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mRCC: When is TKI/I-O Combination Therapy Appropriate?

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: I don’t want to perseverate on this topic, but I think it is an interesting one. What do you think about this element of demographics? Patients on axitinib-pembrolizumab, to my recollection, were largely from areas of the world where they might not have access to secondary therapies. There’s a fairly large contingent from what are termed other countries. These are outside North America and Western Europe. Could that have led to some distinction in terms of OS [overall survival] that we’re seeing at this point?

Neeraj Agarwal, MD: If you look across the trial comparison, an equal number of patients in the axitinib-avelumab study and axitinib-pembrolizumab study got post-trial treatment. An equal number of patients got PD-L1 [programmed death-ligand 1] or PD-1 [programmed cell death protein 1]–directed therapy. Equal number of patients got VEGF-TKIs in both arms. So there was no difference in post-trial treatment. However, if you just take 1 trial and see, after sunitinib, how many patients actually got PD-1 inhibitors, you are looking at, like, less than one-third of patients who are getting these therapies.

So yes, I think that remains a concern, in my view. When I’m looking at a very similar progression-free survival [PFS], the magnitude of progression-free survival is around 4 months with axitinib-pembrolizumab versus sunitinib. But then you see overall survival benefit with a hazard ratio of 0.53, a 10% difference in patients who are alive after 1 year; that doesn’t seem to fit well, in my view. And that can be explained only by fewer patients actually seeing any PD-1 inhibitor, less than one-third. Having said that, I think I will come to the point that time will tell how these trials are going to do.

Sumanta Kumar Pal, MD: OK, very good.

Tian Zhang, MD: I agree. At most of our clinics, patients are seeing that immunotherapy in the second-line setting, right?

Neeraj Agarwal, MD: Yes.

Tian Zhang, MD: If they’re on a VEGF-TKI in that frontline, we’re alternating to a different mechanism of action in the second line. So absolutely the fact that these patients were enrolled in countries who may not have access to the second-line immunotherapy is worrisome. But it shouldn’t have factored into that first-line PFS, the first time to progression, and also the overall survival improvement. So certainly, there is a lot to be learned from these trials.

Circling back to your comment that you’re still going to use ipilimumab-nivolumab, I think very much we’re shooting for these complete responses. We want to improve upon the complete responses, so I hope there will be many providers and physicians like yourself, Neeraj, who are really dependent on the immunotherapy, a pure immunotherapy combination strategy, up front, because we really want to enroll to our phase III PEDIGREE trial through the Alliance Group. And that is really building on that pure immunotherapy combination up front.

Neeraj Agarwal, MD: Let me just make 2 comments. First of all, if you look at the IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] data, I was talking about how many patients actually see second-line therapy and how many patients see third-line therapy. That was a real-world population, not a clinical trial population—so frailer, older maybe, and with more comorbidities. And even in that patient population, 51% of patients were seeing second-line therapy. That has become my benchmark. When I’m looking at a clinical trial, and I see how many post-trial treatment therapies were received following this clinical trial–eligible patient population, they’re not reaching up to 50%. I’m intrigued—why not? And then that tells me about the resources and what is available in that given country.

Tian Zhang, MD: Sure.

Neeraj Agarwal, MD: Now, coming back to ipilimumab-nivolumab, yes, for first-line therapy, if I’m going for immunotherapy, I am looking at complete responses. But there are many patients. Just building upon that, I said axitinib-avelumab, axitinib-pembrolizumab, unless I see higher complete responses down the line, which will hopefully happen. And if we see a progression-free survival or overall survival benefit of 10 months, another point is, why don’t we just sequence monotherapy with a VEGF-TKI such as cabozantinib, followed by nivolumab?

If you extrapolate just looking at hazard ratio of cabozantinib with sunitinib, 0.48 in the CABOSUN trial, and that was an intermediate and high-risk patient population, 42% of patients had bone metastasis, so very aggressive disease biology. If we just extrapolate to the overall patient population, you are looking at a progression-free survival with cabozantinib of almost 15 months as a monotherapy. It’s just a discussion point because we don’t have head-to-head comparisons of this.

So if I’m not able to get complete responses from these regimens of TKIs plus I-Os [immuno-oncology], then my thought process is, why shouldn’t I just make it very simple for my patients and use a VEGF-TKI that is very good, like cabozantinib, followed by nivolumab? Both are associated with 5-month overall survival benefit as individual agents. See, if I’m seeing a similar magnitude of overall survival with axitinib-pembrolizumab or axitinib-avelumab without really durable complete responses, my tendency would be to just use a simple combination.

Tian Zhang, MD: Right.

Neeraj Agarwal, MD: A simple sequence.

Tian Zhang, MD: Right. So to add to that, you don’t really know if the sequence is additive for the progression-free survival. We had this Twitter chat and a lot of discussion was made about the synergy of the combination and whether that combination really prolongs what would have been additive improvement. And so I think in this first-line setting, what the right agent is to add in, how we should add that in, when we should add that in, and if we should do an adaptive strategy are all pertinent questions and ways we can hopefully improve upon treatment of patients in the future.

