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Novel Agents for Gastroesophageal Cancer

Panelists: Johanna C. Bendell, MD, Sarah Cannon Research Institute; Yelena Y. Janjigian, MD, Memorial Sloan Kettering Cancer Center; Manish Shah, MD, Weill Cornell Medical College; Ian Chau, MD, Royal Marsden Hospital
Published Online: Tuesday, Jan 10, 2017



Transcript:

Johanna Bendell, MD:
Manish, you had a presentation at ESMO. We’re talking about all these new agents that are out there. We just heard from Ian about a new antibody. Tell us about Stat3.

Manish Shah, MD: Stat3 is an essential protein that is often phosphorylated and activated in several cancers including gastric cancer. And it is a feature that actually provides stemness, a feature that allows cancer stem cells to become active, proliferate, and also become somewhat resistant to chemotherapy. It has immune properties, as well. So, activation of Stat3 actually inhibits immune infiltrates from penetrating as well. For the first time, a company named Boston Biomedical has a Stat3 inhibitor—and so that is now in a phase III study in the second-line setting. It’s called the BRIGHTER study, and I think that there is a real potential to add one more drugs to our armamentarium.

Johanna Bendell, MD: I love it. Now we have to learn about stemness. We learned about immunotherapy. We still have more development going on along the HER2 pathway with pertuzumab.

Yelena Janjigian, MD: Absolutely. Well, we had the advantage of building on what has been known in breast cancer for decades. Trastuzumab has been around for gastric cancer since 2009, but, unfortunately, we’re not certainly curing patients. The majority of patients progress after less than seven months on therapy. And so, the idea is to build on targeting HER2 with pertuzumab, which is also a monoclonal antibody that binds at a different site of the binding domain of HER2. And this is the trial that is currently ongoing, in a randomized fashion, looking at the ToGA regimen which is 5FU/trastuzumab with or without pertuzumab. So, the study hopefully will be reported in the near future, and we’re awaiting the results. It’s not prime time yet.

Johanna Bendell, MD: So, we follow breast cancer yet again. We’ve got to get ahead of them at some point in this HER2 story.

Manish Shah, MD: There’s one other trial I should mention, and this is the matrix metalloproteinase inhibitor. Brivanib was actually the original one maybe 10 years ago, and this class of drugs was limited because of toxicity—fatigue. But, Gilead actually has a drug which is an MMP-9 inhibitor that has shown very encouraging results in the first-line setting. And so, they’ve moved on to a phase III study, as well. So the drug development is again accelerating in upper GI cancers.

Johanna Bendell, MD: It’s so interesting. The way that I try to describe it to patients with the matrix metalloproteinase inhibitors is that to be able to grow or to invade, the tumor’s got to break down its surrounding area and this helps it do that and particularly seems to be effective for gastric cancer patients.

Manish Shah, MD: It comes back to what Ian said about modifying the tumor microenvironment and how that could actually have profound effects.

Johanna Bendell, MD: So interesting. So much going on right now, new research. Ian, I wanted to catch you. You gave a wonderful discussion on a new study that just had some expanded results presented at ESMO of a new antibody for patients with gastric cancer. Can you tell us a little bit about that?

Ian Chau, MD: Yes. There is a new target, in fact, called claudin 18.2 which goes back to TCGA, in fact, and was identified in the genome-stable subtype which is more associated with diffuse histology, and they actually identified that it can form a fusion protein and drive the biology into much more aggressive diffuse histology. And this is found mainly in gastric mucosa, in gastric cancer, not in the rest of the body, so it does seem to be a very good target in gastric cancer. The company generated a monoclonal antibody called IMAB362, and they’ve done a study in a randomized phase II setting of standard chemotherapy, epirubicin/oxaliplatin/capecitabine (EOX), with two different doses of this IMAB362. First of all, the primary endpoint is an improvement in progression-free survival for which they did find a significant improvement; at the median level it’s almost a three-month difference. But, more importantly, in the overall survival analysis, which using the original dose, which is an 800-mg loading dose followed by 600 mg with each cycle of EOX, they also found an almost five-month improvement in overall survival.

And, at this year’s ESMO, what they presented is the second arm where they use a 1000-mg/kg dose of the antibody in conjunction with EOX, and they showed both a progression-free survival and overall survival advantages. Again, the magnitude of benefit is probably slightly less than the lower dose, but, nevertheless, still compared to the control arm, there was a significant improvement. I think this is a randomized phase II. We, in the past, have been disappointed so many times. There were so many encouraging randomized phase II studies that then didn’t read out in phase III.

