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Treatment Options for Right-Sided CRC

Panelists: Johanna C. Bendell,MD, Sarah Cannon Research Institute; Dirk Arnold, MD, PhD, KTB Klinik fur Tumorbiologie GmbH & Co. KG ; Heinz-Josef Lenz, MD, FACP, USC Center for Molecular Pathway and Drug Discovery; Zev A. Wainberg, MD, UCLA Medical Center
Published: Friday, Dec 14, 2018



Transcript: 

Johanna C. Bendell, MD:
So Heinz, right-sided tumor, first-line therapy; to EGFR or not to EGFR?

Heinz-Josef Lenz, MD, FACP: I don’t. I use bevacizumab [Avastin]. I have always used EGF receptor [inhibitors] in first line, but with the location data we have seen, I don’t use it anymore in first line. The biggest question is, if there is a role in later lines and we don’t know. Now, we know from a lot of gene-expression analysis that there is a subgroup of right-sided, which benefits, but we at the moment have another reasonable, reliable tool to identify them. So I start with bevacizumab, always. And I think the data all suggest that when you look at 80405 [CALGB/SWOG 80405].

Johanna C. Bendell, MD: And we do have the late-line study—the initial Canadian study of cetuximab [Erbitux] versus best supportive care, which also suggests that the right-sided tumors did not benefit.

Heinz-Josef Lenz, MD, FACP: It doesn’t work. I think there is a subgroup when you look at the data; there is interesting data on everything. Because the right-sided [tumors] are poorly differentiated, and when you’re poorly differentiated, you don’t have an EGF receptor. It goes along with histology. So when you look at a poorly differentiated patient, I know it will not work. Now, if you have a moderately differentiated or well differentiated, there is a chance the EGF receptor is expressed and that maybe some of them have benefit. It’s not a reliable tool, but you get a little bit an idea from pathology what the different patient status is.

Johanna C. Bendell, MD: Now, Dirk, in the EU, does the right sided also hold true for the Europeans?

Dirk Arnold, MD, PhD: I personally completely agree with what Heinz was expressing. However, there is some belief that this is what these combined analyses brought out, that patients, despite the fact that they don’t have a gain in overall survival and their prognosis, if they are treated with right-sided RAS wild types with an anti-EGFR, they may respond, at least. They may even respond better than patients who are treated with chemotherapy and bevacizumab. So I would say there is a niche for use, which is in perioperative treatment in liver metastases or whatever are potentially resectable, and response is urgently needed. But that’s a mini niche, so this tiny niche may be there, but generally it should not be recommended.

Heinz-Josef Lenz, MD, FACP: And Dirk is right: For the [CALGB/SWOG] 80405 trial of FOLFIRI [irinotecan/5-FU/leucovorin] or FOLFOX [oxaliplatin/5-FU/leucovorin] and cetuximab, they had response rate of 60% on the right side, overall 80%. So I think in these patients who are heavily symptomatic, you need a response; it didn’t translate into PFS [progression-free survival] and overall survival. I think in this situation, I agree with you, you could consider it.

Johanna C. Bendell, MD: Now, you know, maybe it’s a lack of new agents for the treatment of colon cancer, but somehow there has been this resurgence of thinking about combining a VEGF and an EGFR inhibitor. Tell us a little, Dirk, about the PACE trial data that Randy Hecht [Joel R. Hecht, MD] presented several years ago, which we all thought was going to be positive, for sure. I was putting my nickel on it. Tell us a little bit about what happened there, but now we’re seeing people think about bringing them together again.

Dirk Arnold, MD, PhD: Right. There were some rather later-line data within second and third line, which show some benefit in combining chemotherapy plus anti-VEGFR plus anti-EGFR, and it started more than 10 years, maybe 15 years ago with the BOND trial, which was following this principle of BOND-2 trial. The PACE trial you’ve been mentioning, and there’s also a trial from the Netherlands, the CAIRO trial.

Johanna C. Bendell, MD: That’s right.

Dirk Arnold, MD, PhD: So there were nearly 2500 patients who underwent treatment with this combination in at least 2 phase III trials, and there was no benefit for these patients. So this was then left as this therapeutic principle. And to me it’s not understood why not; in second or third line, there seems to be a bit of synergy which has not been observed in the all-comers first-line trials.