Bradley McGregor, MD: But I think to your point earlier, not all patients get second-line treatment. And it’s unclear if the TKI/I-O combination is truly synergistic or if we’re just covering all our bases, right? So if you have someone whom you’re worried about and who is sick, you’re worried that they have progressive disease, and for those patients a TKI I/O is approved, I’m going to go for TKI/I-O in those patients because I want to cover all bases. Response rates seem to be the highest with those combinations than anything else. And if I’m worried that I only have 1 shot to treat this patient, I think that there’s going to be a role for TKI/I-O in those patients. The rates of progressive disease and best response are lower with that than anything else. And so I think there are those patients to whom you’re going to want to think about giving that combination, for the simple reason that you just cover all your bases.

Tian Zhang, MD: Right. You put everything up front and make sure that they can, from whatever mechanism, have a response. I will look at the opposite end of that spectrum. We always talk about the favorable-risk patient, right?

Neeraj Agarwal, MD: Or frail patients with comorbidities, right?

Tian Zhang, MD: But just for a moment, thinking about the favorable-risk patient, do we need the added toxicity of the combination? And so we know that with pembrolizumab alone, from the KEYNOTE-427 trial cohort A, we have data about pembrolizumab monotherapy as well. There is a portion, about 3%, who have complete responses even from pembrolizumab alone. And so is the toxicity necessary for a combination, or can we get by with just a monotherapy and use your sequential approach? But go ahead with your frail patient.

Neeraj Agarwal, MD: I just want to say that I agree with you, Brad, that we are not going to have a perfect regimen right now for all our patients. So I think that’s what we learn during our training, how to customize treatment.

Tian Zhang, MD: That’s right.

Neeraj Agarwal, MD: And I think that will continue to be the paradigm for now, customizing therapy for our patients until we have biomarkers. So I think I have not given up on sequencing. That’s what I’m saying.

Tian Zhang, MD: Yes.

Neeraj Agarwal, MD: That simple sequencing, cabozantinib followed by nivolumab, remains very attractive to me for many patients: favorable-risk patients, patients with comorbidities, patients who I cannot rely on as far as their background is concerned, or patients where their distance from the cancer center is concerning. I think anytime I’m not sure about compliance or many factors that play in, such as how likely is it that patients are going to call us, I would likely go with a sequence.

Transcript Edited for Clarity

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Transcript: 

Sumanta Kumar Pal, MD: I don’t want to perseverate on this topic, but I think it is an interesting one. What do you think about this element of demographics? Patients on axitinib-pembrolizumab, to my recollection, were largely from areas of the world where they might not have access to secondary therapies. There’s a fairly large contingent from what are termed other countries. These are outside North America and Western Europe. Could that have led to some distinction in terms of OS [overall survival] that we’re seeing at this point?

Neeraj Agarwal, MD: If you look across the trial comparison, an equal number of patients in the axitinib-avelumab study and axitinib-pembrolizumab study got post-trial treatment. An equal number of patients got PD-L1 [programmed death-ligand 1] or PD-1 [programmed cell death protein 1]–directed therapy. Equal number of patients got VEGF-TKIs in both arms. So there was no difference in post-trial treatment. However, if you just take 1 trial and see, after sunitinib, how many patients actually got PD-1 inhibitors, you are looking at, like, less than one-third of patients who are getting these therapies.

So yes, I think that remains a concern, in my view. When I’m looking at a very similar progression-free survival [PFS], the magnitude of progression-free survival is around 4 months with axitinib-pembrolizumab versus sunitinib. But then you see overall survival benefit with a hazard ratio of 0.53, a 10% difference in patients who are alive after 1 year; that doesn’t seem to fit well, in my view. And that can be explained only by fewer patients actually seeing any PD-1 inhibitor, less than one-third. Having said that, I think I will come to the point that time will tell how these trials are going to do.

Sumanta Kumar Pal, MD: OK, very good.

Tian Zhang, MD: I agree. At most of our clinics, patients are seeing that immunotherapy in the second-line setting, right?

Neeraj Agarwal, MD: Yes.

Tian Zhang, MD: If they’re on a VEGF-TKI in that frontline, we’re alternating to a different mechanism of action in the second line. So absolutely the fact that these patients were enrolled in countries who may not have access to the second-line immunotherapy is worrisome. But it shouldn’t have factored into that first-line PFS, the first time to progression, and also the overall survival improvement. So certainly, there is a lot to be learned from these trials.

Circling back to your comment that you’re still going to use ipilimumab-nivolumab, I think very much we’re shooting for these complete responses. We want to improve upon the complete responses, so I hope there will be many providers and physicians like yourself, Neeraj, who are really dependent on the immunotherapy, a pure immunotherapy combination strategy, up front, because we really want to enroll to our phase III PEDIGREE trial through the Alliance Group. And that is really building on that pure immunotherapy combination up front.

