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CheckMate-227 and the Role of TMB in NSCLC

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: Wednesday, Mar 27, 2019



Transcript: 

Mark A. Socinski, MD: I think one of the things we were anticipating next is what immunotherapy [I-O] strategies are going to be the next line of success. And the next kind of strategy was adding a CTLA-4 [cytotoxic T-lymphocyte–associated protein 4] inhibitor to a PD-1 [programmed cell death protein 1] or PD-L1 [programmed death-ligand 1] inhibitor. And so I wanted to ask Leora, is there a situation today where you would consider doing that? Or, how do you see the current situation with that strategy?

Leora Horn, MD, MSc, FRCPC: Right now in non–small cell lung cancer there’s no role for that. CheckMate-227 is still out there trying to answer that question. A complicated 2,000-patient study that we’ve seen 300 patients here and 500 patients there presented and changing biomarkers, moving from PD-L1 to TMB [tumor mutational burden]. We had a press release that the TMB data were withdrawn from the FDA not because maybe the TMB-high did well, but because also the TMB-low patients did well on that regimen. And so it’s pretty confusing but right now in non–small cell lung cancer, outside of clinical trials, there’s really no role for nivolumab and ipilimumab.

Mark A. Socinski, MD: And we’ve seen that with the other combination of durvalumab.

Leora Horn, MD, MSc, FRCPC: Right.

Mark A. Socinski, MD: And tremelimumab too.

Leora Horn, MD, MSc, FRCPC: Right. And at ESMO [the European Society for Medical Oncology meeting] we saw that DURVA [durvalumab] and tremelimumab was a negative trial as well, and so it did not meet its PFS [progression-free survival] endpoint.

Mark A. Socinski, MD: I’ll ask you and John I guess because I was going to turn to John and ask, is TMB dead, is tumor mutation burden dead?

Leora Horn, MD, MSc, FRCPC: I don’t think it’s dead. I just think that it maybe needs to be redefined. The problem with that marker as well is it was, first it was 10 mutations per megabase, then it was 16, and it was using the foundation panel as a surrogate or versus doing the actual sequencing. So I don’t think it’s dead, it’s just been a moving target of what is TMB-high, and can we do blood. There’s studies like B-F1RST that are out there that had interesting data as well at ESMO. So I think that we’re still struggling figuring out what is the best predictor, or that we should give patients I-O, and what’s a predictor that maybe we shouldn’t give in I-O. But I don’t think it’s dead. It’s a reiteration.

John V. Heymach, MD, PhD: I guess I have a little different perspective on this as regards to the CheckMate-227. It’s true that the markers changed during the study, but I think it’s important to identify that they were locked before the patients were unblinded. So it is truly a perspective one with a set TMB score there, 10. I think the 16’s applying for the blood markers.

And I think it’s important to acknowledge that it actually did exactly what was hypothesized for PFS. You know it really is pretty striking that there is an enormous PFS, or a very substantial PFS benefit for a nonchemotherapy-containing regimen, in the TMB-high. And in the TMB-low, there was actually no PFS advantage. So insofar as the primary or the coprimary endpoint was PFS in the TMB-high group, you know that was a success.

But as you said, there is now this interesting finding that the OS [overall survival] benefit seems to extend to the TMB-negative, which is interesting. And this argues that there must be post-progression benefit from getting the combination that you’re not seeing from that tumor shrinkage. And I think from my perspective that’s a very intriguing finding, and it suggests that the patients who may be benefiting from this regimen may extend beyond that narrow group.

Mark A. Socinski, MD: So, John, I wanted to ask you: What should be the message to community oncologists? Because many of them are sending tumor specimens to laboratories, various labs that will remain nameless, and often that comes back on the first page. And it’s there and you know it and the question is, what do you with that?

John V. Heymach, MD, PhD: Well, so in 2019, as of right now the TMB is not a marker that’s useful for selecting therapies. It may be in the future. One of the ancillary benefits, in fact I think in some ways what may turn out to be the greatest benefit, is if people are getting TMB, you’re going to find a lot of those driver mutations as an ancillary benefit that people were missing before. That may turn out to be as much if not more of a benefit.

But it also points out that PD-L1 alone will not end up being the full story. There’s other data saying that the genomic markers may also impact it. So right now, I think the message is, everybody should get immunotherapy. We’re refining who’s going to get the most benefit or who would get the most benefit from combination immunotherapy. But still right now unless somebody’s got an overwhelming reason in terms of autoimmune disease or a transplant, as Heather said, there’s nobody that shouldn’t get immunotherapy with non–small cell lung cancer, I think.

Mark A. Socinski, MD: Yes. So we’ve taken again the standard second-line, put it with our first-line regimens. Although there are the patients, the greater than 50 percenters. I find myself doing monotherapy much more frequently in nonsquamous than in squamous. You know squamous, I think  still the data aren’t robust in my opinion. And I’m more likely even in a greater than 50 percenter to use the CARBO [carboplatin]/taxane plus PEMBRO [pembrolizumab].

Heather A. Wakelee, MD: The 407 regimen.

Mark A. Socinski, MD: Yes. And so I think that that’s true.

