Rana R. McKay, MD, FASCO, is a professor in the Department of Medicine and Department of Urology at the University of California, San Diego Health.

 Ben, I want to ask you a different question altogether. Let’s get our dirty linen out in public and put it on the table. What’s going on in the good-risk patients? Do we need to be giving those patients combination therapy, or is sunitinib hard to beat?

 That’s a really interesting question. The CheckMate 214 study included good-risk patients, but not in the primary end point. They did carve them out in their analysis, and ipilimumab-nivolumab didn’t seem to improve on the performance of sunitinib in that population. It gets a little more difficult with these other TKI [tyrosine kinase inhibitor]–I/O [immuno-oncology] studies because they lumped all the IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] risk patients together—the good, intermediate, and poor-risk patients—in primary and secondary end points. They did some subsequent analysis of the favorable good-risk patients. There, the results that are so good in the total population are more muted or diminished in the favorable-risk group. 

For instance, to my knowledge, with all of the TKI–I/O combinations, if you look at overall survival with whichever combination vs sunitinib, there’s no statistically significant improvement in terms of overall survival. There are improvements in PFS [progression-free survival]. For instance, there are improvements with response rates but not in terms of that important end point of overall survival. These patients clearly do well. We also get a feel or an understanding about how well they do because buried within this favorable-risk group are patients who have oligometastatic disease that we sometimes do surveillance for or that you can do metastasis-directed therapy for. This population clearly does well with a variety of approaches; therefore, it gets challenging.

 It’s always risky to disagree with Ulka. 

 This is a place where we need better biomarkers. Ideally, within the favorable-risk group, I’d like to tease out the population that needs the combination treatment. Right now, the only way to do that is with clinical parameters. 

 I’m going to push you a little, Ulka, if I may?

 We don’t have good biomarkers. PD-L1 as a biomarker has performed. I’ll come back to that in a minute. I hear a lot about patient selection beyond the IMDC classification in broad terms. I agree with what you said. Let’s go beyond there, because sometimes people say, “Cabozantinib is for patients with bone metastases, those with liver metastases should get lenvatinib-pembrolizumab and, and for brain metastases, this 1 is a bit better.” How do you select? Is there any patient selection, or is it, “We’re fishing for stuff because we haven’t got other things to talk about”?

 The sites of metastases is a big 1. That’s not incorporated in any of our IMDC or MSKCC [Memorial Sloan Kettering Cancer Center] prognostic criteria. Bone metastases, liver metastases—clearly, if somebody is favorable risk by all other criteria but has liver involvement, in my mind, they’re poor risk. They need that combination immune-based regimen. On the other hand, there are lung metastases that are distals and slowly progressing. Sometimes you don’t have that timeline, so you have to create it. But those patients are on surveillance. To me, the favorable-risk group is a huge mixed bag. The liver and bone metastases make it clinically easy to determine that we need to do aggressive therapy.

 What you’re saying is you can pick between VEGF TKI–I/O and I/O–I/O–based on the presence and absence of metastases, which I don’t disagree with. For bone metastases and liver metastases, you’re giving VEGF TKI–I/O combinations.

 I’d go to at least a combination regimen. 

 This is still in the good-risk patients?

 In the good-risk patients, you’re trying to distinguish between good risk based on the signs of the disease. That seems fair. Let’s go broader, and let’s just go around the table a little and talk about the intermediate- and poor-risk population. Let’s talk about bone metastases, liver, metastases, brain metastases, and sarcomatoid features. Do you want to start with bone, Eric? How do you look at bone metastases? Is there a specific regimen that you use?

 If I had to, I’d choose between I/O–I/O vs I/O–TKI.

 You wouldn’t be differentiating between the different I/O–TKIs. You see them all essentially as interchangeable. Or is there a specific regimen for bone metastases?

 Cabozantinib has a reputation of being good in bone, but whether this has been validated is unclear.

 Based on my clinical experience, as well as the data out there, the cabozantinib-nivolumab combination for an individual who has bone metastases is a good regimen. I wouldn’t choose axitinib-pembrolizumab. 

