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TKIs for EGFR Del19 and Beyond Progression

Panelists:Benjamin P. Levy, MD, Mount Sinai Health Systems;Chandra P. Belani, MD, Penn State Cancer Institute;Marina Garassino, MD, National Cancer Institute Milan, Italy;Sarah B. Goldberg, MD, MPH, Yale Cancer Center;Ramaswamy Govindan, MD, Washington University School of Medicine;Mark G. Kris, MD, Memorial Sloan-Kettering Cancer Center
Published: Thursday, Aug 18, 2016


Transcript:

Benjamin P. Levy, MD:
Just shifting gears a little bit: the deletion 19 story. What about afatinib seeming to show a survival advantage in the subset analysis from the LUX-Lung 3 and 6 trials? To my knowledge, it’s the only survival advantage we’ve seen. Wasn’t it “intent-to-treat” population? This was a mutation that some say is predictive; it’s quite sensitive no matter what TKI you give. Are people using afatinib in a del19 patient based on those data? It didn’t seem to shake out in the LUX-Lung 7 data by the way.

Mark G. Kris, MD: A lot more are getting bevacizumab with erlotinib. But what an amazing thing, though. The paper from the gefitinib versus afatinib trial just came out. I’d ask you to look at the waterfall plots in that; it’s very odd. The waterfall for gefitinib and afatinib in exon 19-deleted patients is identical.

Benjamin P. Levy, MD: Yes, it didn’t bear out.

Mark G. Kris, MD: Which is really unusual. We all make our living by doing these things, and most times we say, “Oh, it’s a subgroup analysis, if it’s not yours.” So, it’s hard to say. I find that whole trial, actually, that Sarah was talking about, a little tough to know how it changes practice. My gut would probably be to give afatinib.

Benjamin P. Levy, MD: Okay. TKI of choice, Chandra?

Chandra P. Belani, MD: Erlotinib.

Benjamin P. Levy, MD: Erlotinib?

Chandra P. Belani, MD: We have used it for a long time, and we have been able to treat all these patients. The patients are comfortable, the physicians are comfortable, the investigators are comfortable, and the nurses are comfortable. For me, the choice is still erlotinib. And though afatinib was better than gefitinib in that randomized trial, we really could not say that it is better than erlotinib.

Ramaswamy Govindan, MD: Mark, do you give afatinib and bevacizumab in del19?

Mark G. Kris, MD: I haven’t made that switch yet, but I intend to. We’re going to have that osimertinib and bevacizumab trial, so that’s going to be my choice.

Sarah B. Goldberg, MD, MPH: That’ll be first-line?

Mark G. Kris, MD: Yes.

Benjamin P. Levy, MD: Let’s move on and really tackle this in terms of the treatment continuum for a patient who received an EGFR TKI up front. Eventually, at some point, their tumor will grow, they will develop progression. I would just make the comment that progression in this setting is heterogeneous; not all progression is the same. We have to consider oligometastatic progression versus overall disease progression, factoring in whether a patient is symptomatic or not and factoring in the potential presence of T790M. So, Marina, can you just talk a little bit about your approach to treatment beyond progression and how you manage progression? And also what lesion do we re-biopsy if we’re heading towards a new treatment for that patient?

Marina Garassino, MD: After about 12 months, more or less, 50% of patients progress, and they can progress with the oligometastatic progression. In this case, we try to squeeze all the benefit of the EGFR TKIs. In Italy, we use them according to the toxicity profiles. For example, we avoid using afatinib in old people for the toxicity. We would really like to use erlotinib and bevacizumab. But if you have a slow disease without symptoms and the progression is low, you try to use the EGFR tyrosine kinase inhibitors until you really can’t.

What we do in our center is try to monitor the T790M, but, in reality, we don’t know if we have significance of monitoring the T790M, although we have the third-generation EGFR TKI. When the burden of the disease is very present, we re-biopsy the patient or we try to do a liquid biopsy. But, in general, we prefer to re-biopsy the patients because the way in which the progression can appear is that the pictures are very heterogeneous—and it’s true that in 50%, 70% of cases you may have the T790M, but you have 40% of cases in which you may have the epithelial mesenchymal transformation, the small-cell lung cancer transformation. I think that morphology is still important. Then you can test for MET, for HER2, for all the mechanisms of resistance.

