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Sequencing Agents in Metastatic Colorectal Cancer

Panelists:Johanna C. Bendell, MD, Sarah Cannon Research Institute; Edward Garon, MD, Jonsson Comprehensive Cancer Center at UCLA; Roy Herbst, MD, Yale School of Medicine; Yelena Y. Janjigian, MD, Memorial Sloan Kettering Cancer Center; Manish Shah, MD, Weill Cornell Medical College; Mark Socinski, MD, University of Pittsburgh
Published: Monday, Jul 18, 2016


Transcript:

Mark A. Socinski, MD:
Let me ask our colorectal friends. Obviously you have the disease in which we have the greatest number of approved agents—bevacizumab, ramucirumab, aflibercept, regorafenib. How does the sequencing go in terms of when do you transition from one to the other? And what’s the average patient seeing nowadays, and throughout the course of their disease?

Johanna Bendell, MD: Let me preface this by saying, I’m going to give you a United States perspective. So, certainly, in Europe, in EGFR inhibitors, there’s a lot of controversy going on right now. But, in general, what we’re seeing in the United States for patients who are eligible and safe to receive anti-angiogenics in the first-line, patients usually start with bevacizumab plus chemotherapy. The most popular chemotherapy backbone right now is FOLFOX, but FOLFIRI is starting to take some, get some more traction as well.

And then for patients who do well on the anti-angiogenic agents, they’re usually moved into the second-line setting. And, in that setting, we usually continue along with the bevacizumab. It’s sort of a, “If it ain’t broke, don’t fix it,” concept. And while there’s just good data with ramucirumab, there’s just as good data with aflibercept. The concern about the aflibercept toxicity comes into play. With ramucirumab, it would be reasonable to switch, but again it’s the, “If it ain’t broke, don’t fix it.” I think that if there’s data that emerges with ramucirumab about dosing—so, like if we see that there may be a better efficacy with dosing of ramucirumab or increasing that dose—maybe we’ll see more usage in the second-line setting at a higher dose, if that’s proven to be true.

Then, further on down the line in the refractory setting you’re going to see regorafenib used. You may not see patients go directly to regorafenib in the third-line setting because of interplay with other agents that we have—including EGFR inhibitors, and a recently approved agent called TAS-102. But, then, patients will receive regorafenib at some point usually in the refractory setting if the doctors are going to use that.

Manish A. Shah, MD: I think that the message—I think Johanna explained it really well—is that patients have options. Not too long ago there were just a handful of drugs that were approved. And now we have the option to go to a different anti-angiogenic agent, to recycle 5-FU, or come back to oxaliplatin in the second or third-line setting, depending on what was used in the first-line setting. So, I think that with these options, what happens is that you then look at secondary things like toxicity, and matching the agent with the toxicity that you want to risk in terms of how to sequence and type.

Mark A. Socinski, MD: Well, it’s good to be in the land of plenty, right? I remember when I started in this business years ago that we had many fewer options for patients in what we’ve seen in colon cancer and lung cancer, and now in gastric cancer an increasing number of options.

We’ve covered a lot of information throughout this program on the use of anti-angiogenic therapy in lung and gastrointestinal cancers. So, before we end this discussion, I’d like to hear final thoughts from each of panelists, and particularly if there’s anything they’re particularly optimistic about in terms of new therapies. I’ll start with Dr. Bendell.

Johanna Bendell, MD: Well, what a fantastic era we’re living in. All of these new agents that are coming through, all of these new treatment options for our patients. I think I’ll say that the immunotherapy combinations with anti-angiogenics and different ways to attack the angiogenesis pathway, super exciting. Can we improve upon the number of patients that respond to immunotherapy by using anti-angiogenesis therapy? Lots of clinical trials out there for our patients right now.

Mark A. Socinski, MD: Eddie?

