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Metastatic Colorectal Cancer: Multiple Lines of Therapy

Insights From: Tanios Bekaii-Saab, MD, Mayo Clinic; Johanna C. Bendell, MD, Sarah Cannon Research Institute
Published: Wednesday, Oct 03, 2018



Transcript: 

Johanna C. Bendell, MD: In terms of selecting the best treatment for patients as first-line therapy, the most common regimen that’s being used now in the United States is probably FOLFOX [folinic acid/fluorouracil(5-FU)/oxaliplatin] plus bevacizumab, which has been the standard for quite a number of years now. For some people, we might consider using FOLFOXIRI [folinic acid/5-FU/oxaliplatin/irinotecan] plus bevacizumab, particularly for the patients with BRAF-mutated colon cancer. For a young patient in whom you’re looking for a good response—somebody who might be able to go to surgical resection—we have ways to increase the amount of tumor shrinkage. But when using more aggressive regimens up front, we should always remember to get patients into the maintenance therapies after about 4 to 6 months of treatment to allow them to have a better quality of life while they’re still on their first-line therapy.

Tanios Bekaii-Saab, MD: When we look at colorectal cancer, we know clearly that first line is pretty much determined on chemotherapy plus bevacizumab. For some patients with left-sided, RAS wild-type, BRAF V600E wild-type, or HER2-nonamplified tumors, there’s also the option of adding an EGFR inhibitor instead of bevacizumab.

Second-line therapy really depends on what you do in the first-line setting and some of the molecular profiling of the tumor. If you’re on the right side, chemotherapy plus bevacizumab is your first-line regimen regardless of RAS or BRAF status.

Second-line therapy, in terms of what we have available to us today in clinic, would be to switch the chemotherapy and continue the bevacizumab. For the rare patient who may have a BRAF V600E mutation, we have the option of introducing a MEK inhibitor plus a BRAF inhibitor plus/minus an EGFR inhibitor. That’s an option, whether right- or left-sided disease, although primarily on the left side. For the HER2-amplified tumors, preference would be for a clinical trial including these HER2-targeted therapies. For MSI [microsatellite instability]–high tumors, which occur in about 4% of patients, the preference is for a PD-1 inhibitor in the second or third line.

Most patients are actually going to go through 1 or 2 lines of chemotherapy plus a biologic, and there could be a switch of biologic or a switch of chemotherapy. We end up in the third line, and then we have 2 options in the refractory setting: regorafenib and TAS-102. Regorafenib is an agent that’s a multitype kinase inhibitor. TAS-102 is a more traditional cytotoxic agent. It’s part of the superfamily of fluoropyrimidines that specifically seems to work when 5-FU or capecitabine do not, at least in some cases.

Both agents were compared with placebo in 2 separate studies. Both agents had very similar outcomes in terms of improvements. Historically, they look somewhat similar. Their toxicities are different: hand-foot syndrome reaction and fatigue with regorafenib, neutropenia and fatigue with TAS-102, and some GI [gastrointestinal] toxicities in both.

They’ve never been compared head-to-head, so it’s very difficult to make inferences about which one should go first. In practice, you have to think about your patients. Where do we have some data? We just have a little bit of data in the RECOURSE trial. We know that regorafenib given ahead of TAS-102 does not seem to affect the activity of TAS-102. On the other hand, with regorafenib, we don’t have that sequential data. Mind you, with TAS-102, that sequential data essentially came from subgroup analysis, so it has some weaknesses to it.

There are also the indirect inferences from 2 studies, TERRA and CONCUR, which used a less heavily pretreated patient population and moved TAS-102 and regorafenib versus placebo up the line. Regorafenib seems to essentially—historically, at least—gain more power when you move it up the line. TAS-102 remained similarly effective across lines without differences—historically, at least—in the data.

In my clinic, I tend to prefer to start with regorafenib first followed by TAS-102, except for patients who have some mild liver dysfunction or patients who may have had hand-and-foot syndrome with capecitabine, and, although the reaction is different, the idea of having hand-foot syndrome reaction is still certainly not pleasant for them. They would opt out of that option. So, these are the 2 groups of patients to consider.

Johanna C. Bendell, MD: There’s a lot of discussion going on right now within the colorectal cancer field about what you should use first for your treatment. There’s a lot of discussion particularly around whether or not to use TAS-102 or regorafenib first. Some people are concerned about toxicities associated with regorafenib, and so there’s been some suggestion that if you use this first while patients are feeling better, they may have a better outcome.

There was a very interesting randomized phase II Japanese study that looked at regorafenib versus cetuximab and which one to use first. It really seemed to show that using regorafenib in an earlier line of therapy provided more benefit for patients, so this is bringing that question into play. Now, personally, do I use regorafenib before an EGFR inhibitor for patients with advanced RAS wild-type colorectal cancer? Not yet, but I think it begs the question such that we need to look a little bit further into it.

