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A Win for Small-Cell Lung Cancer: IMPOWER 133

Panelists: Mark A. Socinski, MD, Advent Health Cancer Institute; John V. Heymach, MD, PhD, MD Anderson Cancer Center; Leora Horn, MD, MSc, FRCPC, Vanderbilt University Medical Center; Mohammad Jahanzeb, MD, University of Miami Health System; Heather A. Wakelee, MD, Stanford University Medical Center; Jarushka Naidoo, MBBCh, Sidney Kimmel Cancer Center
Published: Monday, Apr 01, 2019



Transcript: 

Mark A. Socinski, MD: Sure, okay. So let’s transition. You know one of my comments early on was after a long drought in stage III disease, after chemoradiotherapy, we had the PACIFIC data. After even a longer drought in small-cell, we had finally some positive data. I think you’re aware of that.

Leora Horn, MD, MSc, FRCPC: Vaguely.

Mark A. Socinski, MD: Could you walk us through the IMpower small-cell trial?

Leora Horn, MD, MSc, FRCPC: So that was a randomized phase III trial looking at… carboplatin/cisplatin was not part of the backbone and etoposide with or without atezolizumab in patients with extensive-stage disease. And that is the first positive study that we’ve had in small cell. There was no benefit in terms of response rate. It’s hard to beat 65% response rate in small cell. But there was a PFS [progression-free survival] benefit of 2 months and then there was an OS [overall survival] benefit of 2 months. And the first time we’re hitting over 1 year in overall year in extensive stage small cell.

Probably the most common questions that I get from folks in the community is my patient has brain METS [metastases]. And patients had to have treated brain METS and be stable to go on study. So what do you do in that patient who needs to have whole brain radiation at the same time that they’re starting on therapy? And I think we’re learning a little bit as we go. In our practice, we have been starting chemo and adding radiation with cycle 2 and finding it seemed fairly safe in the CNS [central nervous system]. And then the consolidation radiation therapy, which consolidation radiation was also not part of the study because for many of those patients that was their target lesion. But it has become a new standard of care and a new regimen that we’re using because we do see a lot of those patients.

Mark A. Socinski, MD: I think it has changed the standard of care. I don’t need to give another patient carbo [carboplatin]/etoposide for extensive-stage small cell and realize the benefit we were getting there, which hasn’t changed in a bit. So I do think this has changed our practice.

Mohammad Jahanzeb, MD: Well, I think so. After nearly 4 decades it was about time, so we were all ready and primed, and this is after hundreds of negative trials of whatever we added to carbo/etoposide, we couldn’t move the needle, and we finally have. But I think that it begs for the question about doublet immunotherapy, which unlike non–small cell where we are debating and coming up on the side of not using it, in second line after carbo/etoposide failure, I’ve seen good results with ipi/nivo [ipilimumab/nivolumab].

I actually have 4 patients who have done well out of about 12 that I’ve treated, and 2 of those amazingly are on breaks. And both of them have gone beyond 12 months on break. There was never such a thing. I’ve never seen a thing as break from therapy from extensive-stage small cell.

Mark A. Socinski, MD: Yeah, when it works, it works, right?

Mohammad Jahanzeb, MD: Right. So then the question is, would you save it for second line or not. And my view always is to never save things for later because that later may not come for that patient.

Mark A. Socinski, MD: Yeah, particularly since we have had some recent negative data from a maintenance trial in immunotherapy. So, again, I don’t know what the magic is of giving it with the cytotoxic component. 

Mark A. Socinski, MD: Yeah. John, you know we’ve talked in the non–small cell about PD-L1 and tumor mutation burden [TMB]. What do we know about that in small cell?

