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Optimal Therapy for BRAF-Mutated mCRC

Panelists: Johanna C. Bendell,MD, Sarah Cannon Research Institute; Dirk Arnold, MD, PhD, KTB Klinik fur Tumorbiologie GmbH & Co. KG ; Heinz-Josef Lenz, MD, FACP, USC Center for Molecular Pathway and Drug Discovery; Zev A. Wainberg, MD, UCLA Medical Center
Published: Friday, Dec 14, 2018



Transcript: 

Johanna C. Bendell, MD:
BRAF mutation plus MSI [microsatellite instability] really suggests that these are somatic mutations, not germline, Lynch syndrome, or hypermethylation. This is that key to understanding about testing for Lynch [syndrome] for these patients.

Heinz-Josef Lenz, MD, FACP: Yeah. I think it’s very important that MSI trumps BRAF in that situation. So that means when you have immunotherapies, it doesn’t matter if the patient is BRAF mutant, and it doesn’t matter if they’re methylator phenotype; it works the same, which is amazing. How MSI can overcome this incredible prognostic factor, which is another mystery, we don’t know. But when you look at BRAF mutant without MSI, they have features of an MSI signature. So there is something. It’s not a coincidence that if you have BRAF mutation, 30% will also have MSI. So there is some common background genetically.

Johanna C. Bendell, MD: And thinking about special populations, I mean, Zev, everybody is talking about HER2 [human epidermal growth factor receptor 2]. I thought you’re just supposed to find out if breast or gastric cancer patients were HER2. What does this mean for the world of colon cancer?

Zev A. Wainberg, MD: First of all, it’s pretty rare in colon cancer. If you look at the data, it’s—depending on what you read—4 or 5% maybe. Predominantly and almost exclusively, in my opinion, there is no reason to test a RAS-mutant patient for HER2. They’re usually left-sided. And most of the excitement, I would say, came from the Italian study, if I’m not mistaken, combining trastuzumab [Herceptin] and lapatinib [Tykerb] without chemotherapy. And now there are a number of newer HER2 targeted therapies, where there’s a SWOG trial that’s looking at the combination of Herceptin or trastuzumab, I should say, with chemotherapy versus cetuximab [Erbitux] at control. And there are second-generation HER2 ADCs [antibody–drug conjugates] that are very exciting and potent drugs that are also looking particularly at HER2 CRC [colorectal cancer]. Because it would be a rare group within a presumably high enough response rate, that may be sufficient for us to get some sort of accelerated path toward approval if it can be demonstrated in that group.

So, I think we haven’t any new target, so to speak, and this is not a new target. This is about one of the oldest targets we have, but it’s repurposed here. And in those patients now, I think there’s some suggestion that some HER2 blockade may make sense. So why not check it. It’s easy enough to do.

Johanna C. Bendell, MD: True. So Dirk, if you check first-line therapy, you have a HER2-positive patient and they’re left-sided, does that influence your choice of whether or not to use an EGFR inhibitor in these patients?

Dirk Arnold, MD, PhD: I think the decision is then to go with the EGFR inhibitor because this patient is also RAS wild type. Therefore, I would clearly use an anti-EGF receptor inhibitor given the good evidence in this situation.

Johanna C. Bendell, MD: So you would, for a HER2-positive patient, use an EGFR inhibitor?

Dirk Arnold, MD, PhD: Yes.

Johanna C. Bendell, MD: Heinz?

Heinz-Josef Lenz, MD, FACP: I probably would not. Because it is one of the mechanisms of resistance. A reason you combine both in the SWOG trial with the pertuzumab [Perjeta] and the cetuximab. So for the HER2-positive, I would use the combination of HER1 and HER2.

Johanna C. Bendell, MD: I mean definitely controversial as you can see here. There’s some data.

Zev A. Wainberg, MD: No data yet.

Dirk Arnold, MD, PhD: Let me ask. We have to learn a bit more about the predictive quality and really what the outcome with the anti-HER2 treatment is. Since we have seen this terrible failure of all these drugs, which work so nicely in anti-HER2 management in gastric cancer, which works so nicely in breast cancer, double inhibition, all these elegant principles. We’ve really got such a gain for patients with breast cancer, and we learned that this is something different in gastric cancer. And I’m not sure what it means in colorectal cancer.

Heinz-Josef Lenz, MD, FACP: So I think we know melanoma is different from colon cancer. And gastric cancer is not the same thing as colon cancer. So one of the biggest issues in HER2 breast versus gastric is that in gastric you lose HER2 under treatment; 16 to 17% you lose the amplification of the expression. That’s the reason the second line works in breast. It’s not that they don’t work; it’s that the target is not there anymore. So I think that’s the reason we cannot translate one to the other, and we need to learn more about the genomics. Because what I recently saw is actually very interesting. That we can have a HER2-negative tumor, that can turn positive. So it goes both ways, and I think we’ll learn more about the genomics. And if there are treatment implications, I don’t know, but it is very interesting, because we think it’s negative.


