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Novel Combinations in mRCC: Axi/Pembro vs Axi/Avelumab

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’m going to shift gears now, and this is probably going to be the most exciting portion of our dialogue today—not that any of it has been dull, frankly. We had some very candid discussions during our Twitter chat essentially trying to tiebreak between some of the data sets we saw at ASCO GU [Genitourinary Cancers Symposium]. I’m going to start with you, Tian, with a tough question of which is better: axitinib-avelumab or axitinib-pembrolizumab. You knew that was coming.

Tian Zhang, MD: I knew that was coming, but I really don’t think we have head-to-head comparisons. I really love Dr Bernard Escudier’s editorial in the New England Journal of Medicine, in which he places all 3 of these trials in context and in juxtaposition. In that table, he puts pembrolizumab with axitinib, avelumab with axitinib, and then nivolumab with ipilimumab and compares across the characteristics of the trials. One of the things that stuck out to me was the higher percentage of favorable-risk patients in the pembrolizumab-axitinib trial, and it was about 31% compared with 23% and 21% in the other 2 trials. It was a higher number of favorable-risk patients, and we’re seeing an earlier overall survival [OS] difference in that trial. And so I think these favorable-risk patients are really driving what we’re seeing are the differences here in this KEYNOTE trial.

Some of the other differences that I saw across the trials were that the complete response rates were very different. We already talked a little bit about it, but pembrolizumab-axitinib had a complete response rate around 5.8% compared with avelumab-axitinib, which was right around 3.8%, and then nivolumab-ipilimumab had around 10.2% in that table. And so it’s very different and depends, as we say, on what we’re shooting for in that first-line setting.

And then finally as we think about the overall survival differences, we’ve seen the overall survival improvements compared with sunitinib in this first-line setting with the KEYNOTE-426 trial, as well as with the CheckMate 214 trial. I think for avelumab-axitinib, the data are just not mature enough to make that call. And as Dr Toni K. Choueiri said from the GU ASCO stage, it’s not over till it’s over. I think we still need to wait for the overall survival endpoints there.

Sumanta Kumar Pal, MD: Pull out your crystal ball for a minute, if you will, and I know this is a challenging question. But what’s going to happen? Are we going to see an OS advantage with the same magnitude with axitinib-avelumab as compared with axitinib-pembrolizumab? What do you think?

Tian Zhang, MD: I think that the baseline characteristics of these patients were a bit different, but I do think that we’ll see an overall survival benefit at some point. And maybe 2 years from now, when we see that report out, I can be proven right. But I am hopeful that we’ll have multiple agents and more prospects and potential treatment options available for our patients.

Sumanta Kumar Pal, MD: Interesting. A little-known fact: Brad’s office is right next to Dr Choueiri’s at Dana-Farber Cancer Institute in Boston, Massachusetts, so we’re going to be listening to his words very, very carefully. He has the insider’s perspective here. What are you going to use if faced with the option of axitinib-avelumab and axitinib-pembrolizumab? With a patient sitting right in front of you, which are you going to counsel them to take?

Neeraj Agarwal, MD: I’m assuming you’re not sitting next to Dr Choueiri.

Bradley McGregor, MD: I think with the data we have at this point in time, right now 1 of them has an overall survival benefit and 1 does not, with similar follow-up. Now granted, the trials enrolled at different rates, and you had different factors overall, but right now that’s where we’re at. So I think overall survival is important. Patients want to know, “What’s going to give me the best chance to be alive in a year?” We can say that pembrolizumab-axitinib is better than sunitinib, but we can’t say that for axitinib-avelumab. So I think today, right now, it’s pembrolizumab-axitinib. But again, it’s not over till it’s over.

As we get more data, that certainly may change. Axitinib-avelumab does seem to be very well tolerated. The rates of immune-related adverse events and the need for high-dose steroids were much lower than we see with nivolumab-ipilimumab. Now, we haven’t seen those data reported for pembrolizumab-axitinib, but it did seem to be very well tolerated. The infusion reactions that we were concerned about with avelumab, with appropriate premedications, were much fewer. So axitinib-avelumab is certainly a well-tolerated regimen. And so I think with more follow-up, we’ll have a better sense.

