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Further Exploring TKI/I-O Combination Regimens in mRCC

Panelists: Sumanta Kumar Pal, MD, City of Hope; Neeraj Agarwal, MD, MS, Huntsman Cancer Institute; Bradley McGregor, MD, Dana-Farber Cancer Institute; Tian Zhang, MD, Duke Cancer Institute
Published: Monday, Apr 29, 2019



Transcript: 

Sumanta Kumar Pal, MD:
So we’ve talked about combinations such as axitinib-avelumab or axitinib-pembrolizumab, but clearly these aren’t the only VEGF/I-O combinations that are out there. Some of the regimens that I was actually quite excited about, like bevacizumab-atezolizumab, haven’t really progressed along as fast as I would have liked. But Tian, can you tell us what we’ve gleaned from that experience?

Tian Zhang, MD: I think from the data that we heard at last year’s GU ASCO [Genitourinary Cancers Symposium] in 2018, we really heard some early PFS [progression-free survival] data. I think the OS [overall survival] data are slow to mature, but we’re learning a lot about molecular signatures from the IMmotion151 trial. And so Dr David McDermott and Dr Brian Rini did a great job of profiling these tumors and thinking about who responds to what treatment. In the randomized setting, there’s a patient who has RNA sequencing data with gene expression that are high for angiogenesis signatures that really respond better to sunitinib over the immunotherapy combinations.

And then there are other patients who have more of an inflammatory gene expression signature that respond more to the immunotherapy combination. And so I think this is absolutely right. As we’re learning more about these patients, studying, we have such valuable information from our clinical trials. Even if the trial itself has not had all positive results. We’re still learning quite a bit from correlative work for biomarker stratification and really thinking about next how we can identify patients who might respond to 1 treatment over another.

Sumanta Kumar Pal, MD: So Brad, tell us the reality. Tian, I agree with you. We’ve got these angiogenesis signatures, these immune signatures. Are we ultimately going to be using these in clinical practice? What do you think?

Bradley McGregor, MD: I don’t know. I think what we’ve seen with that is atezolizumab and bevacizumab is obviously very intriguing, but I think we need to look at other combinations. Do we see that same signature? Is that same signature relevant with axitinib and pembrolizumab? And I think we don’t know those data, so we don’t know that yet.

Neeraj Agarwal, MD: There are so many things that have to be accomplished before we can even use them in the clinic.

Bradley McGregor, MD: Right.

Tian Zhang, MD: Right.

Neeraj Agarwal, MD: First of all, I want to start with a much simpler biomarker that tells clinicians in very simple words what it means, instead of showing different types of signatures and how they are going to correlate with response. It is very difficult for an oncologist who is not really teaching on a regular basis or reading on a regular basis. There are busy oncologists out there who have the capacity to see patients with 200 different kinds of cancer. I think we need simple biomarkers, prospectively validated and easily available, before we can use them.

Tian Zhang, MD: I think scientifically it’s very interesting and certainly early on in these biomarker-directed days. And you’re right, these data take a long time to generate. They’re not real-time in terms of decision making in the clinic. As we get further along, especially for cellular infiltrates and things like this, and as we understand more about the tumor microenvironment, I’m still hopeful that eventually we’ll get to a place where we can use some of these data for our decision making.

Sumanta Kumar Pal, MD: But you’re right, the field is just changing so quickly; it’s so hard to keep pace. And that really brings us to our next topic, which is the emerging spectrum of trials that we’re going to see reading out maybe over the next couple of years. There’s a big phase III trial looking at lenvatinib and pembrolizumab as compared with sunitinib. We’ve got a trial of cabozantinib and nivolumab versus sunitinib. And Brad, rather than just sort of spelling out the trial designs and so forth, I want you to pull out your crystal ball and tell us which of these regimens are going to be winners a couple of years from now.

Bradley McGregor, MD: I think when you look at the phase I data from lenvatinib and pembrolizumab, they were obviously incredibly intriguing. Response rates were something we haven’t seen before—well over 60%. So I think certainly, we’re very excited. When I enroll a patient on that trial and they get lenvatinib and pembrolizumab, they’re all superhappy because they hear about it. So I think obviously this could be intriguing. The not-talked-about-much arm is that lenvatinib-everolimus combination in the frontline setting. I can say anecdotally, it’s an active regimen. While there are concerns about toxicities, I think with close monitoring and management, it’s actually going to be well tolerated. So I think that will be very interesting, not just lenvatinib-pembrolizumab but also the lenvatinib-everolimus approach, which I think may actually have a synergistic effect such that both of them are better than either one, additive and sequential.

