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Later Lines of Therapy for Metastatic Colorectal Cancer

Insights From: Tanios Bekaii-Saab, MD, Mayo Clinic; Johanna C. Bendell, MD, Sarah Cannon Research Institute
Published: Monday, Oct 08, 2018



Transcript:

Tanios Bekaii-Saab, MD: Almost 90% or more of patients who progressed through first-line therapy will make it to the second line. Second-line options will depend on what you’ve done in the first line. For most United States physicians, chemotherapy plus bevacizumab is the primary option. For some, on the left-sided, RAS wild-type, BRAF wild-type, HER2-nonamplified disease, they choose to start with an EGFR inhibitor plus chemotherapy.

Let’s start with all these patients who will receive chemotherapy plus bevacizumab in the first line, regardless of their genetic or molecular subtyping. In the second line, you switch their chemotherapy. If you start with FOLFIRI [folinic acid/fluorouracil/irinotecan], you go to FOLFOX [folinic acid/fluorouracil/oxaliplatin]; if you start with FOLFOX, you switch to FOLFIRI. And then you have the option of continuing the VEGF inhibitor bevacizumab. You continue bevacizumab to the second line. I think with right-sided disease, that makes sense. On the left side, however, that only makes sense in those patients who have RAS mutations or HER2 amplifications. For BRAF mutations, that’s a particular-case scenario.

For those patients who are RAS wild-type, BRAF wild-type, and HER2 nonamplified, if you started with chemotherapy plus bevacizumab, your second-line treatment has to be an EGFR inhibitor plus chemotherapy. The reason for that is we know that the EGFR inhibitors work pretty well in this group of patients, and I wouldn’t want to wait until third-line therapy before I initiate that treatment.

For those patients, you can use EGFR inhibition in the first line, then possibly VEGF inhibitors and bevacizumab in the second line plus chemotherapy. If you started with bevacizumab, then use an EGFR inhibitor in the second line. For the BRAF V600E mutation, we’ll try to have them on a clinical trial with a RAF inhibitor plus a MEK inhibitor plus/minus an EGFR inhibitor, and now the NCCN [National Comprehensive Cancer Network] guidelines do list this as an option that we sometimes consider using.

For right-sided disease, it’s bevacizumab then bevacizumab, regardless of the mutation status, and then third line would be regorafenib or TAS-102 as an acceptable option. On the left side, again, regorafenib would be your third-line option, or TAS-102 would be an acceptable option.

What percentage of patients actually make it to the third-line setting? We think up to 50% to 60% of patients who started first-line therapy will end up in the third line. When you get to the fourth line, you lose even more of those patients. It will end up being 25% to 30% of patients who end up in the fourth line. So, if you use regorafenib—which I do in my clinic—in the third line, then TAS-102 follows. If you use TAS-102 in the third line, then regorafenib would follow.

For the case of the HER2-amplified patients, in the second line, usually we shift them to one of our clinical trials with a drug called tucatinib plus trastuzumab. That’s a study we have at our site and a number of other sites nationally. That essentially bypasses the need for an EGFR inhibitor. We know from the MD Anderson experience, at least in 2 cohorts, that the HER2-amplified patients do not seem to have benefit from EGFR inhibitors. That makes sense, understanding the interplay between EGFR and HER2. It’s not surprising to see that if there is a benefit, it’s minimal.

A very important question as we move beyond second line to third line is: What do you do with those patients in the third, fourth, or fifth line if they have right-sided disease? Do we ever expose them to EGFR inhibitors? The answer is, although the data are very weak for EGFR inhibitors and although those are RAS wild-type patients, I still think there’s a place for them.

There’s a study that essentially looked at EGFR inhibitors—cetuximab versus best supportive care—that suggested in the later lines of therapy, there may still be a little bit of survival advantage for cetuximab versus best supportive care. There was no PFS [progression-free survival] advantage, but there was [an] overall survival advantage that could essentially tell us there may still be a role for EGFR inhibitors in later lines of therapy in patients with right-sided disease. Usually, I use it after regorafenib and possibly after TAS-102, if I run out of options.

On the left side, in the RAS wild-type, HER2-amplified patients, I get back to these EGFR inhibitors sometime between the third and the fifth line of therapy. There are nuances, of course, to all these. The MSI [microsatellite instability]–high patients go on a PD-1 inhibitor, and I actually try to move it to the first-line setting if the insurance will allow me. I will wait beyond the second line, and that’s 4% of patients. It’s a landscape that keeps on shifting, but overall, parts of it remain quite stable.

