 Moving to relapsed/refractory metastatic clear cell RCC [renal cell carcinoma], Dr Voss, could you summarize the phase 3 METEOR, CheckMate-025, and the randomized phase 2 of lenvatinib/everolimus? Obviously, the 3 regimens are approved.

 These are studies that led to the development of regimens that have now been on the market for some time. We have to take a detour through the history of kidney cancer and think back to what the landscape was at the time. METEOR and CheckMate-025 were conducted in parallel, essentially in an environment where the standard of care to treat kidney cancer was that of targeted therapies only. Clear cell kidney cancer was predominantly treated with TKIs [tyrosine kinase inhibitors] directed against angiogenesis. But remember that at the time, one of the standards of care in the second-line setting was the oral mTOR inhibitor everolimus. The typical sequence of events at the time would be to treat with a TKI in the first line and then after progression to a second line. Both trials that you referenced, Toni, took aim at that standard approach, and both now try to challenge that second-line gold standard everolimus with then, new agents. One of them was cabozantinib, which we’ve talked about quite a bit today. Cabozantinib was the new kid on the block at the time. The sequence proposed was to give cabozantinib in patients who had received at least 1 TKI. There was no maximum prior lines of therapy in METEOR. They were then randomized to either receive everolimus or cabozantinib. It was the first study in kidney cancer that was able to demonstrate superior overall survival [OS] and progression-free survival [PFS]. It had a novel design of its own going from a PFS end point to a secondary OS end point with an addition of more patients. And both were demonstrated to be superior over everolimus. There was a much higher response rate also. It established cabozantinib as a new standard of care in pretreated kidney cancer.

The second one, which probably had historically the biggest impact of all the studies we've discussed today, was the CheckMate-025 study because it signified the advent of checkpoint inhibitors in kidney cancer. Again, patients who had 1 or 2 TKIs received either everolimus as a standard of care or nivolumab monotherapy. The primary end point for that study was overall survival. This study demonstrated superior overall survival. Secondary end point was higher response rate in the second-line setting for the immunotherapy. Better quality of life data tolerance improved. There was a PFS signal that now we're all very familiar with in that earlier on you didn't really see the benefit immunotherapy. And then with more time, you could see curves separate.

The third study that you mentioned was a bit of an oddball. It was a phase 2 trial that was very well designed with strict inclusion criteria. This was the lenvatinib/everolimus pivotal trial. A phase 2 that enrolled patients in the second- and only the second-line setting. Everyone had to have had 1 TKI and nothing else. And then they were randomized again: standard of care, everolimus; or new TKI, lenvatinib, which is a co-inhibitor of VEGF, FGFR, and other kinases; or the combination of the 2. A 3-arm, 50 patients each, 150-patient total trial. Not a big trial, a phase 2 study that was originally designed as a registration trial. But it ended up showing such a strong signal for the combination that the company was able to take the data to the FDA and was granted approval for the lenvatinib/everolimus combination.

The efficacy data there were going from everolimus to lenvatinib to the combinations. We saw a step-wise increase of not only response rate and PFS, which was the primary end point, but there was also a very strong overall survival signal on that study. And that’s ultimately what convinced the FDA to its approval.

These were the standards that were established in a time when we did not have I/O [immune-oncology] combinations in the first line. The key question, obviously, is now that we have these regimens on the market as on paper, second-line options, how do we apply them in a world where we treat most patients in the front line, at least intermediate/poor risk, with combinations?

Videos

Clinical Trials for Relapsed/Refractory mRCC 

: Dr Escudier, what’s your vision here? Remember how we started together, you and I, 15 years ago with the shark cartilage trial? This hasn’t worked. But now we have things that work, and I would like your opinion for our audience here about 3 trials. We don’t have the results of these 3 trials. One finished accrual, 2 are accruing. How can they potentially shape the landscape of frontline therapy for metastatic RCC [renal cell carcinoma]? Let’s start with the trial that finished accrual, CLEAR. How do you think this trial will do, especially if we don't have from the first analysis an overall survival benefit?

: I think…sunitinib is going to beat everolimus, so that is going to be another regimen that is going to be in the same range as pembrolizumab/axitinib and nivolumab/cabozantinib. The big surprise will be if we go to 20 months-plus PFS [progression-free survival], if we go to 80% response, I would be surprised. But that would be probably the only thing that would make me change my mind, but I think it’s going to be a toxic regimen. More toxic than nivolumab/cabozantinib and pembrolizumab/axitinib. Once again, I might be wrong. That’s what should happen here. I’m sure survival will be positive at the first interim analysis because that has been the case for all very active regimens. I would be surprised if it changes our mind. However, it’s not the same drug as cabozantinib. It’s not the same drug as axitinib. We’ll have to look at the group, especially, we have VEGF here. We have the medication with cabozantinib. We have a different drug with axitinib. I still think we will have to work on our biomarkers because we cannot say we are going to use the same regimen wherever we want. I don’t think we should.