Transcript Edited for Clarity 
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Transcript: 

Johanna C. Bendell, MD: In terms of selecting the best treatment for patients as first-line therapy, the most common regimen that’s being used now in the United States is probably FOLFOX [folinic acid/fluorouracil(5-FU)/oxaliplatin] plus bevacizumab, which has been the standard for quite a number of years now. For some people, we might consider using FOLFOXIRI [folinic acid/5-FU/oxaliplatin/irinotecan] plus bevacizumab, particularly for the patients with BRAF-mutated colon cancer. For a young patient in whom you’re looking for a good response—somebody who might be able to go to surgical resection—we have ways to increase the amount of tumor shrinkage. But when using more aggressive regimens up front, we should always remember to get patients into the maintenance therapies after about 4 to 6 months of treatment to allow them to have a better quality of life while they’re still on their first-line therapy.

Tanios Bekaii-Saab, MD: When we look at colorectal cancer, we know clearly that first line is pretty much determined on chemotherapy plus bevacizumab. For some patients with left-sided, RAS wild-type, BRAF V600E wild-type, or HER2-nonamplified tumors, there’s also the option of adding an EGFR inhibitor instead of bevacizumab.

Second-line therapy really depends on what you do in the first-line setting and some of the molecular profiling of the tumor. If you’re on the right side, chemotherapy plus bevacizumab is your first-line regimen regardless of RAS or BRAF status.

Second-line therapy, in terms of what we have available to us today in clinic, would be to switch the chemotherapy and continue the bevacizumab. For the rare patient who may have a BRAF V600E mutation, we have the option of introducing a MEK inhibitor plus a BRAF inhibitor plus/minus an EGFR inhibitor. That’s an option, whether right- or left-sided disease, although primarily on the left side. For the HER2-amplified tumors, preference would be for a clinical trial including these HER2-targeted therapies. For MSI [microsatellite instability]–high tumors, which occur in about 4% of patients, the preference is for a PD-1 inhibitor in the second or third line.

Most patients are actually going to go through 1 or 2 lines of chemotherapy plus a biologic, and there could be a switch of biologic or a switch of chemotherapy. We end up in the third line, and then we have 2 options in the refractory setting: regorafenib and TAS-102. Regorafenib is an agent that’s a multitype kinase inhibitor. TAS-102 is a more traditional cytotoxic agent. It’s part of the superfamily of fluoropyrimidines that specifically seems to work when 5-FU or capecitabine do not, at least in some cases.

Both agents were compared with placebo in 2 separate studies. Both agents had very similar outcomes in terms of improvements. Historically, they look somewhat similar. Their toxicities are different: hand-foot syndrome reaction and fatigue with regorafenib, neutropenia and fatigue with TAS-102, and some GI [gastrointestinal] toxicities in both.

They’ve never been compared head-to-head, so it’s very difficult to make inferences about which one should go first. In practice, you have to think about your patients. Where do we have some data? We just have a little bit of data in the RECOURSE trial. We know that regorafenib given ahead of TAS-102 does not seem to affect the activity of TAS-102. On the other hand, with regorafenib, we don’t have that sequential data. Mind you, with TAS-102, that sequential data essentially came from subgroup analysis, so it has some weaknesses to it.

There are also the indirect inferences from 2 studies, TERRA and CONCUR, which used a less heavily pretreated patient population and moved TAS-102 and regorafenib versus placebo up the line. Regorafenib seems to essentially—historically, at least—gain more power when you move it up the line. TAS-102 remained similarly effective across lines without differences—historically, at least—in the data.

In my clinic, I tend to prefer to start with regorafenib first followed by TAS-102, except for patients who have some mild liver dysfunction or patients who may have had hand-and-foot syndrome with capecitabine, and, although the reaction is different, the idea of having hand-foot syndrome reaction is still certainly not pleasant for them. They would opt out of that option. So, these are the 2 groups of patients to consider.

Johanna C. Bendell, MD: There’s a lot of discussion going on right now within the colorectal cancer field about what you should use first for your treatment. There’s a lot of discussion particularly around whether or not to use TAS-102 or regorafenib first. Some people are concerned about toxicities associated with regorafenib, and so there’s been some suggestion that if you use this first while patients are feeling better, they may have a better outcome.

There was a very interesting randomized phase II Japanese study that looked at regorafenib versus cetuximab and which one to use first. It really seemed to show that using regorafenib in an earlier line of therapy provided more benefit for patients, so this is bringing that question into play. Now, personally, do I use regorafenib before an EGFR inhibitor for patients with advanced RAS wild-type colorectal cancer? Not yet, but I think it begs the question such that we need to look a little bit further into it.

Transcript Edited for Clarity 
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