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EGFR Therapy as Upfront Colorectal Cancer Treatment

Insights From: Charles S. Fuchs, MD, Harvard Medical School; Daniel G. Haller, MD, FACP, FRCP, Perelman School of Medicine; Richard Kim, MD, University of South Florida College of Medicine
Published: Monday, Mar 21, 2016


Transcript:

Daniel G. Haller, MD, FACP, FRCP:
I would say that the timing of RAS testing has changed with the FIRE-3 trial report from Europe, which showed a 7.5-month survival advantage for cetuximab over bevacizumab. This raises the issue of, should everyone get EGFR therapy first? Of course, the CALGB/SWOG 80405 trial in the US did not show that. They’re totally different trials. One study is not right, the other one is not wrong. It just simply raises the issue of more patients being considered for EGFR therapy up front. In my mind, those patients tend to be the people with high tumor volume and bulky tumors where response rate is clearly high with cetuximab, and therefore, patients might get a better benefit in terms of their tumor control with an EGFR agent. And the other group are the people with potentially resectable liver metastases. Those are the two people that I most often consider for EGFR therapy up front. So, I want RAS testing before I make those decisions in that patient population.

Richard Kim, MD: Testing for RAS mutations is very important up front regardless of whether you use an EGFR drug or an anti-VEGF drug such as bevacizumab because we know that in the first-line setting, that if you are a doctor who gives EGFR drugs up front, you need the RAS status up front to make sure you have a predictive marker that will tell you which patients won’t respond to the drug. In terms of testing for the metastatic site and the primary site, there’s plenty of data out there. The concordance rate between the primary site and the metastatic site is about 95%. So, if you have any specimen available, I think testing one or the other could be reasonable in this setting.

In the first-line setting, there clearly are data out there that say you could use EGFR drug or bevacizumab up front. It’s your choice in terms of how you practice. Having said that, if you’re going to use the EGFR drug up front, there’s clearly a biomarker that predicts who won’t respond to the drug. And that’s the RAS testing. In the first-line setting, we will test for KRAS up front to see if you have a mutation. Because if you have the KRAS mutations, then obviously you will use a bevacizumab-based regimen, rather than your EGFR drugs. If you are a doctor who will use bevacizumab up front, there has been data looking at KRAS as a predictive marker for bevacizumab. But the clarity of data has shown that the efficacy of bevacizumab is independent of a RAS mutation. So, it is important to test it up front if you can use EGFR drugs. However, if you’re going to use bevacizumab up front, it may not be as important. But having the RAS data up front is very important, because now you have a battle plan in terms of what to do after first-line. So, even if you don’t use an EGFR drug up front, if you have the RAS status up front, you will know what to give patients first-, second-, third-, and fourth-line.

Charles S. Fuchs, MD, MPH: I think it’s really important to get all-RAS testing when you see that new patient with metastatic disease, because we realize that there are a variety of biologics you can use in frontline therapy. They’re all realistic and effective options, and you want to make an informed decision. You don’t want to make the decision because, well, I don’t have data, and therefore, I’m going to make the choice that I don’t need data for. That’s not the way to practice medicine. So, we clearly need to get all-RAS testing. We have to get in real-time, so that you can actually sit down with the patient and say, you know what, you’re KRAS-mutant. We’re not going to proceed with an EGFR antibody. Alternatively, you’re KRAS wild-type, here are the advantages of using an EGFR antibody as opposed to a VEGF inhibitor. But that’s the kind of conversation we need to have with patients.