: The study that is accruing now is COSMIC-313. It’s the only study, now at least, that is accruing with a modern control arm of combination or with a non-sunitinib. Nivolumab/ipilimumab is the control and nivolumab/ipilimumab/cabozantinib is experimental arm. What do you think about the study and its positioning?

: One, it has the best study design. We go against a new standard of care; that is a good design. Second, we all want to see what the triplet does. I’m still thinking that it’s going to be toxic, but toxicity is OK if we step forward in terms of activity, complete remission [CR], and that’s what I want to see. I hope we will see it. I know from my own experience that it’s more toxic than nivolumab/ ipilimumab. That’s probably one of the most important trials we have actually. We need to get these data as soon as possible to know whether we should go to a triplet. That’s a hope we all have, to cure more patients, and that’s probably the best way. We’ll see. It’s ongoing.

: And how do you feel about PDIGREE? That’s an Alliance group study and gives nivolumab/ipilimumab then transitions to cabozantinib if there is progression, where the randomization between nivolumab and cabozantinib/nivolumab happens in patients who have stable disease or partial response but not CR. What do you think the place is of this regimen?

: I think it’s a little premature. I don’t like the design of the study, although I know it’s a US one. I think the big question we still have, and we need a good study to do that, is should we continue with PD-1 or PD-L1 blockade after first I/O [immune-oncology therapy] here? That’s why I like the CONTACT study, which is going to come with atezolizumab/cabozantinib versus cabozantinib, because at least it’s a first phase 3, which is going to maybe answer the question of continuing. I don’t like the phase 2 of pembrolizumab/lenvatinibpost-I/O because it’s just a phase 2 and I’m still thinking we need a control arm with monotherapy here. So [PDIGREE] will give us an idea, but it’s not perfect, I prefer CONTACT-03 as the best study, which is 1-to-1.

Upcoming Combination Trials for mRCC

 To answer Martin, where I’m giving I/O [immune-oncology] post-I/O it’s nivolumab/ipilimumab, It was one of the studies we presented at ASCO [the American Society of Clinical Oncology annual meeting] 2020. We saw a 15% response rate in a non-VEGF regimen with nivolumab/ipilimumab post-I/O, and the responses were in this fraction RCC [renal cell carcinoma] trial well maintained. You could still say there is ipilimumab alone. Unfortunately, there are no studies in the modern era with ipilimumab alone. There’s an NCI [National Cancer Institute] study from many years ago with different dosages of ipilimumab that shows significant toxicity. Higher doses of ipilimumab, 3 and 10 mg/kg. But there was activity. Even in this 15%, you cannot rule out that single-agent ipilimumab. But I have been giving the combination, especially if the patient has sarcomatoid histology. Dr Tannir led a study where nivolumab/ipilimumab in untreated patients with sarcomatoid renal cell cancer, remind me, Nizar, the complete responses were 18% or 20%?

The overall response rate [ORR] was 60% and 18% CR [complete response] rate. And the median OS [overall survival] was 31 months for sarcomatoid. It's something we haven't seen before. Sunitinib for the sarcomatoid had a median OS of 13 months. It hasn't changed over a decade, 2 decades of targeted therapy. For sarcomatoid, TKIs [tyrosine kinase inhibitors] alone don't work that well. But you consider pembrolizumab/axitinib, and atezolizumab/bevacizumab also had good ORR and CRs, but the most compelling or most impressive results are with nivolumab/ipilimumab in sarcomatoid. Again, but not mentioned, those patients with intermediate risk or risk who have sarcomatoid—we're talking about clear cell here—they have 50% PD-L1 positivity, and this is where I think nivolumab/ ipilimumab works. Toni, you at [Dana-Farber Cancer Institute] did the OMNIVORE trial. The Germans or the Europeans did the TITAN study, and Michael Atkins, [MD,] led the trial with [Hoosier Cancer Research Network]…. The data are clear. If you are going to use ipilimumab, the best time to use ipilimumab is in combination with nivolumab up front, not post-pembrolizumab/axitinib or post-nivolumab monotherapy and then you do the ipilimumab later. It’s clear. The responses you mentioned, at best 15%.... Clearly, ipilimumab is, in my opinion, the drug that produces the memory T cells that provide that durability when you give I/O-I/O therapy.

