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Sequencing Therapy in CRC: E7208 Trial

Panelists: Howard Hochster, MD, FACP, Rutgers Cancer Institute; Joleen Hubbard, MD, Mayo Clinic; Christopher Lieu, MD, University of Colorado School of Medicine; John Marshall, MD, Georgetown University Hospital; Tony Saab, MD, Mayo Clinic
Published: Friday, Feb 22, 2019



Transcript: 

John L. Marshall, MD:
Howard, I want to give you the floor back right away, and I want to talk about second-line therapy. We all go in a bunch of different directions here, particularly in that patient who, as we’ve been discussing, has a left-sided RAS wild-type, BRAF wild-type cancer. You led a great study. We participated and enrolled in this clinical trial to relook at the combination of VEGF and EGF in the second-line setting. Maybe you can set the stage and give us a little information on the results of that trial.

Howard S. Hochster, MD, FACP: Well we’re taking about the ECOG [Eastern Cooperative Oncology Group] 7208 trial. So that was for RAS wild-type patients. We started back in the days when the question was, “Should you continue bevacizumab?” In this particular study, we used the combination of cetuximab plus ramucirumab for second line, with irinotecan without the ramucirumab.

So this was a little bit controversial because the original trials looking at FOLFOX with an anti-VEGF and an anti-EGF were negative and somewhat even worse than without the combination of the 2 antibodies. But I want to just make everybody recall to your mind that none of those were selected for RAS. Half the patients should not have gotten the anti-EGF because they had the RAS mutation.

John L. Marshall, MD: Now, you and I are the only ones on this panel old enough to remember the BOND studies, which combined VEGF and EGF. And then we went to the frontline without enrichment, and that’s where we backed off. And so you were sort of relooking at this now that we know about enrichment.

Howard S. Hochster, MD, FACP: Right. So I think if you really look at RAS wild-type patients, this study would support the fact that you have a little bit better PFS [progression-free survival] and response rate when you combine the 2 antibodies with irinotecan in the second line. For this study, the patients had to receive an oxaliplatin-based chemotherapy and an anti-VEGF in the first line and be RAS wild type.

So it was very hard to make the eligibility very precise, in terms of when you progressed. And if you said they had to progress on FOLFOX and bevacizumab, you didn’t really have many patients because of what we all described about maintenance. So we kind of opened it to like when you think the patient’s ready for irinotecan as, quote, second line. Even though they may have had a little progression with maintenance and whatever, they could still get into the study. And it turns out that the interval between when they got their last oxaliplatin and when they started this is probably the biggest predictor, which kind of tells you the people who have good biology and have maintenance and observation for a long time before starting second line will benefit the most.

John L. Marshall, MD: I was partly disappointed. I was hoping that study was going to show us that repeat signal that we saw from BOND-2 of this higher response rate of the dual-antibody approach. And it looked OK. It wasn’t negative. That’s equally important—that it wasn’t negative.

Howard S. Hochster, MD, FACP: I think it just opens the door for further exploration of the combination of the 2 antibodies to get rid of the notion that you can’t really give an anti-VEGF with an anti-EGF.

John L. Marshall, MD: Joleen, let me ask you a hard question, and maybe none of us actually know the answer. Is ramucirumab the same as bevacizumab? Do they actually play the same way clinically? Is there a time when you’re using ramucirumab in colon cancer?

Joleen M. Hubbard, MD: You know, theoretically, they should act fairly similar. When we look at the clinical trial that established ramucirumab, the data were fairly similar compared with the bevacizumab beyond progression. So I think that the efficacy is probably similar. We’re a little bit concerned about some of the adverse effects and how many people came off the ramucirumab study because of adverse effects. At our institution, we’re primarily using bevacizumab. I think the 1 situation in which I would use ramucirumab is if you have a rapid progressor on bevacizumab. That might be a situation in which I would use ramucirumab second line.

Howard S. Hochster, MD, FACP: I just want to point out, again, that in our study, ECOG 7028, when we tried to give the full doses with ramucirumab, it was too toxic. There was a lot of grade 3 and 4 mucositis and diarrhea and some septic events. The treatment ended up being a dose reduction to the minus-1 level, so everything got reduced down a little bit. And there is definitely more toxicity with ramucirumab and cetuximab when you combine them than if you just take ramucirumab with FOLFIRI, which kind of looked very similar to bevacizumab and FOLFIRI.

John L. Marshall, MD: And to my memory, bevacizumab doesn’t bring that toxicity with the doublet, if I can remember back that far.