 At that very targeted VEGF inhibition, this seems not quite as good. With lenvatinib-pembrolizumab, we have updated data presented by Bob Motzer at KCA [International Kidney Cancer Symposium] last year, showing that from subset analysis, lenvatinib-pembrolizumab is probably good for these hard-to-treat areas like bone and liver. Cabozantinib-nivolumab and lenvatinib-pembrolizumab would be my go-to regimens for those difficult-to-treat areas.

 Let’s go to the liver. Does it worry you that 1 of the regimens is essentially more transaminitis? Are you picking any regimens with liver metastases or, are they all the same?

 With liver, there isn’t necessarily anyone that’s more active. I come back to this: are you in visceral crisis and in need of a short-term response right away? Or do I have the luxury of the primary PD [progressive disease] rate, which with CheckMate 214 is around 20%, 17%? Can I risk that? That’s my barrier. If somebody has 1 liver metastasis and that’s all that they have, or maybe they’ve got disease elsewhere, then I’m not worried. Even if it grows a little, I’m not going to hurt that individual. I tend to favor I/O–I/O. I want to give the option of long-term disease, durability, and long-term disease control. If I’m worried about visceral crisis, if I’m worried about multiple hepatic metastases, I’m going to run into trouble. I have to get that disease in check first. Then I lean toward an I/O of VEGF combination. Generally, I like the nivolumab-cabozantinib regimen because the lower dose of the cabozantinib is easy to tolerate. Patients do well and feel better on it. I like that regimen, but I don’t think there’s a specific differentiator for the liver.

Videos

Shared insight on the importance of sites of metastases and how they may impact first-line treatment selection in advanced clear cell RCC.

Advanced Clear Cell RCC: Role of Site of Metastases in Selecting First-Line Therapy

 Ulka, it’s over to you next. You’ve got the pleasure of talking about some of the latest data with CheckMate 214, the ipilimumab-nivolumab trial. Do you want to give the group a little background about the ipilimumab-nivolumab study, where we are, and what we’ve seen recently?

 CheckMate 214 was the first immune-based regimen study in frontline metastatic kidney cancer. It was the first 1 to compare to sunitinib, which was the standard at the time. Now there are 5 other regimens that have shown efficacy and have proven and gotten FDA approval. CheckMate 214 compared ipilimumab-nivolumab combination with sunitinib. This was a randomized study on patients with untreated metastatic kidney cancer. The primary end point was overall survival [OS], and this was focused on intermediate- and poor-risk-disease patients. 

The results of the study, which have been updated with 5-year follow-up, showed that survival significantly improved with ipilimumab-nivolumab combination compared with sunitinib. Median survival is now in the range of 55.7 months with ipilimumab-nivolumab, which is close to 5-year median survival in these patients. Even at the 4-year mark, there was about an 11% increase in the number of patients who were still alive after ipilimumab-nivolumab combination as compared with sunitinib. It’s remarkable efficacy.

The toxicity has its nuances, and careful management is essential. As we’ve applied that regimen to our average practice, it has become tougher and tougher. The incidence of toxicities is higher, and they need to be diligently managed and acted upon quickly. Because things like colitis—immune colitis is big with ipilimumab-nivolumab—can get worse very quickly and can be potentially life threatening. Immediate immunosuppression and careful monitoring of the patients is critical.

 We’ve got that regimen. It came out and changed practice. We can all agree on that: long-term durable remissions. Not much later, we saw some axitinib-pembrolizumab data come out. That changed the scene a bit because it got control of disease in some more patients. Rana, do you want an update on the way VEGF–TKI [tyrosine kinase inhibitor] combination has evolved?

 Absolutely. Immunotherapy has demonstrated a track record for excellence and efficacy in RCC [renal cell carcinoma], as has VEGF-targeted therapy. There’s certainly a slew of preclinical data about the combinatorial, immunomodulating strategies of the 2 agents together. There’s still question in the field about whether there’s true synergy or just additive from the 2 components. Nonetheless, KEYNOTE-426 looked at investigating pembrolizumab plus axitinib compared with the gold standard of sunitinib. Patients who were treatment-naïve with locally advanced or metastatic disease and clear-cell histology, and patients were randomized 1:1 to receive the combination with the dosing of axitinib at 5 mg 2 times per day vs sunitinib on a 4 weeks on, 2 weeks off schedule. The primary end point was slightly different from the end point from CheckMate 214, which focused on the intermediate poorest patients. The primary end point was overall survival and PFS [progression-free survival] in the intent-to-treat population. All patients were favorable, intermediate, and poor.