John V. Heymach, MD, PhD: Yeah. Well you know in this study, now there are some data, if you’re looking at a single arm, that come from Memorial Sloan Kettering that suggested TMB was predictive of benefit from immunotherapy, ipi/nivo in that case. But in the IMpower133 study, as Leora could tell us, tumor mutation burden turned out to not be predictive of getting greater overall benefit. And in a way I think that simplifies life, because here we have a regimen with atezolizumab where you’re getting substantial benefit. And for small cell, in particular, it would be challenging to get TMB data back for these patients. These patients often need to start therapy quickly, and you don’t have the ancillary benefits of getting all these driver mutations by virtue of getting a TMB. So it makes life simpler that as of right now, you don’t need PD-L1 data and you don’t need TMB data to start your patient on the IMpower133 regimen.

Mark A. Socinski, MD: So Leora, we have what seemed to me to be kind of conflicting bits of data. We recently had an approval for single-agent nivolumab in third-line small cell, but CheckMate 331, which looked at the maintenance strategy, was a negative trial, which doesn’t quite make sense to me. Does it make sense to you?

Leora Horn, MD, MSc, FRCPC: So it’s hard to know if, based on what MJ said before, if this antigen release and having the I/O [immunocology] agent on board at the same time—because the other trial we know is B-negative—is the comparison of nivolumab to topotecan/amrubicin and in the second-line setting.

Mohammad Jahanzeb, MD: And that’s a pretty low bar, you all agree?

Leora Horn, MD, MSc, FRCPC: It was, but if topotecan looked like a good driver, I might start using. But you know, so the strategy in small cell right now, if we’re going to improve on that strategy, is I don’t know if you want to start a quadruple regimen of CHEMO-NIVO-IPI. But it appears that giving it up front with chemotherapy, that is the solution.

Mark A. Socinski, MD: Yeah, and I never really understood the third-line single agent. I mean, when I use immunotherapy. When I used to use it before the first-line indication, I would use the nivo/ipi. I mean, it doubles the response. If you’re going to do it, you might as well go with the most aggressive thing, and you have to kind of bite the bullet with toxicity. But that’s what I would do.

Jarushka Naidoo, MBBCh: I think another point to take home, obviously, ipi/nivo was something based on early data we were doing in second-line patients with extensive-stage small cell, but those were patients who had only progressed after chemo. Now in the setting of getting chemo plus atezo [atezolizumab], are they going to still derive the same benefit from ipi/nivo? It’s a slightly different population asking a slightly different question. So I think that that will be something to look at, which hasn’t really been looked at before.

Transcript Edited for Clarity

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Transcript: 

Mark A. Socinski, MD: Sure, okay. So let’s transition. You know one of my comments early on was after a long drought in stage III disease, after chemoradiotherapy, we had the PACIFIC data. After even a longer drought in small-cell, we had finally some positive data. I think you’re aware of that.

Leora Horn, MD, MSc, FRCPC: Vaguely.

Mark A. Socinski, MD: Could you walk us through the IMpower small-cell trial?

Leora Horn, MD, MSc, FRCPC: So that was a randomized phase III trial looking at… carboplatin/cisplatin was not part of the backbone and etoposide with or without atezolizumab in patients with extensive-stage disease. And that is the first positive study that we’ve had in small cell. There was no benefit in terms of response rate. It’s hard to beat 65% response rate in small cell. But there was a PFS [progression-free survival] benefit of 2 months and then there was an OS [overall survival] benefit of 2 months. And the first time we’re hitting over 1 year in overall year in extensive stage small cell.

Probably the most common questions that I get from folks in the community is my patient has brain METS [metastases]. And patients had to have treated brain METS and be stable to go on study. So what do you do in that patient who needs to have whole brain radiation at the same time that they’re starting on therapy? And I think we’re learning a little bit as we go. In our practice, we have been starting chemo and adding radiation with cycle 2 and finding it seemed fairly safe in the CNS [central nervous system]. And then the consolidation radiation therapy, which consolidation radiation was also not part of the study because for many of those patients that was their target lesion. But it has become a new standard of care and a new regimen that we’re using because we do see a lot of those patients.

Mark A. Socinski, MD: I think it has changed the standard of care. I don’t need to give another patient carbo [carboplatin]/etoposide for extensive-stage small cell and realize the benefit we were getting there, which hasn’t changed in a bit. So I do think this has changed our practice.