Edward Garon, MD: I think that it’s been interesting to see that this area of angiogenesis inhibition—which, when I started in lung cancer, was sort of the hottest area—in some ways, and people’s enthusiasm may have paled, continues to march along with positive studies in lung cancer. It’s certainly an area that I do have some enthusiasm for. What is interesting, of course, is that it took a long period of time between the preclinical data initially looking at angiogenesis inhibition until you actually had the clinical reality. And we now do have at least proof of concept that this is a strategy that can lead to improving survival in patients with lung cancer. My hope is that people continue to focus on how to better select patients, and how to improve upon the agents so that we can move further with what has been a successful approach of inhibiting angiogenesis in lung cancer.

Mark A. Socinski, MD: Yelena?

Yelena Y. Janjigian, MD: I absolutely agree. This is an exciting time to be an oncologist. We have a lot of different agents, and both diagnostic and predictive ways to select patients for these agents. Angiogenesis inhibitors really have improved our options in second-line setting. And we can’t stop there, we have to build on that benefit. The benefit is there, it’s real, but it’s modest. And the future will be to enrich patients based on specifically the clinical or biologic characteristics, and also add other agents. So, for HER2-positive disease you may do a combination of HER2 agent and angiogenic agent. For patients that are PD-1 expressers, or EBV-positive subtype, we may do a combination with immunotherapy. I think the field is moving forward quickly based on the patient’s willingness to participate in these trials, to undergo secondary biopsies, and to really work with the experts in the field and enroll in important trials that will change the future of this disease.

Mark A. Socinski, MD: Thanks for putting in that plug in about clinical trials, that’s important. Manish?

Manish A. Shah, MD: I think that the other aspect, as we understand who would benefit from anti-angiogenic therapy, is that moving forward in the adjuvant setting in the select population might really change the bar. If we can cure patients with the addition of anti-angiogenic therapy and in the right patient population, I think that would change the landscape entirely. The other aspect that I just wanted to come back to is—at least in gastric cancer—for the first time an anti-angiogenic drug by itself has equal benefit to chemotherapy, something that we really shouldn’t forget. I think with chemotherapy it even adds more benefit. But, there are patients that may benefit from anti-angiogenic therapy, and identifying those patients who have the most benefit might be really critical in terms of how we move forward for that population.

Mark A. Socinski, MD: Well, I want to thank all the panel members. This has been a great discussion, and I agree with the comments. It’s a great time to be an oncologist with the options that we have for all of our patients. So, on behalf of our panel, we thank you for joining us. We hope you found this OncLive Peer Exchange informative. Thank you.

Transcript Edited for Clarity
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Transcript:

Mark A. Socinski, MD:
Let me ask our colorectal friends. Obviously you have the disease in which we have the greatest number of approved agents—bevacizumab, ramucirumab, aflibercept, regorafenib. How does the sequencing go in terms of when do you transition from one to the other? And what’s the average patient seeing nowadays, and throughout the course of their disease?

Johanna Bendell, MD: Let me preface this by saying, I’m going to give you a United States perspective. So, certainly, in Europe, in EGFR inhibitors, there’s a lot of controversy going on right now. But, in general, what we’re seeing in the United States for patients who are eligible and safe to receive anti-angiogenics in the first-line, patients usually start with bevacizumab plus chemotherapy. The most popular chemotherapy backbone right now is FOLFOX, but FOLFIRI is starting to take some, get some more traction as well.

And then for patients who do well on the anti-angiogenic agents, they’re usually moved into the second-line setting. And, in that setting, we usually continue along with the bevacizumab. It’s sort of a, “If it ain’t broke, don’t fix it,” concept. And while there’s just good data with ramucirumab, there’s just as good data with aflibercept. The concern about the aflibercept toxicity comes into play. With ramucirumab, it would be reasonable to switch, but again it’s the, “If it ain’t broke, don’t fix it.” I think that if there’s data that emerges with ramucirumab about dosing—so, like if we see that there may be a better efficacy with dosing of ramucirumab or increasing that dose—maybe we’ll see more usage in the second-line setting at a higher dose, if that’s proven to be true.

Then, further on down the line in the refractory setting you’re going to see regorafenib used. You may not see patients go directly to regorafenib in the third-line setting because of interplay with other agents that we have—including EGFR inhibitors, and a recently approved agent called TAS-102. But, then, patients will receive regorafenib at some point usually in the refractory setting if the doctors are going to use that.