It was a positive study demonstrating improvements in overall survival, improvements in PFS, and improvements in objective response rates. We saw the updates from Dr Brian Rini at ASCO [American Society of Clinical Oncology Annual Meeting] last year. That 42-month follow-up was exciting, demonstrating consistency of that overall survival benefit. The PFS was around 15 months, with the combination and response rates really high: 60% with about a CR [complete response] rate of around 10%. These are exciting data, but they’re a little different from CheckMate 214.

When I have patients in the clinic, and we’re talking about the 2 regimens and trying to think about an I/O [immuno-oncology]–VEGF strategy vs an I/O–I/O strategy, the discussion that we have is, “Do you have to play the short game? Or do you have the luxury of waiting to play the long game?” That’s how I help tease out whether I need to have an immediate up-front response. Or do I have the luxury of being able to give you nivolumab-ipilimumab? That’s the 1 regimen that’s been associated with long-term disease durability. We need additional long-term follow-up from the I/O–VEGF combos. But those are the big discussions we have in the clinic, and I’m sure all of you have with your patients as well.

 Give me the cabozantinib-nivolumab data, a quick summary of where we are with that, and some of the points that differentiate it from axitinib-pembrolizumab.

 Cabozantinib is a small molecule inhibitor of VEGF, but it’s also a small molecule inhibitor of AXL, MERTK, and TYRO3, so the TAM family members as well as MET. It ends up being somewhat more of a complex TKI, which in and of itself is interesting and may have immune modulator theory effects. This study took 40 mg of cabozantinib-nivolumab given IV [intravenously] every 2 weeks vs sunitinib. The primary end point was PFS, although the secondary end points are the usual suspects. You presented the update at GU ASCO [ASCO Genitourinary Cancers Symposium], where these data showed that not only did it meet its PFS end point, which originally a doubling of PFS with a hazard ratio of 0.51, but the overall survival was positive. Even with this update, the hazard ratio remained 0.7. It’s still very good. Objective response rates were in the mid-50% range vs 20s for sunitinib. 

CR rates went from around 8% initially up to 12%. It’s interesting to see the evolution of these data. We’re seeing that with the maintenance of the progression-free survival, there’s a maintenance of superiority from an overall survival perspective—this intriguing complete response rate. To Rana’s point, is this additivity? Is this synergy? We don’t know. The problem is we haven’t done presurgical studies or neoadjuvant studies to look at the interaction of these agents biologically.

 I’m going to round this off with the lenvatinib-pembrolizumab data, which came out last from the CLEAR trial and has the shortest follow-up. The response rate is high, about 70%. The PFS is long, above 20 months. The OS signal looks identical to the other OS signal, which is important. There are more similarities and differences among these regimes as I see it, and I find it hard to differentiate, to be honest. I can find an argument for each. I can say cabozantinib-nivolumab, ...axitinib-pembrolizumab, …lenvatinib-pembrolizumab…. I can see all 3 of those. But I also see—as you suggested, Rana—a distinction with the ipilimumab-nivolumab data. No. 1, it’s a more confined label to intermediate…disease. No. 2, it’s less good at getting initial control of disease. 

The question I’d like us to contemplate is, how important is CTLA4? We saw an ipilimumab-nivolumab adjuvant trial, which didn’t look positive. You said it’s the long game, and I want to get ipilimumab-nivolumab for the long game. Obviously, ipilimumab-nivolumab has the longest follow-up because it’s been going for the longest period. We’re always going to have that discussion. The question is, how much do we think ipilimumab is contributing? How important is it that we give it to our patients? If you’re going to give it, you can only give it in the beginning.