What we biopsy is more simple than re-biopsy. So, we don’t differentiate the primary tumor from the metastases. We just discuss with the multidisciplinary team which is the easiest to re-biopsy, and we biopsy again. And then the story of the T790M is quite intriguing because we started to think that it was a secondary mutation, but now we are coming back [around] because we can find it also in 30% of the metastatic EGFR-mutated patients. I think that in the future we will have an EGFR T790M–mutated disease and the T790M-negative disease, and maybe we will select the treatment according to this.

Benjamin P. Levy, MD: How do you manage oligometastatic progression? So, you haven’t made that decision yet whether you want to re-biopsy or not. Are you addressing that local site with aggressive measures and riding out the TKI? What has the treatment approach in Europe been?

Marina Garassino, MD: We discuss in the multidisciplinary team what to do. I think that this is really important because, for example, if you have just a bone metastasis or a single-brain metastasis, you can do a radiotherapy. But maybe if you have a liver metastasis in a good segment, maybe you can re-biopsy at the time. The multidisciplinary team can help you with those the decisions.

Benjamin P. Levy, MD: Let’s go through a not uncommon scenario. You’ve decided to do the biopsy or the plasma, it’s T790M-negative, there’s no other actionable mutation within that biopsy. Do you institute chemotherapy?

Marina Garassino, MD: Yes.

Benjamin P. Levy, MD: What would be your chemotherapy choice, and would you continue the TKI when instituting the chemotherapy?

Marina Garassino, MD: So, while we try to find T790M, a MET, HER2, if we don’t find any actionable mutation, we go to chemotherapy. The most used regimen in Europe is cisplatin/pemetrexed, different from the United States, I think.

Benjamin P. Levy, MD: I don’t think it’s that different. We all have competing standards here in terms of what we use, but that would certainly be a consideration in the United States, as well. Any other thoughts, in terms of managing progression, and perhaps tips or nuggets of information on how to optimally manage progression?

Mark G. Kris, MD: We would probably tend to continue, in those cases where we don’t find another target, the current TKI until the chemotherapy has taken hold. And then we’d probably stop the TKI.

Benjamin P. Levy, MD: Yes, I think that’s been the message here. Now, you’ve taught me this: when you are going to give chemotherapy, the TKI can come off, but not until the chemotherapy is really instituted.

Transcript Edited for Clarity
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Transcript:

Benjamin P. Levy, MD:
Just shifting gears a little bit: the deletion 19 story. What about afatinib seeming to show a survival advantage in the subset analysis from the LUX-Lung 3 and 6 trials? To my knowledge, it’s the only survival advantage we’ve seen. Wasn’t it “intent-to-treat” population? This was a mutation that some say is predictive; it’s quite sensitive no matter what TKI you give. Are people using afatinib in a del19 patient based on those data? It didn’t seem to shake out in the LUX-Lung 7 data by the way.

Mark G. Kris, MD: A lot more are getting bevacizumab with erlotinib. But what an amazing thing, though. The paper from the gefitinib versus afatinib trial just came out. I’d ask you to look at the waterfall plots in that; it’s very odd. The waterfall for gefitinib and afatinib in exon 19-deleted patients is identical.

Benjamin P. Levy, MD: Yes, it didn’t bear out.

Mark G. Kris, MD: Which is really unusual. We all make our living by doing these things, and most times we say, “Oh, it’s a subgroup analysis, if it’s not yours.” So, it’s hard to say. I find that whole trial, actually, that Sarah was talking about, a little tough to know how it changes practice. My gut would probably be to give afatinib.

Benjamin P. Levy, MD: Okay. TKI of choice, Chandra?

Chandra P. Belani, MD: Erlotinib.

Benjamin P. Levy, MD: Erlotinib?

Chandra P. Belani, MD: We have used it for a long time, and we have been able to treat all these patients. The patients are comfortable, the physicians are comfortable, the investigators are comfortable, and the nurses are comfortable. For me, the choice is still erlotinib. And though afatinib was better than gefitinib in that randomized trial, we really could not say that it is better than erlotinib.

Ramaswamy Govindan, MD: Mark, do you give afatinib and bevacizumab in del19?