Daniel G. Haller, MD, FACP, FRCP: It’s fair when you meet a patient who may have been reading about all the therapies that they can receive, to talk about which ones legitimately they could receive. So, that if somebody, for example, has a BRAF-mutated tumor, this is 10% of people, who have very poor prognoses and median survival is 12 months, somehow discussing the results of FIRE-3 and 80405 with survivals of nearly 3 years, may not be very informative for them. It really doesn’t describe the options they truly may have. So, in patients who have BRAF wild-type tumors and KRAS mutated tumors, treatments may be available to them or not. You have to be honest with them when you first meet them about what their likely sequence is going to be.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

Daniel G. Haller, MD, FACP, FRCP:
I would say that the timing of RAS testing has changed with the FIRE-3 trial report from Europe, which showed a 7.5-month survival advantage for cetuximab over bevacizumab. This raises the issue of, should everyone get EGFR therapy first? Of course, the CALGB/SWOG 80405 trial in the US did not show that. They’re totally different trials. One study is not right, the other one is not wrong. It just simply raises the issue of more patients being considered for EGFR therapy up front. In my mind, those patients tend to be the people with high tumor volume and bulky tumors where response rate is clearly high with cetuximab, and therefore, patients might get a better benefit in terms of their tumor control with an EGFR agent. And the other group are the people with potentially resectable liver metastases. Those are the two people that I most often consider for EGFR therapy up front. So, I want RAS testing before I make those decisions in that patient population.

Richard Kim, MD: Testing for RAS mutations is very important up front regardless of whether you use an EGFR drug or an anti-VEGF drug such as bevacizumab because we know that in the first-line setting, that if you are a doctor who gives EGFR drugs up front, you need the RAS status up front to make sure you have a predictive marker that will tell you which patients won’t respond to the drug. In terms of testing for the metastatic site and the primary site, there’s plenty of data out there. The concordance rate between the primary site and the metastatic site is about 95%. So, if you have any specimen available, I think testing one or the other could be reasonable in this setting.

In the first-line setting, there clearly are data out there that say you could use EGFR drug or bevacizumab up front. It’s your choice in terms of how you practice. Having said that, if you’re going to use the EGFR drug up front, there’s clearly a biomarker that predicts who won’t respond to the drug. And that’s the RAS testing. In the first-line setting, we will test for KRAS up front to see if you have a mutation. Because if you have the KRAS mutations, then obviously you will use a bevacizumab-based regimen, rather than your EGFR drugs. If you are a doctor who will use bevacizumab up front, there has been data looking at KRAS as a predictive marker for bevacizumab. But the clarity of data has shown that the efficacy of bevacizumab is independent of a RAS mutation. So, it is important to test it up front if you can use EGFR drugs. However, if you’re going to use bevacizumab up front, it may not be as important. But having the RAS data up front is very important, because now you have a battle plan in terms of what to do after first-line. So, even if you don’t use an EGFR drug up front, if you have the RAS status up front, you will know what to give patients first-, second-, third-, and fourth-line.

Charles S. Fuchs, MD, MPH: I think it’s really important to get all-RAS testing when you see that new patient with metastatic disease, because we realize that there are a variety of biologics you can use in frontline therapy. They’re all realistic and effective options, and you want to make an informed decision. You don’t want to make the decision because, well, I don’t have data, and therefore, I’m going to make the choice that I don’t need data for. That’s not the way to practice medicine. So, we clearly need to get all-RAS testing. We have to get in real-time, so that you can actually sit down with the patient and say, you know what, you’re KRAS-mutant. We’re not going to proceed with an EGFR antibody. Alternatively, you’re KRAS wild-type, here are the advantages of using an EGFR antibody as opposed to a VEGF inhibitor. But that’s the kind of conversation we need to have with patients.

Daniel G. Haller, MD, FACP, FRCP: It’s fair when you meet a patient who may have been reading about all the therapies that they can receive, to talk about which ones legitimately they could receive. So, that if somebody, for example, has a BRAF-mutated tumor, this is 10% of people, who have very poor prognoses and median survival is 12 months, somehow discussing the results of FIRE-3 and 80405 with survivals of nearly 3 years, may not be very informative for them. It really doesn’t describe the options they truly may have. So, in patients who have BRAF wild-type tumors and KRAS mutated tumors, treatments may be available to them or not. You have to be honest with them when you first meet them about what their likely sequence is going to be.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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