 There’s a study that’s ongoing,…looking at nivolumab vs nivolumab plus ipilimumab in the European context. That’s going to answer that question. If we extrapolate from pembrolizumab, there have been the KEYNOTE-427 data. What’s great about this monotherapy nivolumab is you’re seeing these objective response rates, which are reasonably high. What’s not great about them is the PD [progressive disease] as best response, which is already a little hazardous with 214 [patients] at 18% to 20%. There, it was in the low-30% range. I’ll hypothesize that you’re de-risking the PD as best response to some degree, and you’re probably nailing down the durability of complete response with ipilimumab. Fortunately, we have studies that are going to be able to resolve the speculation.

 Building on that KEYNOTE-427 data, there was also a series of adaptive studies in which patients were started on nivolumab up front and the ipilimumab was layered in later, depending on whether they had a response. That data demonstrate that using I/O by itself, PD-L1 or PD-1 inhibition alone is inferior. We saw lower response rates and complete response rates. The objective response rate was lower. We don’t want to compare across these trials, but the ipilimumab is adding to the complete response rate, the objective response rate, and the durability.

 I’m talking about peak ipilimumab. In 2019, there was a fantastic PFS. We’re beginning to see some uncertainty. I’m really excited about this CA209-8Y8 trial.

Centering conversation on systemic therapy, panelists review trial data behind the first-line combination regimens for patients with advanced clear cell RCC.

Selecting the Appropriate First-Line Therapy in Advanced Clear Cell RCC 

 Ben, I apologize for focusing on you entirely during the first part, but I’m going to keep going. One thing on which I disagree with just about everyone I know about is around this role, because no one seems to discuss the nephrectomy issue. We have a patient—let’s say they’re 72 years old. They’ve got half-dozen lung metastases. They’ve got an 8-cm primary kidney mass. There obviously is intermediate-risk disease with other parameters. They come in and say, “I’ve been told I have lots of options on what I want to do. There seems to be uncertainty about whether I should have my kidney cut out before I have systemic therapy.” What are you telling that individual?

 Those usually end up being long conversations. What I end up recommending to the patient is very individual and nuanced. In the setting right now, we have unclear data about what to do. There’s a lot of clinical judgment that factors into it. Things like whether surgery will remove the bulk of the disease is 1 of those important features. What’s the pace of their disease? Because there’s a delay that’s inherently introduced when you’re doing surgery. Some of those things are certainly important that I take into consideration.

 I agree. It’s a personalized decision where you’re having that shared decision-making. It’s not 1 size fits all, no up-front cytoreductive nephrectomy for patients with newly diagnosed metastatic disease. It’s having that discussion. If somebody’s disease burden is low and they feel good, if they have a couple of lung nodules but the bulk of the disease is in their primary, then I don’t think it’s unreasonable to take out their primary. Maybe you’ve delayed them 3 months for their systemic therapy. You can get a sense of their intermediate risk. They don’t have sarcomatoid. They’re not going to blow up in that 3-month period. It’s shared decision-making. I don’t think it’s 1 size fits all. We have the data from CARMENA, but those data are incredibly biased based off the patients who are enrolled in the trial. Ulka, you’re on the PROBE study, which is going to be important in answering the role of cytoreductive nephrectomy and the era of I/O [immuno-oncology] therapy.

 You talked to us about the PROBE study quickly, which is a bit of a plug as well. It’s likely good. 

I address these patients presenting with synchronous primary and metastases by first trying to decide if I’m going to offer this patient combination immunotherapy. If it’s oligometastatic, with 1 adrenal metastasis, chances are you’re going to remove it, get the patient in complete remission, and just do surveillance. Barring that, the majority of your synchronous metastatic patients are going to be with a number of multiple metastases, for which you’re going to offer a combination immunotherapy-based regimen.

Then we should do the immune-based regimen first for a set time period. Three months is about where that lies—somewhere between 10 and 14 weeks—and then we assess the disease. If they have a response or stable disease, then they’re eligible for randomization on the SWOG 1931 trial, or PROBE, which randomizes them to get immediate cytoreductive nephrectomy or continue immunotherapy-based regimen.

The big problem is that we don’t have evidence of cytoreductive nephrectomy helping them at this point. Whether the systemic therapy is overpowering enough and has improved in efficacy that the chance that cytoreductive nephrectomy will add something, it could be small. But there are enough preclinical data and some clinical data from melanoma. We just heard that neoadjuvant immune-based regimen followed by local therapy makes a big difference compared with doing up-front cytoreductive nephrectomy and follow-up. The neoadjuvant seems to be superior.

