab, but I think both regimens, for those more troublesome organ sites, I think are reasonable.

Bruno, anything to add about site of metastases?

 I agree. I don’t use it. Bone is an indicator to choose one way or the other, regimen-wise. I agree with the fact that disease that’s life-threatening, causing organ damage, would require a regimen that perhaps is more associated with a high response rate. I think that it’s my choice, not organ-based, but clinical life-threatening. It could be bone, it could be lung, could be liver.

 Not specifically, even though the cabozantinib bone is something that always comes to my mind when we see it, because of obviously the history of the medication.

I think we all remember that bone scan from the prostate cancer patient. I think that’s colored a lot. That’s in my opinion, but…

 I would be interested to see a PSMA [prostate-specific membrane antigen] scan for that.

A brief discussion on the patient and disease characteristics that help to inform selection of best therapy for patients with advanced clear cell renal cell carcinoma.

Factors in Selecting First-Line Therapy for Patients With Advanced Clear Cell RCC

® “Evolving Treatments for Advanced Renal Carcinoma: ASCO 2023 and Beyond”. I’m Dr. Brian Rini. I am a professor of medicine at Vanderbilt-Ingram University Cancer Center, and I’m joined today by expert panelists in renal cell carcinoma [RCC]. I’d like to welcome my esteemed fellow panelists to introduce themselves, and we’ll start with you, Stephanie.

 Hi, my name is Stephanie Berg. I am at the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute [in Boston, Massachusetts].

 Hi, I’m Dr. Eric Jonasch. I’m a medical oncologist at [The University of Texas] MD Anderson Cancer Center in Houston, Texas.

 Hi, I’m Betsy Plimack. I’m deputy director and professor at Fox Chase Cancer Center in Philadelphia, Pennsylvania.

 Hi, I’m Bruno Bastos. I’m in medical oncology at the Baptist Health Miami Cancer Institute in Miami, Florida.

It’s really great to have you all here. It’s been an exciting time in kidney cancer over the last several years and [with] some new data at ASCO [the American Society of Clinical Oncology meeting] this year. We’re going to start with the landscape of kidney cancer, ASCO data, how it may impact your practice. We’ll go down some rabbit holes of other data and toxicity management and all the sorts of clinical practice. We’ll focus on clear cell first, frontline. We’ll move to the refractory space where we had a big phase 3 [study] presented, and then we’ll talk about non–clear cell. We have a couple cases to augment the discussion.

Let’s start off by talking about frontline clear cell kidney cancer. As you all know, this is a disease that predominantly [affects] men in their 50s and 60s. We see a lot of these patients; they can present asymptomatically incidentally, they can present with hematuria symptoms. We’ll probably not get into the debulking nephrectomy debate, but let’s talk about patients who have advanced metastatic disease and need treatment. The landscape has been immune-based doublets. Ipilimumab-nivolumab with long-term durable response data, and then 1 of 3 IO-TKI [immuno-oncology–tyrosine kinase inhibitor] regimens, all of which have shown survival advantages. Axitinib-pembrolizumab, cabozantinib-nivolumab, and lenvatinib-pembrolizumab, in short. Then just let me briefly summarize what we saw or what we heard about at ASCO. Then I’m going to ask each of you to comment about your initial reactions to the data. We’ll take it from there as a jumping-off point.

So we heard 2 updates. We heard a KEYNOTE-426 [NCT02853331] update, which was a 5-year minimum follow-up update. Then we heard from the lenvatinib-pembrolizumab CLEAR trial [NCT02811861], a 4-year minimum update. I think they were similar, and just to summarize, response rate advantages and PFS [progression-free survival] advantages were maintained as you would expect, because most of those events have occurred already. What we saw in the overall survival is that advantage was still maintained, but those hazard ratios are drifting up over time. Axitinib-pembrolizumab was 0.53; initially it was 0.84 at this analysis. Lenvatinib-pembrolizumab, I don’t remember the exact numbers, but 0.79 today. So they’re kind of moving up over time as patients get more therapy. Let’s start with that as a jumping-off point. Bruno, let me ask you to comment first. What were your initial reactions to the data? Do you think it’s going to impact your practice? If so, how?

 I think as you said, we have many options at this indication. When we see this patient population and the numbers, the hazard ratio is changing a bit, but the PFS and the response rate is maintained. To me, I think it’s just corroborated that those regimens are effective regimens that can be used up front; combinations of VEGF [vascular endothelial growth factor], TKI and IO. It give us clinicians more confidence that we are providing good care to our patients. However, this overall survival may make us think about perhaps the second- and third-line therapies [that] are coming along, are improving in the main, and that probably changed a little bit, this hazard ratio, as opposed to a few years ago that did not exist.

It doesn‘t sound like it‘ll impact your practice. I should have asked you and the other panelists.