Sumanta Kumar Pal, MD: Interesting. Tell us about the why. Why is it that we see this magnitude of OS benefit with axitinib-pembrolizumab and we’re not seeing it at this point with axitinib-avelumab? The office must be buzzing with that conversation.

Bradley McGregor, MD: I think we don’t know. It’s hard to say. For now, we see the differences. It’s odd: You would think that the favorable risk being higher in pembrolizumab-axitinib would make it harder to get an overall survival benefit, and that they may do better with TKI [tyrosine kinase inhibitor] alone. We saw that in CheckMate 214, but yet we see this here. So I think there are a lot of things that are going on. When you look at the axitinib-avelumab enrollment, they enrolled quite a few patients, and then they put the trial on hold for a while because they were changing the analysis. And then they enrolled again. And so maybe just with more follow-up, you’re going to see more events, but it’s going to be delayed. So I think more time will tell. The PFS [progression-free survival] data for axitinib-avelumab are certainly very intriguing. It’s just that if they bear out, there probably will be an OS benefit but in more time.

Neeraj Agarwal, MD: But it’s likely not owing to different patient populations because it’s a randomized trial. So if you look at the 6% complete response or 5.8% complete response with axitinib-pembrolizumab, even the sunitinib arm in that patient population also had 3% complete response, right? So it’s twice as much as some agents have. But the bigger question is, Why we use immunotherapy in patients with RCC [renal cell carcinoma] as first-line therapy? We are using immune therapy for complete responses, for complete durable responses. So if we look at axitinib-avelumab or axitinib-pembrolizumab compared with sunitinib, they’re inducing twice as many complete responses. Look at the ipilimumab-nivolumab combination compared with sunitinib: You have 10 times as many complete responses. So if I’m using a treatment regimen, an immunotherapy regimen, I’m using it for complete responses. So I would rather use ipilimumab-nivolumab.

Sumanta Kumar Pal, MD: Well, Professor Agarwal, I’m not going to let you off that easy. As you guys know, 1 of my best friends is sitting across the table from me here. But I asked Tian, and I asked Brad, if you have a patient in front of you, which are you going to pick? Between axitinib-pembrolizumab and axitinib-avelumab, what’s your choice?

Neeraj Agarwal, MD: Oh, I won’t pick any of them. I’d pick ipilimumab and nivolumab.

Sumanta Kumar Pal, MD: Oh, but what if your hospital formulary, for whatever reason, doesn’t have nivolumab and ipilimumab? Now what are you going to choose?

Neeraj Agarwal, MD: Axitinib-pembrolizumab.

Sumanta Kumar Pal, MD: Why?

Neeraj Agarwal, MD: Overall survival.

Sumanta Kumar Pal, MD: Got it. That makes sense. And now you gave us some good reasons why baseline demographics might not explain the overall survival difference. So what can? Why are we seeing this different signal between the 2 trials?

Neeraj Agarwal, MD: I must tell you, this is so intriguing and perplexing. They are very similar combinations. If you look at the PFS hazard ratios compared with sunitinib, which accounts for difference in patient population, it’s 30% favorable risk, 20% favorable risk. But you’re comparing with a common comparator, which is sunitinib, right? The hazard ratio is for progression-free survival is exactly similar, 0.69. If you look at the increase in the response rates, they’re 35% to 60% in KEYNOTE-426—the axitinib-pembrolizumab trial—and 25% to 52% with axitinib-avelumab. So overall responses, progression-free survival benefit is exactly similar.

Tian Zhang, MD: I will say, though, that if you look at the same data, the hazard ratios were the same but the median progression-free survival actually reflects the population. So looking at the KEYNOTE study, the median progression-free survival for the combination was about 15 months, compared with 11 months for sunitinib, with a bigger portion of favorable-risk patients. If you look at the JAVELIN Renal 101 trial, you see that progression-free survival with the avelumab-axitinib arm was about 13.8 months, compared with about 8.4 months for sunitinib, so it’s very reflective of the different disease populations that were enrolled and the poor-risk patients who were on the JAVELIN Renal 101 trial.

