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Addition of Bevacizumab to Up-front therapy for EGFR+ NSCLC

Panelists: Mark A. Socinski, MD, Florida Hospital Cancer Institute; Tracey L. Evans, MD, University of Pennsylvania; Alexander Drilon, MD, Memorial Sloan Kettering Cancer Center; Vali A. Papadimitrakopoulou, MD, The University of Texas MD Anderson Cancer Center; Jared Weiss, MD, UNC Lineberger Comprehensive Cancer Center
Published: Wednesday, Mar 01, 2017


Transcript:

Mark Socinski, MD:
Vali, we saw really exciting data first at ASCO and now published, and this is using bevacizumab in addition to erlotinib in this setting. Your perspective?

Vali Papadimitrakopoulou, MD: The use of this combination actually has a long history behind it, and there have been preclinical data suggesting that there would be synergy in combining an EGFR TKI with an antiangiogenic agent. There are data suggesting that you may increase intratumoral concentration of the EGFR TKI because of reorganization of the vasculature that supports the tumor as well as specific data that speaks to the antiangiogenics acting against resistance mechanisms for EGFR TKIs. So, plenty of rationale, and the clinical trial showed a dramatic difference combining bevacizumab and erlotinib versus erlotinib alone. It was done in Japan, a dramatic difference favoring the combination in terms of progression-free survival.

Mark Socinski, MD: Dramatically different.

Vali Papadimitrakopoulou, MD: Yes, 16 months versus 9 months.

Mark Socinski, MD: Almost a doubling.

Vali Papadimitrakopoulou, MD: Yes. That definitely provides us an opportunity to treat our patients and obtain that longer progression-free survival in the first-line setting, leaving other options that are also long-lasting in the duration of response for the second-line setting. So, I think the sequence of therapy becomes less of a question if you associate erlotinib in combination with bevacizumab. The question comes up, should we also be combining other EGFR TKIs with erlotinib and should we expect the same degree of benefit?

Mark Socinski, MD: Right. But let me get your perspective on this: I’m going to steal a term from my young colleague here and that is that adding bevacizumab to a TKI really changes the game. As Jared had said, it medicalizes the treatment. You have a patient coming every 3 weeks, and even though I think this is probably a low-risk population for the known side effects, the problem with bevacizumab is the side effects are both unpredictable and can be catastrophic. There’s bowel perforation, bleeding, RPLS (reversible posterior leukoencephalopathy syndrome)—all these sorts of things that can happen with bevacizumab. And we don’t know that it adds to survival. I want to get your perspective on that, but also your perspective on why not save bevacizumab until they start progressing. We’ll talk about T790M in a moment, but can you buy some time before you sequence to the next line of therapy, particularly in those patients that may not have T790M disease?

Vali Papadimitrakopoulou, MD: So, I think the combination is to be used in selected patients, and there are clinical characteristics that put people at higher risk for the side effects of bevacizumab. If you start with a patient with uncontrolled hypertension, an older patient, or a patient that cannot really come back and forth for the medicalized treatment, that would be an argument against using bevacizumab. To your point about saving bevacizumab, and we can talk more later, there are data that are out there for patients with a T790M mutation, where this combination of erlotinib/bevacizumab was quite active. There was a study coming from Switzerland, and it also demonstrated a progression-free survival of 16 months in that second-line setting, so there may be more mileage that can be obtained later down the line, to your point, if you add bevacizumab to a patient that may have limited options for therapy.

Mark Socinski, MD: Let me ask the panel. For newly diagnosed patients with exon 19, do you add bevacizumab to your TKI?

Alexander Drilon, MD: No, not outside the confines of a protocol.

Mark Socinski, MD: Tracey?

Tracey Evans, MD: I don’t, no.

Jared Weiss, MD: I’m waiting for the United States data for now, but no.

Vali Papadimitrakopoulou, MD: I do occasionally.

Mark Socinski, MD: Our good friend, Jack West, does this a lot in Seattle. It’s an interesting perspective on what these data mean, but different thought leaders have different opinions, and it’s influenced some in terms of their practice, but not others. To Jared’s point, we have a United States-based trial that’s the same design and that’s being run by Tom Stinchcombe.

