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IMpower-150: EGFR-Mutated Subset Analysis

Panelists: David R. Gandara, MD, UC Davis Comprehensive Cancer Center; Everett E. Vokes, MD, University of Chicago Medicine
Published: Sunday, Dec 02, 2018



Transcript:

David R. Gandara, MD:
Now, I’m sure some of our audience is wondering about the EGFR-mutated subset that was included in the IMpower-150 trial where the data suggested that—especially for progression-free survival—there was benefit there that hasn’t been observed in any other immunotherapy trials really. But this is giving 4 drugs, including bevacizumab. Now, I’ve been asked by others, “Would you use this upfront in a patient with an EGFR-mutated lung cancer?” I assume you agree, the answer is no. In other words, we’re going to use an EGFR TKI [tyrosine kinase inhibitor] or maybe a series of TKIs. But, if you came to the point where you’re now at chemotherapy, would you consider, even though it’s not first-line, maybe giving this regimen because it includes bevacizumab as your immunotherapy treatment of choice?

Everett E. Vokes, MD: I think it’s a really important question and it was again discussed here at ESMO [European Society of Medical Oncology] today. The 2 subsets that are intriguing for the IMpower-150 [are] patients with mutation, and patients with liver metastases, where most trials have hedged or not simply excluded patients certainly where the mutations are concerned. But with the addition of bevacizumab, you see [with] the single trial, IMpower-150, an advantage. So, I agree with you that that would be the group of patients to consider using the 4 drugs because the evidence seems to be there, although it is subset analysis.

David R. Gandara, MD:  I think the thing that makes me feel a little better about those data are the fact that we know from multiple randomized studies now, adding bevacizumab to an EGFR TKI, such as erlotinib [Tarceva], improves disease-free survival compared to erlotinib alone. So there seems to be something there. Now, that doesn’t mean that that regimen has necessarily translated into a standard of care. Of course, we have new TKIs now like osimertinib [Tagrisso]. But still it shows that maybe there is something about antiangiogenesis in EGFR-mutated lung cancer, so having a regimen with immunotherapy that also includes bevacizumab could be a potential for that subset of patients.

Everett E. Vokes, MD: So, David, let me ask you then a little bit more about the liver metastases issue, which also came up this morning. It seems to be a group of patients with a particularly poor prognosis and that frequently, also in the immuno-oncology trials, have not fared as well as others. They still might derive benefit but less significant. Is that another group where you would consider this?

David R. Gandara, MD:  I don’t know what to make of the liver metastasis data, although it was quite clear that there was additional benefit for the 4-drug regimen in the IMpower-150 trial in patients with liver metastasis. In the subsequent trials, including the 2 that were presented today, the other IMpower studies, that didn’t prove true. Now, the difference was bevacizumab.

So it makes me wonder, is there something about the immune microenvironment in the liver which in general is bad for immunotherapy plus chemotherapy? But, with bevacizumab, maybe you alter that. This is just hypothetical, but otherwise it’s hard to know whether the IMpower-150 is just a one-shot observation or whether it’s actually telling us something about the biology of cancers and how we might approach them.

Everett E. Vokes, MD: Yes, I agree. To me it looks like intriguing data, that for a group of patients with a poor prognosis, one might consider. I don’t think it’s compelling enough at this point to say it’s the standard. Unlike EGFR-mutations, where since you have opposite evidence for when bevacizumab is not part of the regimen, that patients don’t necessarily benefit from the addition of immuno-oncology agent. So, there I think erring on the side of adding bevacizumab. For liver [metastases] I think it’s probably a good idea to look at additional data from other trials. We have one exception that I have to mention as an alliance investigator of this trial that we did, and that’s very similar to the Japanese trial of adding bevacizumab to erlotinib in patients with an EGFR-mutation. Of course, we accrued much less fast. Tom Stinchcombe [Thomas Stinchcombe, MD] presented that at this meeting here as a poster, and we could not, but it’s a much smaller trial [that] reproduced this Japanese observation.

David R. Gandara, MD:  Interesting.

Everett E. Vokes, MD: So, the curves cut one into the other. I think it needs more analysis because of second-line therapy, the emergence of osimertinib.

David R. Gandara, MD:  Right, right.