Neeraj Agarwal, MD: After following that analogy, I fully agree with that. The median survival on the standard-of-care arm tells me about the population. But this is a randomized trial, so that patient population is being equally distributed between the experimental arm and the control arm.

Tian Zhang, MD: That’s true.

Neeraj Agarwal, MD: And going by that analogy, we should have seen a survival benefit with axitinib-avelumab, because if you look at a poorer-risk patient population, a high-risk patient population, they’re expected to have a lower median survival. So for the same number of patients, 800-plus patients, very similar patient numbers, the trial with axitinib-avelumab was powered better for overall survival because you had a much higher risk patient population. So that’s why I’m saying it is so perplexing that overall survival is so convincingly met with a hazard ratio of 0.53 in the axitinib-pembrolizumab trial, and we are seeing a hazard ratio of 0.8 almost with the axitinib-avelumab trial.

Tian Zhang, MD: Not enough events, right?

Neeraj Agarwal, MD: I agree with you. But again, if it was a higher-risk patient population…

Tian Zhang, MD: You would think that they would have enough events by this point.

Neeraj Agarwal, MD: That’s my point.

Tian Zhang, MD: Yes, but Brad’s point is also true, that if the trial was held for a while and then restarted enrolling, that second population of patients, the second cohort, just may not have met their median overall survival.

Neeraj Agarwal, MD: Again, I agree, and time will tell. I hope both trials are positive.

Sumanta Kumar Pal, MD: So all 3 of you have answered that time will tell.

Neeraj Agarwal, MD: No, no, I told you, among these 2, I will choose axitinib-pembrolizumab, because it has overall survival data associated with right now. So there’s definitely a high level of evidence. There’s no doubt.

Tian Zhang, MD: As of February 2019.

Neeraj Agarwal, MD: Right, as of today.

Tian Zhang, MD: That’s right.


Transcript Edited for Clarity
 

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Transcript:

Sumanta Kumar Pal, MD:
I’m going to shift gears now, and this is probably going to be the most exciting portion of our dialogue today—not that any of it has been dull, frankly. We had some very candid discussions during our Twitter chat essentially trying to tiebreak between some of the data sets we saw at ASCO GU [Genitourinary Cancers Symposium]. I’m going to start with you, Tian, with a tough question of which is better: axitinib-avelumab or axitinib-pembrolizumab. You knew that was coming.

Tian Zhang, MD: I knew that was coming, but I really don’t think we have head-to-head comparisons. I really love Dr Bernard Escudier’s editorial in the New England Journal of Medicine, in which he places all 3 of these trials in context and in juxtaposition. In that table, he puts pembrolizumab with axitinib, avelumab with axitinib, and then nivolumab with ipilimumab and compares across the characteristics of the trials. One of the things that stuck out to me was the higher percentage of favorable-risk patients in the pembrolizumab-axitinib trial, and it was about 31% compared with 23% and 21% in the other 2 trials. It was a higher number of favorable-risk patients, and we’re seeing an earlier overall survival [OS] difference in that trial. And so I think these favorable-risk patients are really driving what we’re seeing are the differences here in this KEYNOTE trial.

Some of the other differences that I saw across the trials were that the complete response rates were very different. We already talked a little bit about it, but pembrolizumab-axitinib had a complete response rate around 5.8% compared with avelumab-axitinib, which was right around 3.8%, and then nivolumab-ipilimumab had around 10.2% in that table. And so it’s very different and depends, as we say, on what we’re shooting for in that first-line setting.

And then finally as we think about the overall survival differences, we’ve seen the overall survival improvements compared with sunitinib in this first-line setting with the KEYNOTE-426 trial, as well as with the CheckMate 214 trial. I think for avelumab-axitinib, the data are just not mature enough to make that call. And as Dr Toni K. Choueiri said from the GU ASCO stage, it’s not over till it’s over. I think we still need to wait for the overall survival endpoints there.