Transcript Edited for Clarity.
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Transcript:

Tanios Bekaii-Saab, MD: Almost 90% or more of patients who progressed through first-line therapy will make it to the second line. Second-line options will depend on what you’ve done in the first line. For most United States physicians, chemotherapy plus bevacizumab is the primary option. For some, on the left-sided, RAS wild-type, BRAF wild-type, HER2-nonamplified disease, they choose to start with an EGFR inhibitor plus chemotherapy.

Let’s start with all these patients who will receive chemotherapy plus bevacizumab in the first line, regardless of their genetic or molecular subtyping. In the second line, you switch their chemotherapy. If you start with FOLFIRI [folinic acid/fluorouracil/irinotecan], you go to FOLFOX [folinic acid/fluorouracil/oxaliplatin]; if you start with FOLFOX, you switch to FOLFIRI. And then you have the option of continuing the VEGF inhibitor bevacizumab. You continue bevacizumab to the second line. I think with right-sided disease, that makes sense. On the left side, however, that only makes sense in those patients who have RAS mutations or HER2 amplifications. For BRAF mutations, that’s a particular-case scenario.

For those patients who are RAS wild-type, BRAF wild-type, and HER2 nonamplified, if you started with chemotherapy plus bevacizumab, your second-line treatment has to be an EGFR inhibitor plus chemotherapy. The reason for that is we know that the EGFR inhibitors work pretty well in this group of patients, and I wouldn’t want to wait until third-line therapy before I initiate that treatment.

For those patients, you can use EGFR inhibition in the first line, then possibly VEGF inhibitors and bevacizumab in the second line plus chemotherapy. If you started with bevacizumab, then use an EGFR inhibitor in the second line. For the BRAF V600E mutation, we’ll try to have them on a clinical trial with a RAF inhibitor plus a MEK inhibitor plus/minus an EGFR inhibitor, and now the NCCN [National Comprehensive Cancer Network] guidelines do list this as an option that we sometimes consider using.

For right-sided disease, it’s bevacizumab then bevacizumab, regardless of the mutation status, and then third line would be regorafenib or TAS-102 as an acceptable option. On the left side, again, regorafenib would be your third-line option, or TAS-102 would be an acceptable option.

What percentage of patients actually make it to the third-line setting? We think up to 50% to 60% of patients who started first-line therapy will end up in the third line. When you get to the fourth line, you lose even more of those patients. It will end up being 25% to 30% of patients who end up in the fourth line. So, if you use regorafenib—which I do in my clinic—in the third line, then TAS-102 follows. If you use TAS-102 in the third line, then regorafenib would follow.

For the case of the HER2-amplified patients, in the second line, usually we shift them to one of our clinical trials with a drug called tucatinib plus trastuzumab. That’s a study we have at our site and a number of other sites nationally. That essentially bypasses the need for an EGFR inhibitor. We know from the MD Anderson experience, at least in 2 cohorts, that the HER2-amplified patients do not seem to have benefit from EGFR inhibitors. That makes sense, understanding the interplay between EGFR and HER2. It’s not surprising to see that if there is a benefit, it’s minimal.

A very important question as we move beyond second line to third line is: What do you do with those patients in the third, fourth, or fifth line if they have right-sided disease? Do we ever expose them to EGFR inhibitors? The answer is, although the data are very weak for EGFR inhibitors and although those are RAS wild-type patients, I still think there’s a place for them.

There’s a study that essentially looked at EGFR inhibitors—cetuximab versus best supportive care—that suggested in the later lines of therapy, there may still be a little bit of survival advantage for cetuximab versus best supportive care. There was no PFS [progression-free survival] advantage, but there was [an] overall survival advantage that could essentially tell us there may still be a role for EGFR inhibitors in later lines of therapy in patients with right-sided disease. Usually, I use it after regorafenib and possibly after TAS-102, if I run out of options.

On the left side, in the RAS wild-type, HER2-amplified patients, I get back to these EGFR inhibitors sometime between the third and the fifth line of therapy. There are nuances, of course, to all these. The MSI [microsatellite instability]–high patients go on a PD-1 inhibitor, and I actually try to move it to the first-line setting if the insurance will allow me. I will wait beyond the second line, and that’s 4% of patients. It’s a landscape that keeps on shifting, but overall, parts of it remain quite stable.

Transcript Edited for Clarity.
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