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Future Expectations in Renal Cell Carcinoma

Panelists:Robert A. Figlin, MD, Cedars-Sinai Medical Center; Sandy Srinivas, MD, Stanford University Medical Center; Nizar M. Tannir, MD, FACP, MD Anderson Cancer Center; Martin H. Voss, MD, Memorial Sloan Kettering Cancer Center
Published: Monday, Apr 18, 2016


Transcript:

Robert A. Figlin, MD:
Sandy, before we summarize our visit, have the endpoints in kidney cancer changed? Are we now really thinking about overall survival (OS) as the thing that patients really want and we’d like to give them compared to a decade ago when we were looking for incremental progression-free survival (PFS)? I have yet to have a patient ask me for more PFS?

Sandy Srinivas, MD: Yes. I think with so many agents, we’ve become like breast cancer doctors. It’s nice to have this many choices. The good thing I think about kidney cancer is that many of these are not cross-resistant. There is still VEGF dependence. So even if a patient progresses on one drug, we have the opportunity to give them additional drugs. I would hope that physicians are not quick to switch just so that they can put the patient on nivolumab. Like was mentioned before, the nivolumab trial did allow two prior therapies, so an alternate strategy that I might pose is, as Nizar mentioned, if a patient has had a long response to a TKI, I don’t think it would be wrong to continue with another TKI and use nivolumab as a third option. So I think there are many choices, but to come back to your endpoint question: I think it’s nice that we have raised the bar up and look for OS, and perhaps even cure, as a possibility for these patients.

Robert A. Figlin, MD: This has been a great discussion. We’ve reviewed and discussed a lot of information on the latest in the treatment of advanced kidney cancer and what we can expect to see in the near future. Before we end today’s discussion, I’d like to get final thoughts from each of the panelists. And I’d like you to focus on several things in your concluding remarks: endpoints, how we develop new drugs in this space, absence of complete responses, and the things that are going to make the next leap forward for kidney cancer patients as it has in other diseases. Martin, your thoughts?

Martin H. Voss, MD: So these are certainly exciting times to be developing drugs in kidney cancer. For our patients, I think it’s remarkable to think back to the beginning of the last chapter when the randomized sunitinib versus interferon trial put an end to the cytokine era and moved us into the VEGF TKIs as the new standard. And if you think back to that, the median PFS for cytokines at the time was short of six months. And seeing where we are now as we enter the next step beyond VEGF and mTOR inhibitors, going into the era of adding checkpoint inhibitors to this agent, we have since then pushed the PFS, pushed the OS, into the range of around 30 months. And the fact that we have all these agents available is certainly wonderful news for our patients.

I think if I were to emphasize one thing moving forward, it is that as we have more drugs in our armamentarium and choices get to be more complex, the development of biomarkers is going to be key. And we haven’t spent too much time talking about that today. We need to define biomarkers that can help us choose next steps, biomarkers that can be instituted not only at the time of diagnosis, but maybe also as we sequence patients. [This is true], I think not only in non-clear–cell kidney cancer, which is a heterogeneous group of different disease that need to be better defined to define targets, but also in clear-cell kidney cancer. What are tests that we can develop to know whether after a TKI, the next step should be another TKI or maybe an mTOR inhibitor? There are some tissue markers that push us in that direction, or maybe that patient is going to be exquisitely sensitive to a checkpoint inhibitor. Looking at other diseases, such markers can be found. I think a lot of effort should go into that direction.

Robert A. Figlin, MD: Nizar?

Nizar M. Tannir, MD, FACP: I agree with Martin. I think there are several unmet needs. I mean, certainly, we have come a long way from the days of cytokines. Patients are living longer. It’s a chronic disease, but we’re still not curing many patients, unfortunately. We need to break the barrier. We need to break that cure barrier, and I think it is going to come from understanding the biology, understanding the immune system and the biology of these tumors. And so the unmet need, which is acute right now, is the non-clear–cell space. Patients with metastatic non-clear–cell RCC constitute around 20% of the total population. As we mentioned already today during this visit, the targeted agents that we have right now do not work that well, except perhaps for in the chromophobe histology. So we need to do better here, and it has to come not from one trial like we did with the ESPN and ASPEN trials where we enrolled all the patients with non-clear–cell tumors into these trials. [Instead we need] specific trials for each of these histologies, founded on the biology, on understanding the key pathways or the key mutational drivers of those diseases.