Sumanta Kumar Pal, MD: Pull out your crystal ball for a minute, if you will, and I know this is a challenging question. But what’s going to happen? Are we going to see an OS advantage with the same magnitude with axitinib-avelumab as compared with axitinib-pembrolizumab? What do you think?

Tian Zhang, MD: I think that the baseline characteristics of these patients were a bit different, but I do think that we’ll see an overall survival benefit at some point. And maybe 2 years from now, when we see that report out, I can be proven right. But I am hopeful that we’ll have multiple agents and more prospects and potential treatment options available for our patients.

Sumanta Kumar Pal, MD: Interesting. A little-known fact: Brad’s office is right next to Dr Choueiri’s at Dana-Farber Cancer Institute in Boston, Massachusetts, so we’re going to be listening to his words very, very carefully. He has the insider’s perspective here. What are you going to use if faced with the option of axitinib-avelumab and axitinib-pembrolizumab? With a patient sitting right in front of you, which are you going to counsel them to take?

Neeraj Agarwal, MD: I’m assuming you’re not sitting next to Dr Choueiri.

Bradley McGregor, MD: I think with the data we have at this point in time, right now 1 of them has an overall survival benefit and 1 does not, with similar follow-up. Now granted, the trials enrolled at different rates, and you had different factors overall, but right now that’s where we’re at. So I think overall survival is important. Patients want to know, “What’s going to give me the best chance to be alive in a year?” We can say that pembrolizumab-axitinib is better than sunitinib, but we can’t say that for axitinib-avelumab. So I think today, right now, it’s pembrolizumab-axitinib. But again, it’s not over till it’s over.

As we get more data, that certainly may change. Axitinib-avelumab does seem to be very well tolerated. The rates of immune-related adverse events and the need for high-dose steroids were much lower than we see with nivolumab-ipilimumab. Now, we haven’t seen those data reported for pembrolizumab-axitinib, but it did seem to be very well tolerated. The infusion reactions that we were concerned about with avelumab, with appropriate premedications, were much fewer. So axitinib-avelumab is certainly a well-tolerated regimen. And so I think with more follow-up, we’ll have a better sense.

Sumanta Kumar Pal, MD: Interesting. Tell us about the why. Why is it that we see this magnitude of OS benefit with axitinib-pembrolizumab and we’re not seeing it at this point with axitinib-avelumab? The office must be buzzing with that conversation.

Bradley McGregor, MD: I think we don’t know. It’s hard to say. For now, we see the differences. It’s odd: You would think that the favorable risk being higher in pembrolizumab-axitinib would make it harder to get an overall survival benefit, and that they may do better with TKI [tyrosine kinase inhibitor] alone. We saw that in CheckMate 214, but yet we see this here. So I think there are a lot of things that are going on. When you look at the axitinib-avelumab enrollment, they enrolled quite a few patients, and then they put the trial on hold for a while because they were changing the analysis. And then they enrolled again. And so maybe just with more follow-up, you’re going to see more events, but it’s going to be delayed. So I think more time will tell. The PFS [progression-free survival] data for axitinib-avelumab are certainly very intriguing. It’s just that if they bear out, there probably will be an OS benefit but in more time.

Neeraj Agarwal, MD: But it’s likely not owing to different patient populations because it’s a randomized trial. So if you look at the 6% complete response or 5.8% complete response with axitinib-pembrolizumab, even the sunitinib arm in that patient population also had 3% complete response, right? So it’s twice as much as some agents have. But the bigger question is, Why we use immunotherapy in patients with RCC [renal cell carcinoma] as first-line therapy? We are using immune therapy for complete responses, for complete durable responses. So if we look at axitinib-avelumab or axitinib-pembrolizumab compared with sunitinib, they’re inducing twice as many complete responses. Look at the ipilimumab-nivolumab combination compared with sunitinib: You have 10 times as many complete responses. So if I’m using a treatment regimen, an immunotherapy regimen, I’m using it for complete responses. So I would rather use ipilimumab-nivolumab.