Sumanta Kumar Pal, MD: That’s interesting. This hazard ratio, 0.53, for axitinib-pembrolizumab really stands out in my mind. And my question to you, Tian, is, are we ever going to see something like that again? When these trials mature, is it going to be harder and harder to demonstrate that OS advantage with people getting better second- and third-line therapies?

Tian Zhang, MD: It’s hard to know, right? And you’re right: We have multiple first-line phase I trials going on and phase III first-line trials going on. And PEDIGREE is probably 1 of the latter ones, opening in May of this year. And so we hope that we’ll see these overall survival advantages as we layer in more effective strategies, maybe. We never can predict the future, right, and I’m always hopeful that we’ll have more novel combinations to offer our patients. And so if that’s the case, maybe there are mechanisms that we currently don’t know about that can actually improve outcomes for future patients. So I think we’re getting a lot of these VEGF/immunotherapy checkpoint inhibitor combinations. We’re saturating those, but maybe there are other novel targets that we haven’t talked about.

Sumanta Kumar Pal, MD: That makes sense. Neeraj, I’m going to go to you with the same question I asked Brad, forecasting with the cabozantinib-nivolumab study, CheckMate 9ER, maturing with lenvatinib-pembrolizumab on the horizon. Do you agree with Brad, that lenvatinib with pembrolizumab might be a frontline standard a couple of years from now?

Neeraj Agarwal, MD: I’ll bet on the cabozantinib-nivolumab combination and cabozantinib-atezolizumab combination. So I think cabozantinib and lenvatinib both are very active TKIs, and they also will probably have higher potential to synergize in a true fashion with a PD-1 [programmed cell death protein 1] inhibitor than axitinib. It’s certainly a much more specific VEGF-TKI. So from that perspective, probably a cabozantinib-based combination or lenvatinib-based combination will be considered.

Tian Zhang, MD: We have all these off-target mechanisms as well. Cabozantinib also hits MET and AXL. In addition to the VEGF receptors, lenvatinib hits a variety of FGFR receptors as well. So it’s certainly a wider approach, and we know that MET, for example, is more prevalent in patients with bone metastases. And so certainly thinking about that, tackling more receptors than just the VEGF receptors, can we get more active agents involved earlier? I absolutely agree.


Transcript Edited for Clarity

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Transcript: 

Sumanta Kumar Pal, MD:
So we’ve talked about combinations such as axitinib-avelumab or axitinib-pembrolizumab, but clearly these aren’t the only VEGF/I-O combinations that are out there. Some of the regimens that I was actually quite excited about, like bevacizumab-atezolizumab, haven’t really progressed along as fast as I would have liked. But Tian, can you tell us what we’ve gleaned from that experience?

Tian Zhang, MD: I think from the data that we heard at last year’s GU ASCO [Genitourinary Cancers Symposium] in 2018, we really heard some early PFS [progression-free survival] data. I think the OS [overall survival] data are slow to mature, but we’re learning a lot about molecular signatures from the IMmotion151 trial. And so Dr David McDermott and Dr Brian Rini did a great job of profiling these tumors and thinking about who responds to what treatment. In the randomized setting, there’s a patient who has RNA sequencing data with gene expression that are high for angiogenesis signatures that really respond better to sunitinib over the immunotherapy combinations.

And then there are other patients who have more of an inflammatory gene expression signature that respond more to the immunotherapy combination. And so I think this is absolutely right. As we’re learning more about these patients, studying, we have such valuable information from our clinical trials. Even if the trial itself has not had all positive results. We’re still learning quite a bit from correlative work for biomarker stratification and really thinking about next how we can identify patients who might respond to 1 treatment over another.

Sumanta Kumar Pal, MD: So Brad, tell us the reality. Tian, I agree with you. We’ve got these angiogenesis signatures, these immune signatures. Are we ultimately going to be using these in clinical practice? What do you think?

Bradley McGregor, MD: I don’t know. I think what we’ve seen with that is atezolizumab and bevacizumab is obviously very intriguing, but I think we need to look at other combinations. Do we see that same signature? Is that same signature relevant with axitinib and pembrolizumab? And I think we don’t know those data, so we don’t know that yet.

Neeraj Agarwal, MD: There are so many things that have to be accomplished before we can even use them in the clinic.

Bradley McGregor, MD: Right.