I think our discussion about sequencing and what are we doing for our patients today is going to change quickly. This is a rapidly evolving landscape because, as we discussed, there are several trials in the first-line setting combining immune checkpoint inhibitors with themselves: like, for example, the nivolumab/ipilimumab phase III trial (CheckMate 214) which could become the next standard of care in the first-line setting. [If positive], it will change completely how we are sequencing the agents. Obviously, times are exciting for our patients, but I think it is also important to address the toxicities, as we discussed.

Cost. I think we cannot leave this discussion without talking about cost. How can we make these expensive therapies that have revolutionized the field more effective and how can society afford those expensive therapies? I think this is a totally different discussion for a different day perhaps. But I think we should not forget that this is going to be also a challenge.

Robert A. Figlin, MD: Sandy?

Sandy Srinivas, MD: The last decade was about VEGF TKIs. I think the next decade will be about immunotherapy and how to integrate immunotherapy with the existing drugs that we have. I’m going to echo the other two panelists that it’s going to require a smarter selection of how to sequence drugs based on some biology. So like they do in lung cancer, with each progression, we might have to do biopsies to figure out what’s appropriate for the next step. I’m also going to say that toxicity management is going to become more crucial now than ever before because we’re going to start thinking about survivorship issues. Patients are living longer. What’s the effect of 10 years of a VEGF inhibitor on a patient in terms the heart, hypertension, and the other things? Patients with the immune toxicities may end up having irreversible side effects, especially things like pituitary hypophysitis. So what’s the effect in [terms of hormone] replacement? So I think we have a lot of work cut out, and it’s exciting that there are more questions to be answered.

Robert A. Figlin, MD: I just want to remind you that the decade before the targeted-era decade was the immunotherapy era.

Sandy Srinivas, MD: We’re back in circle.

Robert A. Figlin, MD: We are coming full circle. Thank you so much.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

Robert A. Figlin, MD:
Sandy, before we summarize our visit, have the endpoints in kidney cancer changed? Are we now really thinking about overall survival (OS) as the thing that patients really want and we’d like to give them compared to a decade ago when we were looking for incremental progression-free survival (PFS)? I have yet to have a patient ask me for more PFS?

Sandy Srinivas, MD: Yes. I think with so many agents, we’ve become like breast cancer doctors. It’s nice to have this many choices. The good thing I think about kidney cancer is that many of these are not cross-resistant. There is still VEGF dependence. So even if a patient progresses on one drug, we have the opportunity to give them additional drugs. I would hope that physicians are not quick to switch just so that they can put the patient on nivolumab. Like was mentioned before, the nivolumab trial did allow two prior therapies, so an alternate strategy that I might pose is, as Nizar mentioned, if a patient has had a long response to a TKI, I don’t think it would be wrong to continue with another TKI and use nivolumab as a third option. So I think there are many choices, but to come back to your endpoint question: I think it’s nice that we have raised the bar up and look for OS, and perhaps even cure, as a possibility for these patients.

Robert A. Figlin, MD: This has been a great discussion. We’ve reviewed and discussed a lot of information on the latest in the treatment of advanced kidney cancer and what we can expect to see in the near future. Before we end today’s discussion, I’d like to get final thoughts from each of the panelists. And I’d like you to focus on several things in your concluding remarks: endpoints, how we develop new drugs in this space, absence of complete responses, and the things that are going to make the next leap forward for kidney cancer patients as it has in other diseases. Martin, your thoughts?