And, also, one thing of note is the control arm did not seem to be performing as well as one would expect. Because, obviously, when you’ve got large body of randomized data of EOX in both REAL2 and the REAL3 data, so we know what that drug should do. But, it seems to be less good in this particular study, but maybe because, as I said, this is mainly in a diffuse histology. Although they haven’t actually showed data to say, of the patients recruited, how many patients were classified by lowering classification as a diffuse histology. They used their biomarker assay and they had to be tested positive to go into the study. It is a biomarker-driven study, so I think it is extremely important that they confirm these results in a large-scale phase III study, again, powered for overall survival. And, as I said in my discussion, it was conducted in different geographical regions.

Johanna Bendell, MD: Excellent. This has been extremely informative. Before we end the discussion, I’d like to get final thoughts from each of our panelists. Dr. Chau?

Ian Chau, MD: I think we already talked about how important it is nowadays, knowing more about the molecular characteristics of the tumors in our patients. And, I think, really taking that forward, we need to look at how we can integrate that information and look at agents that maybe are more working in the microenvironment, antiangiogenesis, immunotherapy, and how to make the tumor more visible to the immune system—how to make all these treatments work better. And I think that really is a goal that would integrate all this information to try to improve the survival of our patients more.

Johanna Bendell, MD: Love it. Dr. Janjigian?

Yelena Janjigian, MD: Well, one thing we know about gastric cancer is that it’s a very molecularly complex disease. Because of the nature of the epithelium and where the tumor is located, it will be important to find combination therapies, targeted agents that will help us control the tumor if we ever want to move away from the cytotoxic chemotherapy. Unlike other molecularly driven tumors, it will not be one switch, one target model, and we really need to move toward treatment strategies that combine different biologic agents for them to work better together. There is a lot of development, a lot of interest in the scientific community. And what I tell my patients is that even in my lifetime, as an oncologist, new development and 2 FDA approved drugs appeared in a very short amount of time. It’s important to study this disease—to study in the setting of a clinical trial. Enrollment in trials is important and ultimately make this a chronic illness eventually, a potentially curable illness.

Johanna Bendell, MD: I love it. Dr. Shah, you’ve got the anchorman.

Manish Shah, MD: I think that what’s really clear is that the drug development has really accelerated in gastric cancer. In the last 10 years, we have 5 new drugs that have been approved. I think, as we move forward, we need to learn how to sequence the drugs and combine them in the better way and a smarter way to understand the molecular profiles and be proactive in terms of managing the patient’s side effects. And, altogether, I think with that, we can really improve outcomes, improve their quality of life as they continue with this disease.

Johanna Bendell, MD: I love it. See, you did it beautifully. You had to be anchorman. I love it. So, thanks to all of you for your contributions and this discussion. On behalf of our panel, we thank you for joining us and we hope you found this Peer Exchange® discussion to be useful and informative. Thanks so much!

Transcript Edited for Clarity

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Transcript:

Johanna Bendell, MD:
Manish, you had a presentation at ESMO. We’re talking about all these new agents that are out there. We just heard from Ian about a new antibody. Tell us about Stat3.

Manish Shah, MD: Stat3 is an essential protein that is often phosphorylated and activated in several cancers including gastric cancer. And it is a feature that actually provides stemness, a feature that allows cancer stem cells to become active, proliferate, and also become somewhat resistant to chemotherapy. It has immune properties, as well. So, activation of Stat3 actually inhibits immune infiltrates from penetrating as well. For the first time, a company named Boston Biomedical has a Stat3 inhibitor—and so that is now in a phase III study in the second-line setting. It’s called the BRIGHTER study, and I think that there is a real potential to add one more drugs to our armamentarium.

Johanna Bendell, MD: I love it. Now we have to learn about stemness. We learned about immunotherapy. We still have more development going on along the HER2 pathway with pertuzumab.

Yelena Janjigian, MD: Absolutely. Well, we had the advantage of building on what has been known in breast cancer for decades. Trastuzumab has been around for gastric cancer since 2009, but, unfortunately, we’re not certainly curing patients. The majority of patients progress after less than seven months on therapy. And so, the idea is to build on targeting HER2 with pertuzumab, which is also a monoclonal antibody that binds at a different site of the binding domain of HER2. And this is the trial that is currently ongoing, in a randomized fashion, looking at the ToGA regimen which is 5FU/trastuzumab with or without pertuzumab. So, the study hopefully will be reported in the near future, and we’re awaiting the results. It’s not prime time yet.

Johanna Bendell, MD: So, we follow breast cancer yet again. We’ve got to get ahead of them at some point in this HER2 story.

Manish Shah, MD: There’s one other trial I should mention, and this is the matrix metalloproteinase inhibitor. Brivanib was actually the original one maybe 10 years ago, and this class of drugs was limited because of toxicity—fatigue. But, Gilead actually has a drug which is an MMP-9 inhibitor that has shown very encouraging results in the first-line setting. And so, they’ve moved on to a phase III study, as well. So the drug development is again accelerating in upper GI cancers.