Neeraj Agarwal, MD: Let me just make 2 comments. First of all, if you look at the IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] data, I was talking about how many patients actually see second-line therapy and how many patients see third-line therapy. That was a real-world population, not a clinical trial population—so frailer, older maybe, and with more comorbidities. And even in that patient population, 51% of patients were seeing second-line therapy. That has become my benchmark. When I’m looking at a clinical trial, and I see how many post-trial treatment therapies were received following this clinical trial–eligible patient population, they’re not reaching up to 50%. I’m intrigued—why not? And then that tells me about the resources and what is available in that given country.

Tian Zhang, MD: Sure.

Neeraj Agarwal, MD: Now, coming back to ipilimumab-nivolumab, yes, for first-line therapy, if I’m going for immunotherapy, I am looking at complete responses. But there are many patients. Just building upon that, I said axitinib-avelumab, axitinib-pembrolizumab, unless I see higher complete responses down the line, which will hopefully happen. And if we see a progression-free survival or overall survival benefit of 10 months, another point is, why don’t we just sequence monotherapy with a VEGF-TKI such as cabozantinib, followed by nivolumab?

If you extrapolate just looking at hazard ratio of cabozantinib with sunitinib, 0.48 in the CABOSUN trial, and that was an intermediate and high-risk patient population, 42% of patients had bone metastasis, so very aggressive disease biology. If we just extrapolate to the overall patient population, you are looking at a progression-free survival with cabozantinib of almost 15 months as a monotherapy. It’s just a discussion point because we don’t have head-to-head comparisons of this.

So if I’m not able to get complete responses from these regimens of TKIs plus I-Os [immuno-oncology], then my thought process is, why shouldn’t I just make it very simple for my patients and use a VEGF-TKI that is very good, like cabozantinib, followed by nivolumab? Both are associated with 5-month overall survival benefit as individual agents. See, if I’m seeing a similar magnitude of overall survival with axitinib-pembrolizumab or axitinib-avelumab without really durable complete responses, my tendency would be to just use a simple combination.

Tian Zhang, MD: Right.

Neeraj Agarwal, MD: A simple sequence.

Tian Zhang, MD: Right. So to add to that, you don’t really know if the sequence is additive for the progression-free survival. We had this Twitter chat and a lot of discussion was made about the synergy of the combination and whether that combination really prolongs what would have been additive improvement. And so I think in this first-line setting, what the right agent is to add in, how we should add that in, when we should add that in, and if we should do an adaptive strategy are all pertinent questions and ways we can hopefully improve upon treatment of patients in the future.

Bradley McGregor, MD: But I think to your point earlier, not all patients get second-line treatment. And it’s unclear if the TKI/I-O combination is truly synergistic or if we’re just covering all our bases, right? So if you have someone whom you’re worried about and who is sick, you’re worried that they have progressive disease, and for those patients a TKI I/O is approved, I’m going to go for TKI/I-O in those patients because I want to cover all bases. Response rates seem to be the highest with those combinations than anything else. And if I’m worried that I only have 1 shot to treat this patient, I think that there’s going to be a role for TKI/I-O in those patients. The rates of progressive disease and best response are lower with that than anything else. And so I think there are those patients to whom you’re going to want to think about giving that combination, for the simple reason that you just cover all your bases.

Tian Zhang, MD: Right. You put everything up front and make sure that they can, from whatever mechanism, have a response. I will look at the opposite end of that spectrum. We always talk about the favorable-risk patient, right?

Neeraj Agarwal, MD: Or frail patients with comorbidities, right?

Tian Zhang, MD: But just for a moment, thinking about the favorable-risk patient, do we need the added toxicity of the combination? And so we know that with pembrolizumab alone, from the KEYNOTE-427 trial cohort A, we have data about pembrolizumab monotherapy as well. There is a portion, about 3%, who have complete responses even from pembrolizumab alone. And so is the toxicity necessary for a combination, or can we get by with just a monotherapy and use your sequential approach? But go ahead with your frail patient.

Neeraj Agarwal, MD: I just want to say that I agree with you, Brad, that we are not going to have a perfect regimen right now for all our patients. So I think that’s what we learn during our training, how to customize treatment.

Tian Zhang, MD: That’s right.

Neeraj Agarwal, MD: And I think that will continue to be the paradigm for now, customizing therapy for our patients until we have biomarkers. So I think I have not given up on sequencing. That’s what I’m saying.

Tian Zhang, MD: Yes.

Neeraj Agarwal, MD: That simple sequencing, cabozantinib followed by nivolumab, remains very attractive to me for many patients: favorable-risk patients, patients with comorbidities, patients who I cannot rely on as far as their background is concerned, or patients where their distance from the cancer center is concerning. I think anytime I’m not sure about compliance or many factors that play in, such as how likely is it that patients are going to call us, I would likely go with a sequence.

Transcript Edited for Clarity
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