Mohammad Jahanzeb, MD: Well, I think so. After nearly 4 decades it was about time, so we were all ready and primed, and this is after hundreds of negative trials of whatever we added to carbo/etoposide, we couldn’t move the needle, and we finally have. But I think that it begs for the question about doublet immunotherapy, which unlike non–small cell where we are debating and coming up on the side of not using it, in second line after carbo/etoposide failure, I’ve seen good results with ipi/nivo [ipilimumab/nivolumab].

I actually have 4 patients who have done well out of about 12 that I’ve treated, and 2 of those amazingly are on breaks. And both of them have gone beyond 12 months on break. There was never such a thing. I’ve never seen a thing as break from therapy from extensive-stage small cell.

Mark A. Socinski, MD: Yeah, when it works, it works, right?

Mohammad Jahanzeb, MD: Right. So then the question is, would you save it for second line or not. And my view always is to never save things for later because that later may not come for that patient.

Mark A. Socinski, MD: Yeah, particularly since we have had some recent negative data from a maintenance trial in immunotherapy. So, again, I don’t know what the magic is of giving it with the cytotoxic component. 

Mark A. Socinski, MD: Yeah. John, you know we’ve talked in the non–small cell about PD-L1 and tumor mutation burden [TMB]. What do we know about that in small cell?

John V. Heymach, MD, PhD: Yeah. Well you know in this study, now there are some data, if you’re looking at a single arm, that come from Memorial Sloan Kettering that suggested TMB was predictive of benefit from immunotherapy, ipi/nivo in that case. But in the IMpower133 study, as Leora could tell us, tumor mutation burden turned out to not be predictive of getting greater overall benefit. And in a way I think that simplifies life, because here we have a regimen with atezolizumab where you’re getting substantial benefit. And for small cell, in particular, it would be challenging to get TMB data back for these patients. These patients often need to start therapy quickly, and you don’t have the ancillary benefits of getting all these driver mutations by virtue of getting a TMB. So it makes life simpler that as of right now, you don’t need PD-L1 data and you don’t need TMB data to start your patient on the IMpower133 regimen.

Mark A. Socinski, MD: So Leora, we have what seemed to me to be kind of conflicting bits of data. We recently had an approval for single-agent nivolumab in third-line small cell, but CheckMate 331, which looked at the maintenance strategy, was a negative trial, which doesn’t quite make sense to me. Does it make sense to you?

Leora Horn, MD, MSc, FRCPC: So it’s hard to know if, based on what MJ said before, if this antigen release and having the I/O [immunocology] agent on board at the same time—because the other trial we know is B-negative—is the comparison of nivolumab to topotecan/amrubicin and in the second-line setting.

Mohammad Jahanzeb, MD: And that’s a pretty low bar, you all agree?

Leora Horn, MD, MSc, FRCPC: It was, but if topotecan looked like a good driver, I might start using. But you know, so the strategy in small cell right now, if we’re going to improve on that strategy, is I don’t know if you want to start a quadruple regimen of CHEMO-NIVO-IPI. But it appears that giving it up front with chemotherapy, that is the solution.

Mark A. Socinski, MD: Yeah, and I never really understood the third-line single agent. I mean, when I use immunotherapy. When I used to use it before the first-line indication, I would use the nivo/ipi. I mean, it doubles the response. If you’re going to do it, you might as well go with the most aggressive thing, and you have to kind of bite the bullet with toxicity. But that’s what I would do.

Jarushka Naidoo, MBBCh: I think another point to take home, obviously, ipi/nivo was something based on early data we were doing in second-line patients with extensive-stage small cell, but those were patients who had only progressed after chemo. Now in the setting of getting chemo plus atezo [atezolizumab], are they going to still derive the same benefit from ipi/nivo? It’s a slightly different population asking a slightly different question. So I think that that will be something to look at, which hasn’t really been looked at before.

Transcript Edited for Clarity
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