Mark G. Kris, MD: I haven’t made that switch yet, but I intend to. We’re going to have that osimertinib and bevacizumab trial, so that’s going to be my choice.

Sarah B. Goldberg, MD, MPH: That’ll be first-line?

Mark G. Kris, MD: Yes.

Benjamin P. Levy, MD: Let’s move on and really tackle this in terms of the treatment continuum for a patient who received an EGFR TKI up front. Eventually, at some point, their tumor will grow, they will develop progression. I would just make the comment that progression in this setting is heterogeneous; not all progression is the same. We have to consider oligometastatic progression versus overall disease progression, factoring in whether a patient is symptomatic or not and factoring in the potential presence of T790M. So, Marina, can you just talk a little bit about your approach to treatment beyond progression and how you manage progression? And also what lesion do we re-biopsy if we’re heading towards a new treatment for that patient?

Marina Garassino, MD: After about 12 months, more or less, 50% of patients progress, and they can progress with the oligometastatic progression. In this case, we try to squeeze all the benefit of the EGFR TKIs. In Italy, we use them according to the toxicity profiles. For example, we avoid using afatinib in old people for the toxicity. We would really like to use erlotinib and bevacizumab. But if you have a slow disease without symptoms and the progression is low, you try to use the EGFR tyrosine kinase inhibitors until you really can’t.

What we do in our center is try to monitor the T790M, but, in reality, we don’t know if we have significance of monitoring the T790M, although we have the third-generation EGFR TKI. When the burden of the disease is very present, we re-biopsy the patient or we try to do a liquid biopsy. But, in general, we prefer to re-biopsy the patients because the way in which the progression can appear is that the pictures are very heterogeneous—and it’s true that in 50%, 70% of cases you may have the T790M, but you have 40% of cases in which you may have the epithelial mesenchymal transformation, the small-cell lung cancer transformation. I think that morphology is still important. Then you can test for MET, for HER2, for all the mechanisms of resistance.

What we biopsy is more simple than re-biopsy. So, we don’t differentiate the primary tumor from the metastases. We just discuss with the multidisciplinary team which is the easiest to re-biopsy, and we biopsy again. And then the story of the T790M is quite intriguing because we started to think that it was a secondary mutation, but now we are coming back [around] because we can find it also in 30% of the metastatic EGFR-mutated patients. I think that in the future we will have an EGFR T790M–mutated disease and the T790M-negative disease, and maybe we will select the treatment according to this.

Benjamin P. Levy, MD: How do you manage oligometastatic progression? So, you haven’t made that decision yet whether you want to re-biopsy or not. Are you addressing that local site with aggressive measures and riding out the TKI? What has the treatment approach in Europe been?

Marina Garassino, MD: We discuss in the multidisciplinary team what to do. I think that this is really important because, for example, if you have just a bone metastasis or a single-brain metastasis, you can do a radiotherapy. But maybe if you have a liver metastasis in a good segment, maybe you can re-biopsy at the time. The multidisciplinary team can help you with those the decisions.

Benjamin P. Levy, MD: Let’s go through a not uncommon scenario. You’ve decided to do the biopsy or the plasma, it’s T790M-negative, there’s no other actionable mutation within that biopsy. Do you institute chemotherapy?

Marina Garassino, MD: Yes.

Benjamin P. Levy, MD: What would be your chemotherapy choice, and would you continue the TKI when instituting the chemotherapy?

Marina Garassino, MD: So, while we try to find T790M, a MET, HER2, if we don’t find any actionable mutation, we go to chemotherapy. The most used regimen in Europe is cisplatin/pemetrexed, different from the United States, I think.

Benjamin P. Levy, MD: I don’t think it’s that different. We all have competing standards here in terms of what we use, but that would certainly be a consideration in the United States, as well. Any other thoughts, in terms of managing progression, and perhaps tips or nuggets of information on how to optimally manage progression?

Mark G. Kris, MD: We would probably tend to continue, in those cases where we don’t find another target, the current TKI until the chemotherapy has taken hold. And then we’d probably stop the TKI.

Benjamin P. Levy, MD: Yes, I think that’s been the message here. Now, you’ve taught me this: when you are going to give chemotherapy, the TKI can come off, but not until the chemotherapy is really instituted.

Transcript Edited for Clarity
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