 A friend of mine named Brian tells me that we shouldn’t be doing delayed cytoreductive nephrectomy as a standard of care as it stands. However, I see a lot of patients who, 6 months into therapy, complete response in different areas. There are 2 cm of remaining kidney mass, and they just want the kidney gone. Eric, you’ve done a huge amount of this or neoadjuvant work. You did some work with sunitinib back in the day in the perioperative neoadjuvant setting. What’s your take on this delayed cytoreductive nephrectomy? Do you agree or disagree with Brian?

 It’s hard to know whether the primary that remains in place is having a negative biological effect. At this point, it’s a data-free zone. It’s important that we’re doing studies like PROBE to get some more information. But it’s not necessarily plausible that you’re having a great response everywhere, including that primary tumor. Leaving that primary tumor in place could become a [INAUDIBLE] for further molecular evolution and new metastases development. If you’re seeing shrinkage everywhere, that doesn’t seem plausible. It ends up becoming more of a psychological benefit for the patient. There they say, “We’ve managed to get this piece of disease out; therefore, I’m feeling better.” I’m a little conflicted. We could argue either way whether this will prolong life for the patient to perform that delayed cytoreductive nephrectomy. But if you’re seeing good response everywhere, the likelihood that area is a threat in of itself is probably not high.

 From an educational perspective, is it fair to say, as a take-home message, that individuals with poor risk disease should not be receiving a cytoreductive nephrectomy? Can we all agree on that?

 Great. Can we agree that in patients with intermediate-risk disease, a multidisciplinary discussion with the surgeons, the oncologist, and the patient is wise? The proof around this is very gray, but we all feel that some patients may benefit from that approach. Do we agree on that?

 The role of cytoreductive nephrectomy delays cytoreductive nephrectomy remained an important question within the PROBE trial. We’re excited about the results of that study.

Comprehensive insight to the role of nephrectomy over systemic therapy in patients who receive a diagnosis of advanced clear cell RCC. 

What is the Role of Nephrectomy in Advanced Clear Cell RCC?

® titled “The Evolving Treatment Landscape of Renal Carcinoma: Highlights from ESMO 2022 and Beyond.” I’m Tom Powles. I’m a professor of oncology at Barts Cancer Institute in London [England]. I’d like to introduce the rest of the panel. Eric, would you like to introduce yourself?

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

 I’m Rana McKay. I’m a professor of medicine at the UCSD [University of California San Diego School of Medicine in San Diego, California].

 I’m Ulka Vaishampayan. I’m a professor of medicine and oncology at the University of Michigan [Rogel Cancer Center].

 And I’m Ben Maughan, a professor of genitourinary oncology at the Huntsman Cancer Institute in Salt Lake City, Utah.

 We’re going to kick off this discussion with you, Ben. Can you talk about some of the background of renal cell cancer and some of the issues, perhaps around prevalence and bits around the disease?

 Renal cell carcinoma [RCC] is 1 of the more moderate, or somewhat less frequent, cancers in the United States. It’s about the ninth most frequent cancer that we see, but it’s not the most common cancer that oncologists are faced with in the clinic. As with every cancer, there’s a spectrum of biological activity and therefore prognosis for the patients that we see. Obviously, one distinction is: does the patient have metastatic disease vs localized disease? The treatment paradigms are quite divergent.

 Today we’ll predominantly focus on metastatic.

 Even in the metastatic situation, the biology in the spectrum is variable. We do have some clinical characteristics that we use to help guide or predict what the outcome is going to be for that patient. The 2 most common clinical criteria that we use are the Memorial Sloan Kettering [Cancer Center] or IMDC [International Metastatic RCC Database Consortium] scoring systems. The real bonus, or utility, of both systems is that they use very easy-to-obtain information, things like the hemoglobin or LDH [lactate dehydrogenase], or the time course of when they became metastatic, and you’re starting systemic therapy.

 Eric, why are we using calcium and not using biomarkers from a tissue? 