 It will not impact in my practice at this point right now, up front.

Which is what? I‘m sorry. What‘s your standard go-to?

 I tend to look at both options. The double IO-IO combination or IO-TKI. I tend to get a little concerned about the progression of the disease with IO-IO. And if I feel like there is a patient that is having a disease that perhaps is progressing very rapidly, I tend to stay away a little bit from the IO-IO up front and do IO-TKI. So it’s kind of patient characteristics that makes us, at that moment when I see the patient in the clinic, decide which way I’m going to go. I kind of like the TKI when they have a little bit [of a short half-life]. Mainly because down the line, if the patients need to have an emergency surgery or some sort of procedure like this, you don’t get that nervous about the long half-life of the VEGF-TKI. So that’s something that I see in practice and makes us clinicians a little bit more comfortable when we need to make a decision about that.

So, Betsy, we’ll go down the line here. What’s your current practice in a nutshell? And does the data impact [it]?

 I tend to really avoid the IO-IO, and that’s based on sort of some nuances as we go back and understand these trials, how they were conducted in different points in time. So ipilimumab and nivolumab, that phase 3 trial completed and subsequent nivolumab was not even approved until about 3 months before that trial ended. So very few people in that control arm ever got the option to get nivolumab; [it] just wasn’t approved in the United States or anywhere else. So I think when we look at the hazard ratio for that, we have to keep that in mind. The other thing that was really impressive with these data is that the overall survival curves had very little censoring. They kept really close tabs on the survival of patients in all the TKI combo trials. I don’t think they were as rigorous in the ipilimumab-nivolumab trial because when you came off nivolumab, you came off trial, and they sort of stopped following. I don’t think they expected the results to be as good. I think what’s really important is to look at the top curve, the combination curve, and look at landmarks along the way, if we’re going to cross-compare and note the relationship to a control arm where subsequent therapy changed over time. So in a nutshell, which is what you asked, my practice is either axitinib-pembrolizumab for someone I think is good risk and is going to be on it a long time and therefore can tolerate a long use of TKI, or lenvatinib-pembrolizumab in a patient who just really needs a response right now.

Because lenvatinib-pembrolizumab with higher response rates, but more toxicity is…

 Higher response rates, more toxicity, less primary progression. So you balance those.

 I divide it up between favorable risk and then intermediate and poor. In the intermediate and poor [risk groups,] it’s those people who have threatening disease versus nonthreatening disease. The favorable, I’ll typically use axitinib-pembrolizumab. In the intermediate and poor, if they have nonthreatening disease, I’ll use ipilimumab-nivolumab, and then I’ll use either cabozantinib-nivolumab or lenvatinib-pembrolizumab in those people that have threatening disease.

 This would be large disease burden, metastases to bone, liver. Or disease that if you were to think of the trajectory that you know so far would cause problems if you don’t get a response. Back to Betsy’s point about… best response of ipilimumab-nivolumab being, depending on which group you look at, either 18% or 20%, this is a real consideration for that patient population.

So maybe not a solitary bone metastases per se, but some substantive disease in bone and or liver. Is that fair?

Bulky, defined as something that’s going to perhaps cause some sort of end organ problem. For example, mediastinal adenopathy that if this continues to grow, you’re going to have obstruction.

I think that’s great and I’m only pushing you on it because we talk about that all the time. Bulky, we use these terms. I think we kind of all know as clinicians what they mean, but they probably mean different things to different people. But I think as a general algorithm that symptomatic bulky disease, IO-TKI, I think, is a relative standard. All right, Stephanie, your turn.

I agree with everyone so far. I think that the new data presented, like you were saying, Brian, about the CheckMate 9ER[NCT03141177]CLEAR study, and [KEYNOTE] 426. They’re all very similar. Over time, the hazard ratios were getting a little bit higher. Toxicities are pretty similar, response rates are pretty similar. I also noticed that the CR [complete response] rates are going up for a lot of these studies where we always used to use [CheckMate] 214 as the highest CR rate. We’re seeing now with the IO-TKI is increasing in CR rate. So, in my practice, I do actually like using ipilimumab-nivolumab. I do like that treatment response in that sense, where they can get that time off treatment. But I agree with Betsy about looking at what the trial actually did and how the trial was made up. Really talking about the patients using the IMDC [International Metastatic RCC Database Consortium] score and trying to see if they don’t qualify for a first-line clinical trial, because we do have our triplet studies available, looking into that. But nowadays, my IO-TKI, I have choice. I really do like the subgroup analysis that Andrea Apolo, MD, put out, looking at bone metastases for maybe doing a more cabozantinib-centered good response rate really quickly for lenvatinib. Even though those were all kind of with the different organs with liver and bone, you can’t really extrapolate a lot. But I do think that data is super compelling about if there is a difference between TKIs and where your metastases lie.

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