Johanna C. Bendell, MD: So we’ll wait to see…. Maybe we do start to use those again.


Transcript Edited for Clarity
 

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Transcript: 

Johanna C. Bendell, MD:
So Heinz, right-sided tumor, first-line therapy; to EGFR or not to EGFR?

Heinz-Josef Lenz, MD, FACP: I don’t. I use bevacizumab [Avastin]. I have always used EGF receptor [inhibitors] in first line, but with the location data we have seen, I don’t use it anymore in first line. The biggest question is, if there is a role in later lines and we don’t know. Now, we know from a lot of gene-expression analysis that there is a subgroup of right-sided, which benefits, but we at the moment have another reasonable, reliable tool to identify them. So I start with bevacizumab, always. And I think the data all suggest that when you look at 80405 [CALGB/SWOG 80405].

Johanna C. Bendell, MD: And we do have the late-line study—the initial Canadian study of cetuximab [Erbitux] versus best supportive care, which also suggests that the right-sided tumors did not benefit.

Heinz-Josef Lenz, MD, FACP: It doesn’t work. I think there is a subgroup when you look at the data; there is interesting data on everything. Because the right-sided [tumors] are poorly differentiated, and when you’re poorly differentiated, you don’t have an EGF receptor. It goes along with histology. So when you look at a poorly differentiated patient, I know it will not work. Now, if you have a moderately differentiated or well differentiated, there is a chance the EGF receptor is expressed and that maybe some of them have benefit. It’s not a reliable tool, but you get a little bit an idea from pathology what the different patient status is.

Johanna C. Bendell, MD: Now, Dirk, in the EU, does the right sided also hold true for the Europeans?

Dirk Arnold, MD, PhD: I personally completely agree with what Heinz was expressing. However, there is some belief that this is what these combined analyses brought out, that patients, despite the fact that they don’t have a gain in overall survival and their prognosis, if they are treated with right-sided RAS wild types with an anti-EGFR, they may respond, at least. They may even respond better than patients who are treated with chemotherapy and bevacizumab. So I would say there is a niche for use, which is in perioperative treatment in liver metastases or whatever are potentially resectable, and response is urgently needed. But that’s a mini niche, so this tiny niche may be there, but generally it should not be recommended.

Heinz-Josef Lenz, MD, FACP: And Dirk is right: For the [CALGB/SWOG] 80405 trial of FOLFIRI [irinotecan/5-FU/leucovorin] or FOLFOX [oxaliplatin/5-FU/leucovorin] and cetuximab, they had response rate of 60% on the right side, overall 80%. So I think in these patients who are heavily symptomatic, you need a response; it didn’t translate into PFS [progression-free survival] and overall survival. I think in this situation, I agree with you, you could consider it.

Johanna C. Bendell, MD: Now, you know, maybe it’s a lack of new agents for the treatment of colon cancer, but somehow there has been this resurgence of thinking about combining a VEGF and an EGFR inhibitor. Tell us a little, Dirk, about the PACE trial data that Randy Hecht [Joel R. Hecht, MD] presented several years ago, which we all thought was going to be positive, for sure. I was putting my nickel on it. Tell us a little bit about what happened there, but now we’re seeing people think about bringing them together again.

Dirk Arnold, MD, PhD: Right. There were some rather later-line data within second and third line, which show some benefit in combining chemotherapy plus anti-VEGFR plus anti-EGFR, and it started more than 10 years, maybe 15 years ago with the BOND trial, which was following this principle of BOND-2 trial. The PACE trial you’ve been mentioning, and there’s also a trial from the Netherlands, the CAIRO trial.

Johanna C. Bendell, MD: That’s right.

Dirk Arnold, MD, PhD: So there were nearly 2500 patients who underwent treatment with this combination in at least 2 phase III trials, and there was no benefit for these patients. So this was then left as this therapeutic principle. And to me it’s not understood why not; in second or third line, there seems to be a bit of synergy which has not been observed in the all-comers first-line trials.

Johanna C. Bendell, MD: So we’ll wait to see…. Maybe we do start to use those again.


Transcript Edited for Clarity
 
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