Johanna Bendell, MD: It’s so interesting. The way that I try to describe it to patients with the matrix metalloproteinase inhibitors is that to be able to grow or to invade, the tumor’s got to break down its surrounding area and this helps it do that and particularly seems to be effective for gastric cancer patients.

Manish Shah, MD: It comes back to what Ian said about modifying the tumor microenvironment and how that could actually have profound effects.

Johanna Bendell, MD: So interesting. So much going on right now, new research. Ian, I wanted to catch you. You gave a wonderful discussion on a new study that just had some expanded results presented at ESMO of a new antibody for patients with gastric cancer. Can you tell us a little bit about that?

Ian Chau, MD: Yes. There is a new target, in fact, called claudin 18.2 which goes back to TCGA, in fact, and was identified in the genome-stable subtype which is more associated with diffuse histology, and they actually identified that it can form a fusion protein and drive the biology into much more aggressive diffuse histology. And this is found mainly in gastric mucosa, in gastric cancer, not in the rest of the body, so it does seem to be a very good target in gastric cancer. The company generated a monoclonal antibody called IMAB362, and they’ve done a study in a randomized phase II setting of standard chemotherapy, epirubicin/oxaliplatin/capecitabine (EOX), with two different doses of this IMAB362. First of all, the primary endpoint is an improvement in progression-free survival for which they did find a significant improvement; at the median level it’s almost a three-month difference. But, more importantly, in the overall survival analysis, which using the original dose, which is an 800-mg loading dose followed by 600 mg with each cycle of EOX, they also found an almost five-month improvement in overall survival.

And, at this year’s ESMO, what they presented is the second arm where they use a 1000-mg/kg dose of the antibody in conjunction with EOX, and they showed both a progression-free survival and overall survival advantages. Again, the magnitude of benefit is probably slightly less than the lower dose, but, nevertheless, still compared to the control arm, there was a significant improvement. I think this is a randomized phase II. We, in the past, have been disappointed so many times. There were so many encouraging randomized phase II studies that then didn’t read out in phase III.

And, also, one thing of note is the control arm did not seem to be performing as well as one would expect. Because, obviously, when you’ve got large body of randomized data of EOX in both REAL2 and the REAL3 data, so we know what that drug should do. But, it seems to be less good in this particular study, but maybe because, as I said, this is mainly in a diffuse histology. Although they haven’t actually showed data to say, of the patients recruited, how many patients were classified by lowering classification as a diffuse histology. They used their biomarker assay and they had to be tested positive to go into the study. It is a biomarker-driven study, so I think it is extremely important that they confirm these results in a large-scale phase III study, again, powered for overall survival. And, as I said in my discussion, it was conducted in different geographical regions.

Johanna Bendell, MD: Excellent. This has been extremely informative. Before we end the discussion, I’d like to get final thoughts from each of our panelists. Dr. Chau?

Ian Chau, MD: I think we already talked about how important it is nowadays, knowing more about the molecular characteristics of the tumors in our patients. And, I think, really taking that forward, we need to look at how we can integrate that information and look at agents that maybe are more working in the microenvironment, antiangiogenesis, immunotherapy, and how to make the tumor more visible to the immune system—how to make all these treatments work better. And I think that really is a goal that would integrate all this information to try to improve the survival of our patients more.

Johanna Bendell, MD: Love it. Dr. Janjigian?

Yelena Janjigian, MD: Well, one thing we know about gastric cancer is that it’s a very molecularly complex disease. Because of the nature of the epithelium and where the tumor is located, it will be important to find combination therapies, targeted agents that will help us control the tumor if we ever want to move away from the cytotoxic chemotherapy. Unlike other molecularly driven tumors, it will not be one switch, one target model, and we really need to move toward treatment strategies that combine different biologic agents for them to work better together. There is a lot of development, a lot of interest in the scientific community. And what I tell my patients is that even in my lifetime, as an oncologist, new development and 2 FDA approved drugs appeared in a very short amount of time. It’s important to study this disease—to study in the setting of a clinical trial. Enrollment in trials is important and ultimately make this a chronic illness eventually, a potentially curable illness.

Johanna Bendell, MD: I love it. Dr. Shah, you’ve got the anchorman.

Manish Shah, MD: I think that what’s really clear is that the drug development has really accelerated in gastric cancer. In the last 10 years, we have 5 new drugs that have been approved. I think, as we move forward, we need to learn how to sequence the drugs and combine them in the better way and a smarter way to understand the molecular profiles and be proactive in terms of managing the patient’s side effects. And, altogether, I think with that, we can really improve outcomes, improve their quality of life as they continue with this disease.

Johanna Bendell, MD: I love it. See, you did it beautifully. You had to be anchorman. I love it. So, thanks to all of you for your contributions and this discussion. On behalf of our panel, we thank you for joining us and we hope you found this Peer Exchange® discussion to be useful and informative. Thanks so much!

Transcript Edited for Clarity
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