Howard S. Hochster, MD, FACP: Yeah. Well it didn’t in that setting, right—back in the BOND trials, that’s true.


Transcript Edited for Clarity

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Transcript: 

John L. Marshall, MD:
Howard, I want to give you the floor back right away, and I want to talk about second-line therapy. We all go in a bunch of different directions here, particularly in that patient who, as we’ve been discussing, has a left-sided RAS wild-type, BRAF wild-type cancer. You led a great study. We participated and enrolled in this clinical trial to relook at the combination of VEGF and EGF in the second-line setting. Maybe you can set the stage and give us a little information on the results of that trial.

Howard S. Hochster, MD, FACP: Well we’re taking about the ECOG [Eastern Cooperative Oncology Group] 7208 trial. So that was for RAS wild-type patients. We started back in the days when the question was, “Should you continue bevacizumab?” In this particular study, we used the combination of cetuximab plus ramucirumab for second line, with irinotecan without the ramucirumab.

So this was a little bit controversial because the original trials looking at FOLFOX with an anti-VEGF and an anti-EGF were negative and somewhat even worse than without the combination of the 2 antibodies. But I want to just make everybody recall to your mind that none of those were selected for RAS. Half the patients should not have gotten the anti-EGF because they had the RAS mutation.

John L. Marshall, MD: Now, you and I are the only ones on this panel old enough to remember the BOND studies, which combined VEGF and EGF. And then we went to the frontline without enrichment, and that’s where we backed off. And so you were sort of relooking at this now that we know about enrichment.

Howard S. Hochster, MD, FACP: Right. So I think if you really look at RAS wild-type patients, this study would support the fact that you have a little bit better PFS [progression-free survival] and response rate when you combine the 2 antibodies with irinotecan in the second line. For this study, the patients had to receive an oxaliplatin-based chemotherapy and an anti-VEGF in the first line and be RAS wild type.

So it was very hard to make the eligibility very precise, in terms of when you progressed. And if you said they had to progress on FOLFOX and bevacizumab, you didn’t really have many patients because of what we all described about maintenance. So we kind of opened it to like when you think the patient’s ready for irinotecan as, quote, second line. Even though they may have had a little progression with maintenance and whatever, they could still get into the study. And it turns out that the interval between when they got their last oxaliplatin and when they started this is probably the biggest predictor, which kind of tells you the people who have good biology and have maintenance and observation for a long time before starting second line will benefit the most.

John L. Marshall, MD: I was partly disappointed. I was hoping that study was going to show us that repeat signal that we saw from BOND-2 of this higher response rate of the dual-antibody approach. And it looked OK. It wasn’t negative. That’s equally important—that it wasn’t negative.

Howard S. Hochster, MD, FACP: I think it just opens the door for further exploration of the combination of the 2 antibodies to get rid of the notion that you can’t really give an anti-VEGF with an anti-EGF.

John L. Marshall, MD: Joleen, let me ask you a hard question, and maybe none of us actually know the answer. Is ramucirumab the same as bevacizumab? Do they actually play the same way clinically? Is there a time when you’re using ramucirumab in colon cancer?

Joleen M. Hubbard, MD: You know, theoretically, they should act fairly similar. When we look at the clinical trial that established ramucirumab, the data were fairly similar compared with the bevacizumab beyond progression. So I think that the efficacy is probably similar. We’re a little bit concerned about some of the adverse effects and how many people came off the ramucirumab study because of adverse effects. At our institution, we’re primarily using bevacizumab. I think the 1 situation in which I would use ramucirumab is if you have a rapid progressor on bevacizumab. That might be a situation in which I would use ramucirumab second line.

Howard S. Hochster, MD, FACP: I just want to point out, again, that in our study, ECOG 7028, when we tried to give the full doses with ramucirumab, it was too toxic. There was a lot of grade 3 and 4 mucositis and diarrhea and some septic events. The treatment ended up being a dose reduction to the minus-1 level, so everything got reduced down a little bit. And there is definitely more toxicity with ramucirumab and cetuximab when you combine them than if you just take ramucirumab with FOLFIRI, which kind of looked very similar to bevacizumab and FOLFIRI.

John L. Marshall, MD: And to my memory, bevacizumab doesn’t bring that toxicity with the doublet, if I can remember back that far.

Howard S. Hochster, MD, FACP: Yeah. Well it didn’t in that setting, right—back in the BOND trials, that’s true.


Transcript Edited for Clarity
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