Jared Weiss, MD: And it has completed accrual.

Mark Socinski, MD: Oh, it has? I didn’t know that. So, that’s good.

Jared Weiss, MD: It should have data.

Transcript Edited for Clarity
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Transcript:

Mark Socinski, MD:
Vali, we saw really exciting data first at ASCO and now published, and this is using bevacizumab in addition to erlotinib in this setting. Your perspective?

Vali Papadimitrakopoulou, MD: The use of this combination actually has a long history behind it, and there have been preclinical data suggesting that there would be synergy in combining an EGFR TKI with an antiangiogenic agent. There are data suggesting that you may increase intratumoral concentration of the EGFR TKI because of reorganization of the vasculature that supports the tumor as well as specific data that speaks to the antiangiogenics acting against resistance mechanisms for EGFR TKIs. So, plenty of rationale, and the clinical trial showed a dramatic difference combining bevacizumab and erlotinib versus erlotinib alone. It was done in Japan, a dramatic difference favoring the combination in terms of progression-free survival.

Mark Socinski, MD: Dramatically different.

Vali Papadimitrakopoulou, MD: Yes, 16 months versus 9 months.

Mark Socinski, MD: Almost a doubling.

Vali Papadimitrakopoulou, MD: Yes. That definitely provides us an opportunity to treat our patients and obtain that longer progression-free survival in the first-line setting, leaving other options that are also long-lasting in the duration of response for the second-line setting. So, I think the sequence of therapy becomes less of a question if you associate erlotinib in combination with bevacizumab. The question comes up, should we also be combining other EGFR TKIs with erlotinib and should we expect the same degree of benefit?

Mark Socinski, MD: Right. But let me get your perspective on this: I’m going to steal a term from my young colleague here and that is that adding bevacizumab to a TKI really changes the game. As Jared had said, it medicalizes the treatment. You have a patient coming every 3 weeks, and even though I think this is probably a low-risk population for the known side effects, the problem with bevacizumab is the side effects are both unpredictable and can be catastrophic. There’s bowel perforation, bleeding, RPLS (reversible posterior leukoencephalopathy syndrome)—all these sorts of things that can happen with bevacizumab. And we don’t know that it adds to survival. I want to get your perspective on that, but also your perspective on why not save bevacizumab until they start progressing. We’ll talk about T790M in a moment, but can you buy some time before you sequence to the next line of therapy, particularly in those patients that may not have T790M disease?

Vali Papadimitrakopoulou, MD: So, I think the combination is to be used in selected patients, and there are clinical characteristics that put people at higher risk for the side effects of bevacizumab. If you start with a patient with uncontrolled hypertension, an older patient, or a patient that cannot really come back and forth for the medicalized treatment, that would be an argument against using bevacizumab. To your point about saving bevacizumab, and we can talk more later, there are data that are out there for patients with a T790M mutation, where this combination of erlotinib/bevacizumab was quite active. There was a study coming from Switzerland, and it also demonstrated a progression-free survival of 16 months in that second-line setting, so there may be more mileage that can be obtained later down the line, to your point, if you add bevacizumab to a patient that may have limited options for therapy.

Mark Socinski, MD: Let me ask the panel. For newly diagnosed patients with exon 19, do you add bevacizumab to your TKI?

Alexander Drilon, MD: No, not outside the confines of a protocol.

Mark Socinski, MD: Tracey?

Tracey Evans, MD: I don’t, no.

Jared Weiss, MD: I’m waiting for the United States data for now, but no.

Vali Papadimitrakopoulou, MD: I do occasionally.

Mark Socinski, MD: Our good friend, Jack West, does this a lot in Seattle. It’s an interesting perspective on what these data mean, but different thought leaders have different opinions, and it’s influenced some in terms of their practice, but not others. To Jared’s point, we have a United States-based trial that’s the same design and that’s being run by Tom Stinchcombe.

Jared Weiss, MD: And it has completed accrual.

Mark Socinski, MD: Oh, it has? I didn’t know that. So, that’s good.

Jared Weiss, MD: It should have data.

Transcript Edited for Clarity
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