I/O Therapy After Progression on I/O for mRCC

: Martin, you bring up a great point because I’ve seen both and that’s why you are part of the CONTACT-3. You and Nizar have seen both. Once the patient’s tumor has progressed on I/O, [immuno-oncology], nivolumab/ipilimumab, cabozantinib/nivolumab, pembrolizumab/axitinib, would you use a single-agent TKI [tyrosine kinase inhibitor] or would you say, “I’m taking the pembrolizumab/lenvatinib data, the report in 

, I’m taking atezolizumab/bevacizumab data on the crossover, and I’m going to have an I/O?” Would you do that or do single-agent TKI?

: We must be data-driven. And until there is high-level evidence showing that you need to continue with the PD-1 or the PD-L1 blockade, after already progressing on immune checkpoint inhibitors. Until we have that data from CONTACT-3, or a sequel phase 3 trial to HOPE 111, that Martin alluded to, pembrolizumab/lenvatinib vs lenvatinib, until we have those data and we see that combination arm with pembrolizumab plus lenvatinib or atezolizumab plus cabozantinib beating the single-agent TKI…it is not scientific, and irresponsible, to prescribe PD-L1 after progression on immune checkpoint inhibitors. In Europe, they’ll never do that. Pembrolizumab/axitinib is not approved in Europe as second-line therapy. I wouldn’t think that they will approve pembrolizumab/lenvatinib based on just HOPE 111 post-nivolumab/ipilimumab. We must be good stewards of our resources. Health care is so expensive, and there’s toxicity when you combine a PD-1 or a PD-L1 plus a TKI. Until CONTACT-3 shows positive data, or a subsequent phase 3 trial with pembrolizumab/lenvatinib vs lenvatinib shows positive data for the combination, I will use only a TKI.

I’m not going to dodge your question by answering what the community is doing, I’ll be honest about this. Nizar is making a couple of important points, and the question of resources and the financial toxicity of what we do can’t be understated. What I do in my own practice, I try to be a little bit nuanced about it if I can. The question as to how the disease has behaved up until and through first-line therapy speaks to it because I understand that getting a second I/O TKI without the underlying phase 3 data that we need is juggling resources somewhat irresponsibly. But also, if someone just blew through first-line therapy, and I don’t think that they’re likely to respond to TKI alone, the question is putting them on the TKI alone out of principle, is that a good use of resources?

We have responsibility for our patients. Someone who has rapidly progressed through nivolumab/ipilimumab, for instance, in the first line, absolutely I’ll put the patient on a TKI I/O combination. I understand that axitinib/pembrolizumab was not developed in that space, but we have a lot of data that say it will likely be highly active. I believe that it will be. In some ways, what we are seeing now is a more complex version of what happened in kidney cancer 10 years ago when we started to learn that you can take one TKI, after another TKI, after another TKI. And people wouldn’t stop in the third line because there was no FDA approval. We didn’t say, “Alright, well, we’ve given them pazopanib and then axitinib. They can’t get everolimus because they just had pneumonitis. I’m not going to give them a third TKI because we don’t have an FDA label.” But the moral dilemma here is, that now we have more than 10 regimens on the market. And Nizar is right, for most patients we have the choice and we have the moral obligation if we think that that’s a reasonable thing to do clinically to use the resources responsibly.

 One thing is that we do have prospective data with axitinib, retrospective with cabozantinib post-I/O, and the responses are quite high in the tumor shrinkage. I wouldn’t be surprised…even with the lenvatinib/pembrolizumab study, if this all the TKIs. I’m only aware of CONTACT-3 in the randomized fashion unless there is something else. CONTACT-3 is a study post-I/O, randomizes patients with clear cell and some non-clear cell histologies to cabozantinib as control vs the combination of cabozantinib and atezolizumab. Bernard, in France are you giving I/O post-I/O or is it a nonstarter because you cannot get reimbursed?