 That’s a good question. At this point, despite our best efforts, we haven’t found molecular biomarkers that are necessarily predictive for response. We’re evolving into demonstrating prognosis. For example, with a 

mutation, the prognosis is probably better than with a 

 mutation. But linking this to specific treatments and outcomes in specific treatments, at least in September 2022, we’re not quite there.

 Ben, when you look at the outcome of these patients, they come in and they’ve read about this group of new drugs, these immunotherapies. Many are expecting terrific results. What do you say to your patients when you meet them and they say, “What can I expect next in terms of my life expectancy?”

 That’s a great question. I share some of the enthusiasm that patients have because I remember treating some of these patients as an oncology pharmacist before I became a physician. At that time, we had interferon and high-dose IL-2, which most patients didn’t respond to. I’ve seen over time that transitioning from pharmacists to a physician dramatically improves. I share some of their optimism. They’ve had the duration of responses substantially improved, but the response rates have also dramatically increased. I share some of that enthusiasm, and that oftentimes comes out in my initial conversations with patients.

 What time you do your first CT scan and metastatic disease. Do you tell your patients at baseline what to expect? Or do you wait and say, “We’ll wait for the first response. If you respond, things are going to be OK. If they don’t, we’ve got a problem in our hands.”

 Typically, that first assessment, if there’s no significant new problems that have occurred during those first few months, I do it around 3 months. I usually take the tack of, “Let’s see what that response is, and then we’ll rediscuss where we’re going from there.”

Expert oncologists open their discussion on advanced clear cell RCC by identifying its prevalence and prognoses before moving into treatment considerations. 

Overview on Clear Cell Renal Cell Carcinoma: Prevalence and Prognosis 

Thomas Powles, MD, Barts Cancer Institute, discusses the impact of immunotherapy on the treatment landscape of kidney cancer.

There has been an enormous change in the treatment of kidney cancer in 2017 with studies of immunotherapy in the frontline setting, says Powles.

CheckMate-214 is the study credited with potentially changing the frontline treatment of this disease, demonstrating a reduced risk of death of 32% with the combination on nivolumab (Opdivo) and ipilimumab (Yervoy) compared with sunitinib (Sutent).

Thomas Powles, MD, Barts Cancer Institute, discusses the impact of immunotherapy on the treatment landscape of kidney cancer.
 

Dr. Powles on the Impact of Immunotherapy in Kidney Cancer

Thomas Powles, MD, Barts Cancer Institute, discusses the combination of bevacizumab (Avastin) and atezolizumab (Tecentriq) versus single-agent atezolizumab versus sunitinib (Sutent), which was studied in the randomized, phase II IMmotion150 trial for patients with metastatic renal cell carcinoma (RCC).

The IMmotion150 is the first randomized study in frontline kidney cancer investigating immune checkpoint inhibitors, states Powles.

Dr. Powles on Bevacizumab Plus Atezolizumab in Kidney Cancer

Thomas Powles, MD, Barts Cancer Institute, discusses the future of durvalumab in the treatment of bladder cancer.

In second-line therapy, the selective high-affinity human IgG1 monoclonal antibody durvalumab has shown compelling clinical activity, resulting in a jump directly to the frontline setting in clinical trials. This is ambitious, says Powles, but with frontline chemotherapy showing only modest results in bladder cancer, new therapies need to be tested.

Powles says there is a big chance that durvalumab could replace chemotherapy in the frontline, but combinations still need to be evaluated.

Dr. Powles Discusses the Future of Durvalumab in Bladder Cancer 

Thomas Powles, MD, Barts Cancer Institute, discusses durvalumab as a second-line therapy in locally advanced and metastatic urothelial cancer.

Durvalumab, is a selective, high-affinity human IgG1 monoclonal antibody that binds to both PD-1 and CD80.

In a phase Ib trial, durvalumab was associated with long-term durable responses in patients with metastatic bladder cancer patients who have previously failed on chemotherapy. The response rate was between 20% and 30% and there was also responses reported in the PD-L1—negative population.

According to Powles, durvalumab, along with agents like pembrolizumab (Keytruda), have superseded chemotherapy in the second-line.

Thomas Powles, MD

Articles