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Frontline Therapy for mCRC

Panelists: John Marshall, MD, Georgetown University; Cathy Eng, MD, Vanderbilt University; Tanios Bekaii-Saab, MD, Mayo Clinic; Dustin Deming, MD, University of Wisconsin; Michael Morse, MD, Duke Cancer Institute
Published: Monday, Jul 29, 2019



Transcript: 

John Marshall, MD: What are you telling your patients, Dustin? When you say, “We’re going to send this off for fancy-schmancy testing.” What do you think? Do you warn them that this is going to be great—it’s going to change your life? How do you present that to a patient?

Dustin Deming, MD: It’s actually fairly easy, for colon cancer, to have that discussion because regardless of what that result is, it is going to change how I treat that patient. If we’re using one of these large NGS [next-generation sequencing] panels to do KRAS, NRAS testing, HER2 [human epidermal growth factor receptor 2] amplification—I even like it for retesting MSI [microsatellite instability]. There are about 10% of MSI-high patients who we miss by doing IHC [immunohistochemistry testing] only, and either doing a PCR [polymerase chain reaction]-based or an NGS-based test, in addition, is also important, in my mind.

John Marshall, MD: Even if we’ve got the IHC, I often repeat the genes, because the concordance is not perfect, right?

Dustin Deming, MD: Correct. Granted, this is a colon cancer panel, but MSI outside of colon cancer is a much different beast, and there are different microsatellites that are important to assay. Especially for non-colorectal cancer, performing an NGS-type MSI testing is important.

Tanios Bekaii-Saab, MD: I have to tell you, I’ve selectively have done some of the stage III patients. Now that sounds crazy, but I do it selectively, especially in younger patients. I recall a recent patient who presented with a 9-sontimeter [cm] tumor with no lymph nodes involved. With MSS [microsatellite stability]—all the features, there was some family history—I still thought that there was something there that didn’t make sense. This was a 49-year-old with a 9-sontimeter tumor that is a T4, but lymph node-negative. There were about 30 lymph nodes out, so I sent it. Tumor mutation burden was 239.

John Marshall, MD: We’re finding BRCAs. We’re finding all sorts of….

Tanios Bekaii-Saab, MD: That goes to your primary point that I had a different discussion with the patient. The system was checking this tumor, essentially. That’s why it didn’t metastasize to the lymph nodes and was unlikely to have metastasized beyond the primary. I’ve done it a few times, selectively. Do you do it on everyone? Probably not at this point for stage III, but selectively, it may inform you. It may actually take you on a different path, as well.

John Marshall, MD: Mike, liquid biopsy is used a lot in, say, lung cancer, even as the primary molecular diagnosis. Quicker turnaround time. You control it. You’re not relying on your pathologist to free up the tissue. What’s your perspective on its ability to detect versus tissue-based?

Michael Morse, MD: It would be nice to have a trial similar to the NILE trial that was done for lung in colon, but I think given the breadth of data out there now, it clearly does detect the mutations, at least as well, if not better. The reality is that neither one is perfect, and there are mutations that are picked up on tumor tissue that you don’t see in circulation, and so on.

John Marshall, MD: This is a hotly debated thing. The reason I give you that first dibs is that not everybody may agree with that. There’s the tissue-based belief that you’re going to get more. They’re different. There are different panels. A negative on a liquid, I think, doesn’t absolutely rule out a mutation, and vice versa, right?

Tanios Bekaii-Saab, MD: If you find a BRAF V600E mutation on a liquid, it’s going to be in the tissue.

John Marshall, MD: A positive is a positive.

Tanios Bekaii-Saab, MD: Yes, exactly. If you don’t find it, then there’s a chance you may be missing it. Although, again, they’re getting better-refined with the sensitivity of the test, at least. The specificity is less concerning, actually, than the sensitivity is. The good news is that it’s rare to find false positives that wouldn’t make sense. Most of those patients will have alterations that are essentially linked to a target on the tumor.

John Marshall, MD: Cathy, why do I care where the tumor primary is?

Cathy Eng, MD: The location has great significance in regard to number 1) your treatment options that you’re thinking about, as well as the overall survival of the patient.

John Marshall, MD: How could this be? Why does that make any sense?

Cathy Eng, MD: Well, we’ve clearly shown that right-sided tumors actually fare much worse in regard to overall survival. Also, if you have a right-sided tumor, you should think about testing for MSI-high as well as BRAF.

John Marshall, MD: That doesn’t mean don’t test the lefts, right?