: No, we cannot give I/O post-I/O. It's not that we're not reimbursed because the system is not done like that. But we're not allowed to do that. My point on this discussion is that I'm a afraid that since we have done so much biomarker work, we know that some patients don't need VEGF and some patients don't need I/O. The question for me now is how to change our way to treat patients. What can we do? I would agree with Nizar that some patients would need nivolumab/ipilimumab. And as we don’t have better biomarkers…I think PD-L1–positive tumors have a lot of chance to respond to I/O. I would use I/O-I/O in this patient, certainly, and I have no doubt that this patient should be treated with I/O-I/O because VEGF doesn’t work very well in those patients. Whatever we use, cabozantinib has a little activity but not a lot. Axitinib has little activity, so we should use I/O-I/O. And probably the rest of the patients need to have a TKI, and that’s why the question would be more between pembrolizumab/ axitinib and nivolumab/cabozantinib, in my opinion, at that point here. If we have to do a study, I would not do a large phase 3 nivolumab/ipilimumab versus nivolumab/cabozantinib, or vice versa. I would do it in PD-L1–positive patients because that’s, for me, the best hypothesis we have. I/O-I/O works very well in PD-L1–positive patients, at least in the retrospective analysis of CheckMate-214.

Role of TKI After Progression on I/O for mRCC

 CheckMate 9ER, despite being in the Presidential Symposium at the European Society for Medical Oncology Congress [ESMO], was not the only clinical trial or combination VEGF–I/O [immuno-oncology] presented. Dr Voss, you’ve been involved in several studies at Memorial Sloan Kettering Cancer Center, and you’ve seen the result that Drs Sumanta Pal and Bradley McGregor presented with another combination, with cabozantinib and atezolizumab. That study was named COSMIC-021. If you can discuss first with us the design, the result in your opinion—knowing these is not a randomized study. What’s the practical implication of COSMIC-021?

 Thank you, Toni. COSMIC-021 was presented by Dr Pal at the ESMO meeting this year. This is a combination that conceptually is similar to the cabozantinib-nivolumab combo that we presented so far, but it’s much earlier in its development. Cabozantinib, the same TKI [tyrosine kinase inhibitor] backbone here, is now paired with atezolizumab, which is a PD-L1–directed monoclonal antibody that’s been in development for kidney cancer and has actually been approved for other cancers for some time. The data that were presented by the authors is taken from the COSMIC-021 study, which is a phase 1/2 study that explored this combination specifically in kidney cancer. The data that we saw included mostly patients from the expansion that was pursued in a phase 2 fashion on 2 different dose levels. That’s important to keep in mind.

Atezolizumab was being combined with cabozantinib at full dose, 60 mg per daily. That was a cohort of 30 patients. There was a second patient cohort equal in size, 30 also, who received the same dose of atezolizumab but attenuated dose cabozantinib at 40 milligrams daily. Similar to what was done on the CheckMate 9ER trial. The primary end point for the phase 2 analysis done here was objective response. This enrolled patients with clear cell histology in the first-line setting. Patients had not received other therapies, and patients who had enrolled in this study irrespective of IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] risk status. As seen with the 9ER combination, we saw a high-level of activity here. This is not a randomized trial. There’s no comparator arm. But we got a very strong signal for efficacy in this study. On both arms, it appeared that cabozantinib was given at 60 mg. We saw a high objective rate. The response rate for the 40-mg dose was 50%. At 60 mg, it was 47%. There was some CR [complete response] seen on both of these combinations. Both in the same range. What was striking to me is there was very low failure rate on this regimen. Similar to the cabozantinib-nivolumab combination. Less than 5% of the patients treated on the COSMIC-021 study suffered primary disease progression, which is important as we keep these studies in mind.

Less can be said about progression-free survival with such a small cohort of patients, but it was promising. PFS was 19 months by median on the 1 arm, 15 months on the other. Bottom line here, what I would say in terms of effectiveness seen is, this certainly doesn’t fall short in terms of a signal from the other I/O–TKI combinations we’ve seen. A high objective response rate. Very good progression-free survival data. When you look at the waterfall plot taken from Dr Pal’s presentation, we see that the majority of patients benefit who are put on this regimen in the first-line setting. We can only speculate where this is going to go with further development, but certainly the signal is there.

 No, that’s good. We’ll look at CONTACT-03 a bit later because, hopefully, this study—this pie to our right—was done in I/O naïve. The decision, or at least the consensus, was to move to a combination in the post–I/O setting. The 1 interesting thing—I don’t know if you all agree with me—is the fact that the type of TKI does matter for combination. Sunitinib and pazopanib are both front-runners. We didn’t know how to pick a front-runner. We end up with the COMPARZ study. Because we all struggled with whether we should do sunitinib or pazopanib. Both drugs, unfortunately, failed to combine with a checkpoint inhibitor. We couldn’t move to a phase 2. There was significant disease-limiting toxicity. Sunitinib was tried, and pazopanib was to be combined with nivolumab. Pazopanib was attempted to be combined with pembrolizumab. These didn’t move on. Drugs such as cabozantinib but also axitinib and lenvatinib did make it to phase 3 trial, so that’s refreshing to know. To know that the type of TKI does matter here.