Everett E. Vokes, MD: So, I’m not sure that the original Japanese observation is not the correct one, but this is certainly a fly in the ointment.

Transcript Edited for Clarity

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Transcript:

David R. Gandara, MD:
Now, I’m sure some of our audience is wondering about the EGFR-mutated subset that was included in the IMpower-150 trial where the data suggested that—especially for progression-free survival—there was benefit there that hasn’t been observed in any other immunotherapy trials really. But this is giving 4 drugs, including bevacizumab. Now, I’ve been asked by others, “Would you use this upfront in a patient with an EGFR-mutated lung cancer?” I assume you agree, the answer is no. In other words, we’re going to use an EGFR TKI [tyrosine kinase inhibitor] or maybe a series of TKIs. But, if you came to the point where you’re now at chemotherapy, would you consider, even though it’s not first-line, maybe giving this regimen because it includes bevacizumab as your immunotherapy treatment of choice?

Everett E. Vokes, MD: I think it’s a really important question and it was again discussed here at ESMO [European Society of Medical Oncology] today. The 2 subsets that are intriguing for the IMpower-150 [are] patients with mutation, and patients with liver metastases, where most trials have hedged or not simply excluded patients certainly where the mutations are concerned. But with the addition of bevacizumab, you see [with] the single trial, IMpower-150, an advantage. So, I agree with you that that would be the group of patients to consider using the 4 drugs because the evidence seems to be there, although it is subset analysis.

David R. Gandara, MD:  I think the thing that makes me feel a little better about those data are the fact that we know from multiple randomized studies now, adding bevacizumab to an EGFR TKI, such as erlotinib [Tarceva], improves disease-free survival compared to erlotinib alone. So there seems to be something there. Now, that doesn’t mean that that regimen has necessarily translated into a standard of care. Of course, we have new TKIs now like osimertinib [Tagrisso]. But still it shows that maybe there is something about antiangiogenesis in EGFR-mutated lung cancer, so having a regimen with immunotherapy that also includes bevacizumab could be a potential for that subset of patients.

Everett E. Vokes, MD: So, David, let me ask you then a little bit more about the liver metastases issue, which also came up this morning. It seems to be a group of patients with a particularly poor prognosis and that frequently, also in the immuno-oncology trials, have not fared as well as others. They still might derive benefit but less significant. Is that another group where you would consider this?

David R. Gandara, MD:  I don’t know what to make of the liver metastasis data, although it was quite clear that there was additional benefit for the 4-drug regimen in the IMpower-150 trial in patients with liver metastasis. In the subsequent trials, including the 2 that were presented today, the other IMpower studies, that didn’t prove true. Now, the difference was bevacizumab.

So it makes me wonder, is there something about the immune microenvironment in the liver which in general is bad for immunotherapy plus chemotherapy? But, with bevacizumab, maybe you alter that. This is just hypothetical, but otherwise it’s hard to know whether the IMpower-150 is just a one-shot observation or whether it’s actually telling us something about the biology of cancers and how we might approach them.

Everett E. Vokes, MD: Yes, I agree. To me it looks like intriguing data, that for a group of patients with a poor prognosis, one might consider. I don’t think it’s compelling enough at this point to say it’s the standard. Unlike EGFR-mutations, where since you have opposite evidence for when bevacizumab is not part of the regimen, that patients don’t necessarily benefit from the addition of immuno-oncology agent. So, there I think erring on the side of adding bevacizumab. For liver [metastases] I think it’s probably a good idea to look at additional data from other trials. We have one exception that I have to mention as an alliance investigator of this trial that we did, and that’s very similar to the Japanese trial of adding bevacizumab to erlotinib in patients with an EGFR-mutation. Of course, we accrued much less fast. Tom Stinchcombe [Thomas Stinchcombe, MD] presented that at this meeting here as a poster, and we could not, but it’s a much smaller trial [that] reproduced this Japanese observation.

David R. Gandara, MD:  Interesting.

Everett E. Vokes, MD: So, the curves cut one into the other. I think it needs more analysis because of second-line therapy, the emergence of osimertinib.

David R. Gandara, MD:  Right, right.

Everett E. Vokes, MD: So, I’m not sure that the original Japanese observation is not the correct one, but this is certainly a fly in the ointment.

Transcript Edited for Clarity
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