Cathy Eng, MD: No, that does not mean that.

John Marshall, MD: OK, I just want to be clear. Everybody gets everything.

Cathy Eng, MD: Everyone should get tested.

John Marshall, MD: Right now, everybody gets everything.

Cathy Eng, MD: Everyone should get tested. Obviously, for your right-sided patient, you know that their prognosis might not be as positive.

John Marshall, MD: You tell them that?

Cathy Eng, MD: I don’t tell them that, per se. I do give them information. I don’t say just because you have a right-sided tumor, you’re going to decline quickly, no. I inform them that right-sided tumors may be more aggressive, and that appears to be the case, and we have to be very careful about which treatments we provide to the patient and really take that into account. We have to be prepared for considering next lines of treatment.

John Marshall, MD: Sidedness and the biologics, talk a little bit about that. We’ve got data there, right?

Cathy Eng, MD: We have data. It’s just that left-sided tumors, if you’re all RAS wild-type, may benefit more potentially from anti-EGFR therapy in the frontline setting. The Europeans are large fans of that, as you know. Though, for many of us, sometimes the RAS testing isn’t back yet and the patient wants to get started on therapy. We feel it’s appropriate to go ahead and proceed with anti-VEGF therapy in that setting, as well.

John Marshall, MD: Yes. To Tony’s point earlier, we don’t only need to know RAS, we need to know BRAF and HER2 in that patient if you’re going to use EGFR frontline. That’s now maybe 20%, maybe less than that, who are then candidates.

Tanios Bekaii-Saab, MD: Yes, the pie keeps shrinking—exclude the right, exclude the RAS­-mutated, BRAF V600E-mutated, the HER2­ amplified. There probably are others, as well. If you have all that in hand, it’s great, but most of the time that patient is presenting to us, we don’t.

John Marshall, MD: Mike, in a metastatic patient with right-sided mets [metastases], but let’s make them asymptomatic mets, do I have to give FOLFIRINOX-BEV [folinic acid, fluorouracil, irinotecan, oxaliplatin plus bevacizumab] to this patient?

Michael Morse, MD: Well, FOLFOXIRI-BEV [folinic acid, fluorouracil, oxaliplatin, irinotecan plus bevacizumab].

John Marshall, MD: Should I? Whichever one.

Michael Morse, MD: The TRIBE trial was interesting. As I was sitting through it, I was almost sinking in my seat because I don’t like to give multi-, triple-drug therapies to the average, particularly older, colon cancer patient. I now wonder about that based on the data that were presented. We’re going to talk more about TRIBE later.

John Marshall, MD: We are, but I’m just saying we got this data that, back to sidedness, right-sided tumors are worse. There are some data that suggest that we counter that in some ways with a more aggressive therapy.

Cathy Eng, MD: Right.

John Marshall, MD: Am I required to be more aggressive in that setting?

Michael Morse, MD: I don’t know that you necessarily have to be more aggressive. These are individual discussions with patients.

John Marshall, MD: I can still give a right-sided colon cancer patient FOLFOX-BEV [folinic acid, fluorouracil, oxaliplatin plus bevacizumab] if I want to?

Michael Morse, MD: I wouldn’t have concern. Obviously, there’s other information if they’re MSI-high. I see Tony is disagreeing with this.

Tanios Bekaii-Saab, MD: I will disagree with this.

Cathy Eng, MD: I was going to disagree, too.

Tanios Bekaii-Saab, MD: We’re going to talk about TRIBE-2. If you look at the numbers, and they don’t look fancy, the 27 months, but that’s actually much better than the right-sided EGFR inhibitors.

John Marshall, MD: We’ve seen before, yes.

Tanios Bekaii-Saab, MD: Absolutely. The point is that now we have to be selective of, course. If it’s your 80-year-old patient, for God’s sake, we’re not going to give them FOLFOXIRI [folinic acid, fluorouracil, oxaliplatin, irinotecan]. However, if you’re comfortable giving FOLFIRINOX [folinic acid, fluorouracil, irinotecan, oxaliplatin] to a pancreas cancer patient, I don’t see why you shouldn’t be comfortable considering FOLFOXIRI [folinic acid, fluorouracil, oxaliplatin, irinotecan] for a colorectal cancer patient.

Cathy Eng, MD: I agree with you.

John Marshall, MD: The concern I hear all the time is, I’ve used all my drugs. We have been preaching for the last 5 or 6 years that it’s sequential therapy. It’s making sure that all the patients are exposed to all the drugs. Now, we’re changing our tune, and saying that some sort of induction-intensive therapy pays off long term.