Review of the COSMIC 021 Study for mRCC

®, “Evolving Practice Patterns for Advanced Clear Cell Renal Cell Carcinoma.” I am Toni Choueiri, from the Dana-Farber Cancer Institute in Boston, Massachusetts. Joining me today in this discussion are my colleagues Dr Bernard Escudier, from the Institut Gustave Roussy in Villejuif, France; Dr Rana McKay, from the University of California San Diego; Dr Nizar Tannir, from The University of Texas MD Anderson Cancer Center in Houston; and Dr Martin Voss from Memorial Sloan Kettering Cancer Center in New York.

Today we are going to discuss how recent clinical trials and new FDA approvals are shaping the way we treat metastatic kidney cancer. We’re going to include key topics discussed during the 2020 ESMO [European Society for Medical Oncology Congress] and the potential impact of new data on clinical practice.

Our first segment involves frontline clinical trials in metastatic clear cell RCC [renal cell carcinoma]. We’ll discuss CheckMate 9ER, which was presented during the plenary session at ESMO. We’ll start with Dr McKay to tell about the rationale to that combination and the trials that led to CheckMate 9ER. Dr McKay?

 Thank you, Dr Choueiri. It was exciting to see the CheckMate 9ER data presented at the ESMO meeting this year. The groundbreaking work that led to this combination entering into the phase 3 setting, and ultimately a positive trial, was the work of Andrea Apolo at the NCI [National Cancer Institute], who designed a phase 1 study looking at the combination of nivolumab with cabozantinib and also with ipilimumab. That work was recently published in the 

] before the release of the ESMO data. We know that nivolumab has single-agent activity in RCC as well as cabozantinib. A series of trials have demonstrated that combination I/O [immuno-oncology]–VEGF inhibition has improved outcomes for patients. That provided the rationale, and Andrea’s work actually provided the rationale for the trial going into phase 3.

 Can you review with us the trial design? I can speak before asking Dr Escudier later about the safety and efficacy.

 This was a large phase 3 randomized open-label trial. It enrolled about 650 patients. Patients with newly diagnosed or metastatic RCC that’s treatment-naïve with a clear cell component were randomized 1:1 to receive the combination of nivolumab plus cabozantinib vs sunitinib. The starting dose of cabozantinib for this trial was 40 mg once daily as opposed to the single-agent dose, which is at 60 mg. The primary end point was PFS [progression-free survival], and secondary end points were OS [overall survival] response, duration of response, and safety. The trial was dramatically positive for all 3 efficacy end points, including PFS, OS, and objective response. There was nearly 49% reduction in the risk of progression or death, 40% decrease in the risk of death, and improvement in responses that were observed in the trial. Dramatically positive study.

 The quality-of-life data are quite interesting. They absolutely, truly matter. How patients feel on therapy and how therapy augments their baseline symptoms is critically important. The patients that were enrolled on the trial were heterogeneous. Patients with favorable-risk disease, intermediate-risk disease, and poor-risk disease have a different composition at baseline, and the fact that we did not see a decrement in quality of life with the combination—that’s clinically meaningful with patients. Now that we have several options in the frontline space, these nuances are going to start to come out. How does the patient feel? My patient feels better on this regimen or they’re not feeling terrible on this regimen, and that’s critically important. The quality-of-life data were intriguing. We’re going to need to see more of that as the study evolves and we get additional data. It was a great teaser because part of the most interesting aspect of this work. Now we’ve seen a lot of studies and, not to say they’re largely similar, but that was a differentiating piece for the I/O, this nivolumab-cabozantinib combination.

 Dr Escudier, you’re 1 of my first mentors. I will always look up at you and your initial work with sorafenib and before that changed how we treat renal cell cancer. And that was many years ago. Do you believe, looking at 9ER, that these data will be practice changing?

 They could be. This is an outstanding combination. I was impressed by the data we had both with PFS and OS. What has been for me the most surprising was thinking it would be in phase 3. In fact, it was not. Both on the safety side and the quality of life, as Rana said before. This is impressive.

Martin H. Voss, MD, Memorial Sloan Kettering Cancer Center

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Role of TKI After Progression on I/O for mRCC

Review of the COSMIC 021 Study for mRCC

Introduction and Review of CheckMate 9ER for Metastatic RCC