Sumanta Kumar Pal, MD: Well, Professor Agarwal, I’m not going to let you off that easy. As you guys know, 1 of my best friends is sitting across the table from me here. But I asked Tian, and I asked Brad, if you have a patient in front of you, which are you going to pick? Between axitinib-pembrolizumab and axitinib-avelumab, what’s your choice?

Neeraj Agarwal, MD: Oh, I won’t pick any of them. I’d pick ipilimumab and nivolumab.

Sumanta Kumar Pal, MD: Oh, but what if your hospital formulary, for whatever reason, doesn’t have nivolumab and ipilimumab? Now what are you going to choose?

Neeraj Agarwal, MD: Axitinib-pembrolizumab.

Sumanta Kumar Pal, MD: Why?

Neeraj Agarwal, MD: Overall survival.

Sumanta Kumar Pal, MD: Got it. That makes sense. And now you gave us some good reasons why baseline demographics might not explain the overall survival difference. So what can? Why are we seeing this different signal between the 2 trials?

Neeraj Agarwal, MD: I must tell you, this is so intriguing and perplexing. They are very similar combinations. If you look at the PFS hazard ratios compared with sunitinib, which accounts for difference in patient population, it’s 30% favorable risk, 20% favorable risk. But you’re comparing with a common comparator, which is sunitinib, right? The hazard ratio is for progression-free survival is exactly similar, 0.69. If you look at the increase in the response rates, they’re 35% to 60% in KEYNOTE-426—the axitinib-pembrolizumab trial—and 25% to 52% with axitinib-avelumab. So overall responses, progression-free survival benefit is exactly similar.

Tian Zhang, MD: I will say, though, that if you look at the same data, the hazard ratios were the same but the median progression-free survival actually reflects the population. So looking at the KEYNOTE study, the median progression-free survival for the combination was about 15 months, compared with 11 months for sunitinib, with a bigger portion of favorable-risk patients. If you look at the JAVELIN Renal 101 trial, you see that progression-free survival with the avelumab-axitinib arm was about 13.8 months, compared with about 8.4 months for sunitinib, so it’s very reflective of the different disease populations that were enrolled and the poor-risk patients who were on the JAVELIN Renal 101 trial.

Neeraj Agarwal, MD: After following that analogy, I fully agree with that. The median survival on the standard-of-care arm tells me about the population. But this is a randomized trial, so that patient population is being equally distributed between the experimental arm and the control arm.

Tian Zhang, MD: That’s true.

Neeraj Agarwal, MD: And going by that analogy, we should have seen a survival benefit with axitinib-avelumab, because if you look at a poorer-risk patient population, a high-risk patient population, they’re expected to have a lower median survival. So for the same number of patients, 800-plus patients, very similar patient numbers, the trial with axitinib-avelumab was powered better for overall survival because you had a much higher risk patient population. So that’s why I’m saying it is so perplexing that overall survival is so convincingly met with a hazard ratio of 0.53 in the axitinib-pembrolizumab trial, and we are seeing a hazard ratio of 0.8 almost with the axitinib-avelumab trial.

Tian Zhang, MD: Not enough events, right?

Neeraj Agarwal, MD: I agree with you. But again, if it was a higher-risk patient population…

Tian Zhang, MD: You would think that they would have enough events by this point.

Neeraj Agarwal, MD: That’s my point.

Tian Zhang, MD: Yes, but Brad’s point is also true, that if the trial was held for a while and then restarted enrolling, that second population of patients, the second cohort, just may not have met their median overall survival.

Neeraj Agarwal, MD: Again, I agree, and time will tell. I hope both trials are positive.

Sumanta Kumar Pal, MD: So all 3 of you have answered that time will tell.

Neeraj Agarwal, MD: No, no, I told you, among these 2, I will choose axitinib-pembrolizumab, because it has overall survival data associated with right now. So there’s definitely a high level of evidence. There’s no doubt.

Tian Zhang, MD: As of February 2019.

Neeraj Agarwal, MD: Right, as of today.

Tian Zhang, MD: That’s right.


Transcript Edited for Clarity
 
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