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Gastroesophageal Cancer: Emerging Approaches

Panelists: Johanna C. Bendell, MD, Sarah Cannon Research Institute; Ian Chau, MD, Royal Marsden Hospital; Yelena Y. Janjigian, MD, Memorial Sloan Kettering Cancer Center; Manish A. Shah, MD, Weill Cornell Medicine, New York-Presbyterian Hospital; Kohei Shitara, MD, National Cancer Center Hospital East, Japan
Published Online: Wednesday, Aug 09, 2017



Transcript:

Johanna C. Bendell, MD: Outside of immunotherapy, we have to remember that 80% to 90% of patients aren’t going to respond to immunotherapy. So what else do we have for these folks? Tell us about the claudin.

Ian Chau, MD: The claudins are involved in adhesion of the cells, and certainly, it was highlighted as one of the important molecular events by the TCGA for gastric cancer. There is now an antibody targeted against claudin 18.2, and it was tested in a randomized phase II setting where the control arm was EOX (epirubicin, oxaliplatin, capecitabine), so they did use epirubicin/oxaliplatin/capecitabine with or without this monoclonal antibody. And in that study, they did see a progression-free survival and overall survival benefit. But we also know that this claudin 18.2 seems to be associated with diffuse histology, although in that particular study—which is called FAST—they have not actually reported the relative portion of diffuse versus intestinal histology. So we don’t know whether that is definitely clinically more diffuse histology. But certainly, those are interesting randomized phase II data. But it will require a confirmatory large phase III trial, which I think is impending, so we will see what we get when that study opens up.

Johanna C. Bendell, MD: Very good. And certainly, as Yelena alluded to earlier, there is an importance of some of the molecular profiling. Because we saw some early data at this year’s ASCO about targeting a very rare abnormality, an FGFR abnormality, whether or not it be a translocation with FGFR2b for gastric cancers—and I think those studies continue to go, looking at things like attacking the stem cells with STAT3 inhibitors in combination with chemotherapy. I’m going to toss this last one to my friend here. Tell us about an MMP-9 inhibitor.
Manish A. Shah, MD: So that’s another exciting drug. It’s andecaliximab, and it is a monoclonal antibody that targets MMP-9, which is a matrix metalloproteinase. It’s actually an enzyme that helps break up the immune microenvironment. And there was an expanded cohort phase I study that showed some very encouraging results, and that has led to a phase III study that has also completed accrual. And so we eagerly await the results of that study, hopefully in the next year.

Johanna C. Bendell, MD: Excellent. Before we end this discussion, I want to ask each of you if you’ve got any additional comments, take-home messages for the audience here about what we’ve just discussed. I’m going to start easy with our newcomer who I hope will be a long-term comer. Can you tell us any closing thoughts?

Kohei Shitara, MD: Thank you for giving me this opportunity to join this very exciting discussion. We definitely had many things from other countries, especially since we have some differences between the gastric setting in Japan and other countries. But let’s focus on the usual type of gastric cancer. I think there is no large difference in terms of genomic profile or immunological profile because we have similar frequency of EB virus, MRSA, or other FGFR events. There is no major difference in terms of frequency. If we focus on our response rate to anti–PD-1 therapy, as mentioned before, there seems to be no major difference. And that means that we have more global collaboration. Maybe we do not have enough time to discuss a newer drug, but we have many candidates of new drugs. So to do a phase III trial in one country for each drug is very difficult or impossible. Efficiently, we do collaborations to develop new or good trials for gastric cancer. Thank you.

Johanna C. Bendell, MD: Very good. Thank you. Yelena?

Yelena Y. Janjigian, MD: I absolutely agree. We are realizing, and we’re really on the cusp of solidifying it in the clinically relevant way, that gastric cancer is not 1 disease. It’s at least 4, maybe 5, different molecularly driven diseases. And these small subsets of patients are very difficult to study if we don’t come together and make sure to enroll patients into clinical trials, not really just treating them anecdotally and then never reporting the data and really making the response data public. Memorial Sloan Kettering is doing a GENIE project where we are making available the clinical annotation and response data in addition to the sequencing analysis that we do. And right now, I’m in the process of actually publishing our consecutive set of 500 patients whom we sequenced in gastric cancer, or patient samples. It’s an important effort to share these data across the globe and to plan the next studies together.

Johanna C. Bendell, MD: Dr. Chau?

Ian Chau, MD: I think today’s session really highlights that we need collaborations at all levels at the institution in the localized disease; collaborating with our multidisciplinary team of surgeons, radiologists, radiation oncologists, and then collaborate with our scientists with getting the molecular analysis and trying to incorporate that into our clinical study. And then when we move on to do clinical trials, collaborate nationally/internationally so that we can actually move some of these new treatments quicker and earlier to our patients’ benefit.

Johanna C. Bendell, MD: And Dr. Shah?

Manish A. Shah, MD: I guess I’d like to thank you, Johanna, for moderating such a great discussion. I’ve learned a lot from my colleagues. Obviously, collaboration is an important thing. But I think actually over the last few years, what I’ve really come to appreciate is that this is a quickly evolving field, and we will have new drugs, new treatment options for our patients, and we’ll need to be smart about how to sequence them. How about that for a segue?