Transcript Edited for Clarity

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Transcript: 

Mark A. Socinski, MD: I think one of the things we were anticipating next is what immunotherapy [I-O] strategies are going to be the next line of success. And the next kind of strategy was adding a CTLA-4 [cytotoxic T-lymphocyte–associated protein 4] inhibitor to a PD-1 [programmed cell death protein 1] or PD-L1 [programmed death-ligand 1] inhibitor. And so I wanted to ask Leora, is there a situation today where you would consider doing that? Or, how do you see the current situation with that strategy?

Leora Horn, MD, MSc, FRCPC: Right now in non–small cell lung cancer there’s no role for that. CheckMate-227 is still out there trying to answer that question. A complicated 2,000-patient study that we’ve seen 300 patients here and 500 patients there presented and changing biomarkers, moving from PD-L1 to TMB [tumor mutational burden]. We had a press release that the TMB data were withdrawn from the FDA not because maybe the TMB-high did well, but because also the TMB-low patients did well on that regimen. And so it’s pretty confusing but right now in non–small cell lung cancer, outside of clinical trials, there’s really no role for nivolumab and ipilimumab.

Mark A. Socinski, MD: And we’ve seen that with the other combination of durvalumab.

Leora Horn, MD, MSc, FRCPC: Right.

Mark A. Socinski, MD: And tremelimumab too.

Leora Horn, MD, MSc, FRCPC: Right. And at ESMO [the European Society for Medical Oncology meeting] we saw that DURVA [durvalumab] and tremelimumab was a negative trial as well, and so it did not meet its PFS [progression-free survival] endpoint.

Mark A. Socinski, MD: I’ll ask you and John I guess because I was going to turn to John and ask, is TMB dead, is tumor mutation burden dead?

Leora Horn, MD, MSc, FRCPC: I don’t think it’s dead. I just think that it maybe needs to be redefined. The problem with that marker as well is it was, first it was 10 mutations per megabase, then it was 16, and it was using the foundation panel as a surrogate or versus doing the actual sequencing. So I don’t think it’s dead, it’s just been a moving target of what is TMB-high, and can we do blood. There’s studies like B-F1RST that are out there that had interesting data as well at ESMO. So I think that we’re still struggling figuring out what is the best predictor, or that we should give patients I-O, and what’s a predictor that maybe we shouldn’t give in I-O. But I don’t think it’s dead. It’s a reiteration.

John V. Heymach, MD, PhD: I guess I have a little different perspective on this as regards to the CheckMate-227. It’s true that the markers changed during the study, but I think it’s important to identify that they were locked before the patients were unblinded. So it is truly a perspective one with a set TMB score there, 10. I think the 16’s applying for the blood markers.

And I think it’s important to acknowledge that it actually did exactly what was hypothesized for PFS. You know it really is pretty striking that there is an enormous PFS, or a very substantial PFS benefit for a nonchemotherapy-containing regimen, in the TMB-high. And in the TMB-low, there was actually no PFS advantage. So insofar as the primary or the coprimary endpoint was PFS in the TMB-high group, you know that was a success.

But as you said, there is now this interesting finding that the OS [overall survival] benefit seems to extend to the TMB-negative, which is interesting. And this argues that there must be post-progression benefit from getting the combination that you’re not seeing from that tumor shrinkage. And I think from my perspective that’s a very intriguing finding, and it suggests that the patients who may be benefiting from this regimen may extend beyond that narrow group.

Mark A. Socinski, MD: So, John, I wanted to ask you: What should be the message to community oncologists? Because many of them are sending tumor specimens to laboratories, various labs that will remain nameless, and often that comes back on the first page. And it’s there and you know it and the question is, what do you with that?

John V. Heymach, MD, PhD: Well, so in 2019, as of right now the TMB is not a marker that’s useful for selecting therapies. It may be in the future. One of the ancillary benefits, in fact I think in some ways what may turn out to be the greatest benefit, is if people are getting TMB, you’re going to find a lot of those driver mutations as an ancillary benefit that people were missing before. That may turn out to be as much if not more of a benefit.

But it also points out that PD-L1 alone will not end up being the full story. There’s other data saying that the genomic markers may also impact it. So right now, I think the message is, everybody should get immunotherapy. We’re refining who’s going to get the most benefit or who would get the most benefit from combination immunotherapy. But still right now unless somebody’s got an overwhelming reason in terms of autoimmune disease or a transplant, as Heather said, there’s nobody that shouldn’t get immunotherapy with non–small cell lung cancer, I think.

Mark A. Socinski, MD: Yes. So we’ve taken again the standard second-line, put it with our first-line regimens. Although there are the patients, the greater than 50 percenters. I find myself doing monotherapy much more frequently in nonsquamous than in squamous. You know squamous, I think  still the data aren’t robust in my opinion. And I’m more likely even in a greater than 50 percenter to use the CARBO [carboplatin]/taxane plus PEMBRO [pembrolizumab].

Heather A. Wakelee, MD: The 407 regimen.

Mark A. Socinski, MD: Yes. And so I think that that’s true.

Transcript Edited for Clarity
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