Transcript Edited for Clarity

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Transcript: 

John Marshall, MD: What are you telling your patients, Dustin? When you say, “We’re going to send this off for fancy-schmancy testing.” What do you think? Do you warn them that this is going to be great—it’s going to change your life? How do you present that to a patient?

Dustin Deming, MD: It’s actually fairly easy, for colon cancer, to have that discussion because regardless of what that result is, it is going to change how I treat that patient. If we’re using one of these large NGS [next-generation sequencing] panels to do KRAS, NRAS testing, HER2 [human epidermal growth factor receptor 2] amplification—I even like it for retesting MSI [microsatellite instability]. There are about 10% of MSI-high patients who we miss by doing IHC [immunohistochemistry testing] only, and either doing a PCR [polymerase chain reaction]-based or an NGS-based test, in addition, is also important, in my mind.

John Marshall, MD: Even if we’ve got the IHC, I often repeat the genes, because the concordance is not perfect, right?

Dustin Deming, MD: Correct. Granted, this is a colon cancer panel, but MSI outside of colon cancer is a much different beast, and there are different microsatellites that are important to assay. Especially for non-colorectal cancer, performing an NGS-type MSI testing is important.

Tanios Bekaii-Saab, MD: I have to tell you, I’ve selectively have done some of the stage III patients. Now that sounds crazy, but I do it selectively, especially in younger patients. I recall a recent patient who presented with a 9-sontimeter [cm] tumor with no lymph nodes involved. With MSS [microsatellite stability]—all the features, there was some family history—I still thought that there was something there that didn’t make sense. This was a 49-year-old with a 9-sontimeter tumor that is a T4, but lymph node-negative. There were about 30 lymph nodes out, so I sent it. Tumor mutation burden was 239.

John Marshall, MD: We’re finding BRCAs. We’re finding all sorts of….

Tanios Bekaii-Saab, MD: That goes to your primary point that I had a different discussion with the patient. The system was checking this tumor, essentially. That’s why it didn’t metastasize to the lymph nodes and was unlikely to have metastasized beyond the primary. I’ve done it a few times, selectively. Do you do it on everyone? Probably not at this point for stage III, but selectively, it may inform you. It may actually take you on a different path, as well.

John Marshall, MD: Mike, liquid biopsy is used a lot in, say, lung cancer, even as the primary molecular diagnosis. Quicker turnaround time. You control it. You’re not relying on your pathologist to free up the tissue. What’s your perspective on its ability to detect versus tissue-based?

Michael Morse, MD: It would be nice to have a trial similar to the NILE trial that was done for lung in colon, but I think given the breadth of data out there now, it clearly does detect the mutations, at least as well, if not better. The reality is that neither one is perfect, and there are mutations that are picked up on tumor tissue that you don’t see in circulation, and so on.

John Marshall, MD: This is a hotly debated thing. The reason I give you that first dibs is that not everybody may agree with that. There’s the tissue-based belief that you’re going to get more. They’re different. There are different panels. A negative on a liquid, I think, doesn’t absolutely rule out a mutation, and vice versa, right?

Tanios Bekaii-Saab, MD: If you find a BRAF V600E mutation on a liquid, it’s going to be in the tissue.

John Marshall, MD: A positive is a positive.

Tanios Bekaii-Saab, MD: Yes, exactly. If you don’t find it, then there’s a chance you may be missing it. Although, again, they’re getting better-refined with the sensitivity of the test, at least. The specificity is less concerning, actually, than the sensitivity is. The good news is that it’s rare to find false positives that wouldn’t make sense. Most of those patients will have alterations that are essentially linked to a target on the tumor.

John Marshall, MD: Cathy, why do I care where the tumor primary is?

Cathy Eng, MD: The location has great significance in regard to number 1) your treatment options that you’re thinking about, as well as the overall survival of the patient.

John Marshall, MD: How could this be? Why does that make any sense?

Cathy Eng, MD: Well, we’ve clearly shown that right-sided tumors actually fare much worse in regard to overall survival. Also, if you have a right-sided tumor, you should think about testing for MSI-high as well as BRAF.

John Marshall, MD: That doesn’t mean don’t test the lefts, right?

Cathy Eng, MD: No, that does not mean that.

John Marshall, MD: OK, I just want to be clear. Everybody gets everything.