Manish A. Shah, MD: I think that the message—I think Johanna explained it really well—is that patients have options. Not too long ago there were just a handful of drugs that were approved. And now we have the option to go to a different anti-angiogenic agent, to recycle 5-FU, or come back to oxaliplatin in the second or third-line setting, depending on what was used in the first-line setting. So, I think that with these options, what happens is that you then look at secondary things like toxicity, and matching the agent with the toxicity that you want to risk in terms of how to sequence and type.

Mark A. Socinski, MD: Well, it’s good to be in the land of plenty, right? I remember when I started in this business years ago that we had many fewer options for patients in what we’ve seen in colon cancer and lung cancer, and now in gastric cancer an increasing number of options.

We’ve covered a lot of information throughout this program on the use of anti-angiogenic therapy in lung and gastrointestinal cancers. So, before we end this discussion, I’d like to hear final thoughts from each of panelists, and particularly if there’s anything they’re particularly optimistic about in terms of new therapies. I’ll start with Dr. Bendell.

Johanna Bendell, MD: Well, what a fantastic era we’re living in. All of these new agents that are coming through, all of these new treatment options for our patients. I think I’ll say that the immunotherapy combinations with anti-angiogenics and different ways to attack the angiogenesis pathway, super exciting. Can we improve upon the number of patients that respond to immunotherapy by using anti-angiogenesis therapy? Lots of clinical trials out there for our patients right now.

Mark A. Socinski, MD: Eddie?

Edward Garon, MD: I think that it’s been interesting to see that this area of angiogenesis inhibition—which, when I started in lung cancer, was sort of the hottest area—in some ways, and people’s enthusiasm may have paled, continues to march along with positive studies in lung cancer. It’s certainly an area that I do have some enthusiasm for. What is interesting, of course, is that it took a long period of time between the preclinical data initially looking at angiogenesis inhibition until you actually had the clinical reality. And we now do have at least proof of concept that this is a strategy that can lead to improving survival in patients with lung cancer. My hope is that people continue to focus on how to better select patients, and how to improve upon the agents so that we can move further with what has been a successful approach of inhibiting angiogenesis in lung cancer.

Mark A. Socinski, MD: Yelena?

Yelena Y. Janjigian, MD: I absolutely agree. This is an exciting time to be an oncologist. We have a lot of different agents, and both diagnostic and predictive ways to select patients for these agents. Angiogenesis inhibitors really have improved our options in second-line setting. And we can’t stop there, we have to build on that benefit. The benefit is there, it’s real, but it’s modest. And the future will be to enrich patients based on specifically the clinical or biologic characteristics, and also add other agents. So, for HER2-positive disease you may do a combination of HER2 agent and angiogenic agent. For patients that are PD-1 expressers, or EBV-positive subtype, we may do a combination with immunotherapy. I think the field is moving forward quickly based on the patient’s willingness to participate in these trials, to undergo secondary biopsies, and to really work with the experts in the field and enroll in important trials that will change the future of this disease.

Mark A. Socinski, MD: Thanks for putting in that plug in about clinical trials, that’s important. Manish?

Manish A. Shah, MD: I think that the other aspect, as we understand who would benefit from anti-angiogenic therapy, is that moving forward in the adjuvant setting in the select population might really change the bar. If we can cure patients with the addition of anti-angiogenic therapy and in the right patient population, I think that would change the landscape entirely. The other aspect that I just wanted to come back to is—at least in gastric cancer—for the first time an anti-angiogenic drug by itself has equal benefit to chemotherapy, something that we really shouldn’t forget. I think with chemotherapy it even adds more benefit. But, there are patients that may benefit from anti-angiogenic therapy, and identifying those patients who have the most benefit might be really critical in terms of how we move forward for that population.

Mark A. Socinski, MD: Well, I want to thank all the panel members. This has been a great discussion, and I agree with the comments. It’s a great time to be an oncologist with the options that we have for all of our patients. So, on behalf of our panel, we thank you for joining us. We hope you found this OncLive Peer Exchange informative. Thank you.

Transcript Edited for Clarity
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