Martin H. Voss, MD: So these are certainly exciting times to be developing drugs in kidney cancer. For our patients, I think it’s remarkable to think back to the beginning of the last chapter when the randomized sunitinib versus interferon trial put an end to the cytokine era and moved us into the VEGF TKIs as the new standard. And if you think back to that, the median PFS for cytokines at the time was short of six months. And seeing where we are now as we enter the next step beyond VEGF and mTOR inhibitors, going into the era of adding checkpoint inhibitors to this agent, we have since then pushed the PFS, pushed the OS, into the range of around 30 months. And the fact that we have all these agents available is certainly wonderful news for our patients.

I think if I were to emphasize one thing moving forward, it is that as we have more drugs in our armamentarium and choices get to be more complex, the development of biomarkers is going to be key. And we haven’t spent too much time talking about that today. We need to define biomarkers that can help us choose next steps, biomarkers that can be instituted not only at the time of diagnosis, but maybe also as we sequence patients. [This is true], I think not only in non-clear–cell kidney cancer, which is a heterogeneous group of different disease that need to be better defined to define targets, but also in clear-cell kidney cancer. What are tests that we can develop to know whether after a TKI, the next step should be another TKI or maybe an mTOR inhibitor? There are some tissue markers that push us in that direction, or maybe that patient is going to be exquisitely sensitive to a checkpoint inhibitor. Looking at other diseases, such markers can be found. I think a lot of effort should go into that direction.

Robert A. Figlin, MD: Nizar?

Nizar M. Tannir, MD, FACP: I agree with Martin. I think there are several unmet needs. I mean, certainly, we have come a long way from the days of cytokines. Patients are living longer. It’s a chronic disease, but we’re still not curing many patients, unfortunately. We need to break the barrier. We need to break that cure barrier, and I think it is going to come from understanding the biology, understanding the immune system and the biology of these tumors. And so the unmet need, which is acute right now, is the non-clear–cell space. Patients with metastatic non-clear–cell RCC constitute around 20% of the total population. As we mentioned already today during this visit, the targeted agents that we have right now do not work that well, except perhaps for in the chromophobe histology. So we need to do better here, and it has to come not from one trial like we did with the ESPN and ASPEN trials where we enrolled all the patients with non-clear–cell tumors into these trials. [Instead we need] specific trials for each of these histologies, founded on the biology, on understanding the key pathways or the key mutational drivers of those diseases.

I think our discussion about sequencing and what are we doing for our patients today is going to change quickly. This is a rapidly evolving landscape because, as we discussed, there are several trials in the first-line setting combining immune checkpoint inhibitors with themselves: like, for example, the nivolumab/ipilimumab phase III trial (CheckMate 214) which could become the next standard of care in the first-line setting. [If positive], it will change completely how we are sequencing the agents. Obviously, times are exciting for our patients, but I think it is also important to address the toxicities, as we discussed.

Cost. I think we cannot leave this discussion without talking about cost. How can we make these expensive therapies that have revolutionized the field more effective and how can society afford those expensive therapies? I think this is a totally different discussion for a different day perhaps. But I think we should not forget that this is going to be also a challenge.

Robert A. Figlin, MD: Sandy?

Sandy Srinivas, MD: The last decade was about VEGF TKIs. I think the next decade will be about immunotherapy and how to integrate immunotherapy with the existing drugs that we have. I’m going to echo the other two panelists that it’s going to require a smarter selection of how to sequence drugs based on some biology. So like they do in lung cancer, with each progression, we might have to do biopsies to figure out what’s appropriate for the next step. I’m also going to say that toxicity management is going to become more crucial now than ever before because we’re going to start thinking about survivorship issues. Patients are living longer. What’s the effect of 10 years of a VEGF inhibitor on a patient in terms the heart, hypertension, and the other things? Patients with the immune toxicities may end up having irreversible side effects, especially things like pituitary hypophysitis. So what’s the effect in [terms of hormone] replacement? So I think we have a lot of work cut out, and it’s exciting that there are more questions to be answered.

Robert A. Figlin, MD: I just want to remind you that the decade before the targeted-era decade was the immunotherapy era.

Sandy Srinivas, MD: We’re back in circle.

Robert A. Figlin, MD: We are coming full circle. Thank you so much.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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