Cathy Eng, MD: Everyone should get tested.

John Marshall, MD: Right now, everybody gets everything.

Cathy Eng, MD: Everyone should get tested. Obviously, for your right-sided patient, you know that their prognosis might not be as positive.

John Marshall, MD: You tell them that?

Cathy Eng, MD: I don’t tell them that, per se. I do give them information. I don’t say just because you have a right-sided tumor, you’re going to decline quickly, no. I inform them that right-sided tumors may be more aggressive, and that appears to be the case, and we have to be very careful about which treatments we provide to the patient and really take that into account. We have to be prepared for considering next lines of treatment.

John Marshall, MD: Sidedness and the biologics, talk a little bit about that. We’ve got data there, right?

Cathy Eng, MD: We have data. It’s just that left-sided tumors, if you’re all RAS wild-type, may benefit more potentially from anti-EGFR therapy in the frontline setting. The Europeans are large fans of that, as you know. Though, for many of us, sometimes the RAS testing isn’t back yet and the patient wants to get started on therapy. We feel it’s appropriate to go ahead and proceed with anti-VEGF therapy in that setting, as well.

John Marshall, MD: Yes. To Tony’s point earlier, we don’t only need to know RAS, we need to know BRAF and HER2 in that patient if you’re going to use EGFR frontline. That’s now maybe 20%, maybe less than that, who are then candidates.

Tanios Bekaii-Saab, MD: Yes, the pie keeps shrinking—exclude the right, exclude the RAS­-mutated, BRAF V600E-mutated, the HER2­ amplified. There probably are others, as well. If you have all that in hand, it’s great, but most of the time that patient is presenting to us, we don’t.

John Marshall, MD: Mike, in a metastatic patient with right-sided mets [metastases], but let’s make them asymptomatic mets, do I have to give FOLFIRINOX-BEV [folinic acid, fluorouracil, irinotecan, oxaliplatin plus bevacizumab] to this patient?

Michael Morse, MD: Well, FOLFOXIRI-BEV [folinic acid, fluorouracil, oxaliplatin, irinotecan plus bevacizumab].

John Marshall, MD: Should I? Whichever one.

Michael Morse, MD: The TRIBE trial was interesting. As I was sitting through it, I was almost sinking in my seat because I don’t like to give multi-, triple-drug therapies to the average, particularly older, colon cancer patient. I now wonder about that based on the data that were presented. We’re going to talk more about TRIBE later.

John Marshall, MD: We are, but I’m just saying we got this data that, back to sidedness, right-sided tumors are worse. There are some data that suggest that we counter that in some ways with a more aggressive therapy.

Cathy Eng, MD: Right.

John Marshall, MD: Am I required to be more aggressive in that setting?

Michael Morse, MD: I don’t know that you necessarily have to be more aggressive. These are individual discussions with patients.

John Marshall, MD: I can still give a right-sided colon cancer patient FOLFOX-BEV [folinic acid, fluorouracil, oxaliplatin plus bevacizumab] if I want to?

Michael Morse, MD: I wouldn’t have concern. Obviously, there’s other information if they’re MSI-high. I see Tony is disagreeing with this.

Tanios Bekaii-Saab, MD: I will disagree with this.

Cathy Eng, MD: I was going to disagree, too.

Tanios Bekaii-Saab, MD: We’re going to talk about TRIBE-2. If you look at the numbers, and they don’t look fancy, the 27 months, but that’s actually much better than the right-sided EGFR inhibitors.

John Marshall, MD: We’ve seen before, yes.

Tanios Bekaii-Saab, MD: Absolutely. The point is that now we have to be selective of, course. If it’s your 80-year-old patient, for God’s sake, we’re not going to give them FOLFOXIRI [folinic acid, fluorouracil, oxaliplatin, irinotecan]. However, if you’re comfortable giving FOLFIRINOX [folinic acid, fluorouracil, irinotecan, oxaliplatin] to a pancreas cancer patient, I don’t see why you shouldn’t be comfortable considering FOLFOXIRI [folinic acid, fluorouracil, oxaliplatin, irinotecan] for a colorectal cancer patient.

Cathy Eng, MD: I agree with you.

John Marshall, MD: The concern I hear all the time is, I’ve used all my drugs. We have been preaching for the last 5 or 6 years that it’s sequential therapy. It’s making sure that all the patients are exposed to all the drugs. Now, we’re changing our tune, and saying that some sort of induction-intensive therapy pays off long term.

Transcript Edited for Clarity
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