Tian Zhang, MD: Right.

Neeraj Agarwal, MD: First of all, I want to start with a much simpler biomarker that tells clinicians in very simple words what it means, instead of showing different types of signatures and how they are going to correlate with response. It is very difficult for an oncologist who is not really teaching on a regular basis or reading on a regular basis. There are busy oncologists out there who have the capacity to see patients with 200 different kinds of cancer. I think we need simple biomarkers, prospectively validated and easily available, before we can use them.

Tian Zhang, MD: I think scientifically it’s very interesting and certainly early on in these biomarker-directed days. And you’re right, these data take a long time to generate. They’re not real-time in terms of decision making in the clinic. As we get further along, especially for cellular infiltrates and things like this, and as we understand more about the tumor microenvironment, I’m still hopeful that eventually we’ll get to a place where we can use some of these data for our decision making.

Sumanta Kumar Pal, MD: But you’re right, the field is just changing so quickly; it’s so hard to keep pace. And that really brings us to our next topic, which is the emerging spectrum of trials that we’re going to see reading out maybe over the next couple of years. There’s a big phase III trial looking at lenvatinib and pembrolizumab as compared with sunitinib. We’ve got a trial of cabozantinib and nivolumab versus sunitinib. And Brad, rather than just sort of spelling out the trial designs and so forth, I want you to pull out your crystal ball and tell us which of these regimens are going to be winners a couple of years from now.

Bradley McGregor, MD: I think when you look at the phase I data from lenvatinib and pembrolizumab, they were obviously incredibly intriguing. Response rates were something we haven’t seen before—well over 60%. So I think certainly, we’re very excited. When I enroll a patient on that trial and they get lenvatinib and pembrolizumab, they’re all superhappy because they hear about it. So I think obviously this could be intriguing. The not-talked-about-much arm is that lenvatinib-everolimus combination in the frontline setting. I can say anecdotally, it’s an active regimen. While there are concerns about toxicities, I think with close monitoring and management, it’s actually going to be well tolerated. So I think that will be very interesting, not just lenvatinib-pembrolizumab but also the lenvatinib-everolimus approach, which I think may actually have a synergistic effect such that both of them are better than either one, additive and sequential.

Sumanta Kumar Pal, MD: That’s interesting. This hazard ratio, 0.53, for axitinib-pembrolizumab really stands out in my mind. And my question to you, Tian, is, are we ever going to see something like that again? When these trials mature, is it going to be harder and harder to demonstrate that OS advantage with people getting better second- and third-line therapies?

Tian Zhang, MD: It’s hard to know, right? And you’re right: We have multiple first-line phase I trials going on and phase III first-line trials going on. And PEDIGREE is probably 1 of the latter ones, opening in May of this year. And so we hope that we’ll see these overall survival advantages as we layer in more effective strategies, maybe. We never can predict the future, right, and I’m always hopeful that we’ll have more novel combinations to offer our patients. And so if that’s the case, maybe there are mechanisms that we currently don’t know about that can actually improve outcomes for future patients. So I think we’re getting a lot of these VEGF/immunotherapy checkpoint inhibitor combinations. We’re saturating those, but maybe there are other novel targets that we haven’t talked about.

Sumanta Kumar Pal, MD: That makes sense. Neeraj, I’m going to go to you with the same question I asked Brad, forecasting with the cabozantinib-nivolumab study, CheckMate 9ER, maturing with lenvatinib-pembrolizumab on the horizon. Do you agree with Brad, that lenvatinib with pembrolizumab might be a frontline standard a couple of years from now?

Neeraj Agarwal, MD: I’ll bet on the cabozantinib-nivolumab combination and cabozantinib-atezolizumab combination. So I think cabozantinib and lenvatinib both are very active TKIs, and they also will probably have higher potential to synergize in a true fashion with a PD-1 [programmed cell death protein 1] inhibitor than axitinib. It’s certainly a much more specific VEGF-TKI. So from that perspective, probably a cabozantinib-based combination or lenvatinib-based combination will be considered.

Tian Zhang, MD: We have all these off-target mechanisms as well. Cabozantinib also hits MET and AXL. In addition to the VEGF receptors, lenvatinib hits a variety of FGFR receptors as well. So it’s certainly a wider approach, and we know that MET, for example, is more prevalent in patients with bone metastases. And so certainly thinking about that, tackling more receptors than just the VEGF receptors, can we get more active agents involved earlier? I absolutely agree.


Transcript Edited for Clarity
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