Transcript Edited for Clarity

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Transcript: 

Johanna C. Bendell, MD:
BRAF mutation plus MSI [microsatellite instability] really suggests that these are somatic mutations, not germline, Lynch syndrome, or hypermethylation. This is that key to understanding about testing for Lynch [syndrome] for these patients.

Heinz-Josef Lenz, MD, FACP: Yeah. I think it’s very important that MSI trumps BRAF in that situation. So that means when you have immunotherapies, it doesn’t matter if the patient is BRAF mutant, and it doesn’t matter if they’re methylator phenotype; it works the same, which is amazing. How MSI can overcome this incredible prognostic factor, which is another mystery, we don’t know. But when you look at BRAF mutant without MSI, they have features of an MSI signature. So there is something. It’s not a coincidence that if you have BRAF mutation, 30% will also have MSI. So there is some common background genetically.

Johanna C. Bendell, MD: And thinking about special populations, I mean, Zev, everybody is talking about HER2 [human epidermal growth factor receptor 2]. I thought you’re just supposed to find out if breast or gastric cancer patients were HER2. What does this mean for the world of colon cancer?

Zev A. Wainberg, MD: First of all, it’s pretty rare in colon cancer. If you look at the data, it’s—depending on what you read—4 or 5% maybe. Predominantly and almost exclusively, in my opinion, there is no reason to test a RAS-mutant patient for HER2. They’re usually left-sided. And most of the excitement, I would say, came from the Italian study, if I’m not mistaken, combining trastuzumab [Herceptin] and lapatinib [Tykerb] without chemotherapy. And now there are a number of newer HER2 targeted therapies, where there’s a SWOG trial that’s looking at the combination of Herceptin or trastuzumab, I should say, with chemotherapy versus cetuximab [Erbitux] at control. And there are second-generation HER2 ADCs [antibody–drug conjugates] that are very exciting and potent drugs that are also looking particularly at HER2 CRC [colorectal cancer]. Because it would be a rare group within a presumably high enough response rate, that may be sufficient for us to get some sort of accelerated path toward approval if it can be demonstrated in that group.

So, I think we haven’t any new target, so to speak, and this is not a new target. This is about one of the oldest targets we have, but it’s repurposed here. And in those patients now, I think there’s some suggestion that some HER2 blockade may make sense. So why not check it. It’s easy enough to do.

Johanna C. Bendell, MD: True. So Dirk, if you check first-line therapy, you have a HER2-positive patient and they’re left-sided, does that influence your choice of whether or not to use an EGFR inhibitor in these patients?

Dirk Arnold, MD, PhD: I think the decision is then to go with the EGFR inhibitor because this patient is also RAS wild type. Therefore, I would clearly use an anti-EGF receptor inhibitor given the good evidence in this situation.

Johanna C. Bendell, MD: So you would, for a HER2-positive patient, use an EGFR inhibitor?

Dirk Arnold, MD, PhD: Yes.

Johanna C. Bendell, MD: Heinz?

Heinz-Josef Lenz, MD, FACP: I probably would not. Because it is one of the mechanisms of resistance. A reason you combine both in the SWOG trial with the pertuzumab [Perjeta] and the cetuximab. So for the HER2-positive, I would use the combination of HER1 and HER2.

Johanna C. Bendell, MD: I mean definitely controversial as you can see here. There’s some data.

Zev A. Wainberg, MD: No data yet.

Dirk Arnold, MD, PhD: Let me ask. We have to learn a bit more about the predictive quality and really what the outcome with the anti-HER2 treatment is. Since we have seen this terrible failure of all these drugs, which work so nicely in anti-HER2 management in gastric cancer, which works so nicely in breast cancer, double inhibition, all these elegant principles. We’ve really got such a gain for patients with breast cancer, and we learned that this is something different in gastric cancer. And I’m not sure what it means in colorectal cancer.

Heinz-Josef Lenz, MD, FACP: So I think we know melanoma is different from colon cancer. And gastric cancer is not the same thing as colon cancer. So one of the biggest issues in HER2 breast versus gastric is that in gastric you lose HER2 under treatment; 16 to 17% you lose the amplification of the expression. That’s the reason the second line works in breast. It’s not that they don’t work; it’s that the target is not there anymore. So I think that’s the reason we cannot translate one to the other, and we need to learn more about the genomics. Because what I recently saw is actually very interesting. That we can have a HER2-negative tumor, that can turn positive. So it goes both ways, and I think we’ll learn more about the genomics. And if there are treatment implications, I don’t know, but it is very interesting, because we think it’s negative.


Transcript Edited for Clarity
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