Johanna C. Bendell, MD: I love it. Sequencing, sequencing, sequencing. Well, I’m really excited because it feels like gastrointestinal cancers are making a comeback. We went through a dark spell there where we didn’t have a lot. But now I think we’re emerging back up with so many new potential treatment options—the immunotherapies, combinations with immunotherapies, new targets, new ways to think about how to treat locally advanced disease much through collaboration. And I think what I love about this overall theme and the overall theme of everybody’s comments was the importance that we’re all seeing a coming together and a collaboration globally to change the lives of patients throughout the world. This was a great discussion, and thank you on behalf of our panel, and we thank you for joining us.

Transcript Edited for Clarity

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Transcript:

Johanna C. Bendell, MD: Outside of immunotherapy, we have to remember that 80% to 90% of patients aren’t going to respond to immunotherapy. So what else do we have for these folks? Tell us about the claudin.

Ian Chau, MD: The claudins are involved in adhesion of the cells, and certainly, it was highlighted as one of the important molecular events by the TCGA for gastric cancer. There is now an antibody targeted against claudin 18.2, and it was tested in a randomized phase II setting where the control arm was EOX (epirubicin, oxaliplatin, capecitabine), so they did use epirubicin/oxaliplatin/capecitabine with or without this monoclonal antibody. And in that study, they did see a progression-free survival and overall survival benefit. But we also know that this claudin 18.2 seems to be associated with diffuse histology, although in that particular study—which is called FAST—they have not actually reported the relative portion of diffuse versus intestinal histology. So we don’t know whether that is definitely clinically more diffuse histology. But certainly, those are interesting randomized phase II data. But it will require a confirmatory large phase III trial, which I think is impending, so we will see what we get when that study opens up.

Johanna C. Bendell, MD: Very good. And certainly, as Yelena alluded to earlier, there is an importance of some of the molecular profiling. Because we saw some early data at this year’s ASCO about targeting a very rare abnormality, an FGFR abnormality, whether or not it be a translocation with FGFR2b for gastric cancers—and I think those studies continue to go, looking at things like attacking the stem cells with STAT3 inhibitors in combination with chemotherapy. I’m going to toss this last one to my friend here. Tell us about an MMP-9 inhibitor.
Manish A. Shah, MD: So that’s another exciting drug. It’s andecaliximab, and it is a monoclonal antibody that targets MMP-9, which is a matrix metalloproteinase. It’s actually an enzyme that helps break up the immune microenvironment. And there was an expanded cohort phase I study that showed some very encouraging results, and that has led to a phase III study that has also completed accrual. And so we eagerly await the results of that study, hopefully in the next year.

Johanna C. Bendell, MD: Excellent. Before we end this discussion, I want to ask each of you if you’ve got any additional comments, take-home messages for the audience here about what we’ve just discussed. I’m going to start easy with our newcomer who I hope will be a long-term comer. Can you tell us any closing thoughts?

Kohei Shitara, MD: Thank you for giving me this opportunity to join this very exciting discussion. We definitely had many things from other countries, especially since we have some differences between the gastric setting in Japan and other countries. But let’s focus on the usual type of gastric cancer. I think there is no large difference in terms of genomic profile or immunological profile because we have similar frequency of EB virus, MRSA, or other FGFR events. There is no major difference in terms of frequency. If we focus on our response rate to anti–PD-1 therapy, as mentioned before, there seems to be no major difference. And that means that we have more global collaboration. Maybe we do not have enough time to discuss a newer drug, but we have many candidates of new drugs. So to do a phase III trial in one country for each drug is very difficult or impossible. Efficiently, we do collaborations to develop new or good trials for gastric cancer. Thank you.

Johanna C. Bendell, MD: Very good. Thank you. Yelena?

Yelena Y. Janjigian, MD: I absolutely agree. We are realizing, and we’re really on the cusp of solidifying it in the clinically relevant way, that gastric cancer is not 1 disease. It’s at least 4, maybe 5, different molecularly driven diseases. And these small subsets of patients are very difficult to study if we don’t come together and make sure to enroll patients into clinical trials, not really just treating them anecdotally and then never reporting the data and really making the response data public. Memorial Sloan Kettering is doing a GENIE project where we are making available the clinical annotation and response data in addition to the sequencing analysis that we do. And right now, I’m in the process of actually publishing our consecutive set of 500 patients whom we sequenced in gastric cancer, or patient samples. It’s an important effort to share these data across the globe and to plan the next studies together.

Johanna C. Bendell, MD: Dr. Chau?

Ian Chau, MD: I think today’s session really highlights that we need collaborations at all levels at the institution in the localized disease; collaborating with our multidisciplinary team of surgeons, radiologists, radiation oncologists, and then collaborate with our scientists with getting the molecular analysis and trying to incorporate that into our clinical study. And then when we move on to do clinical trials, collaborate nationally/internationally so that we can actually move some of these new treatments quicker and earlier to our patients’ benefit.

Johanna C. Bendell, MD: And Dr. Shah?

Manish A. Shah, MD: I guess I’d like to thank you, Johanna, for moderating such a great discussion. I’ve learned a lot from my colleagues. Obviously, collaboration is an important thing. But I think actually over the last few years, what I’ve really come to appreciate is that this is a quickly evolving field, and we will have new drugs, new treatment options for our patients, and we’ll need to be smart about how to sequence them. How about that for a segue?

Johanna C. Bendell, MD: I love it. Sequencing, sequencing, sequencing. Well, I’m really excited because it feels like gastrointestinal cancers are making a comeback. We went through a dark spell there where we didn’t have a lot. But now I think we’re emerging back up with so many new potential treatment options—the immunotherapies, combinations with immunotherapies, new targets, new ways to think about how to treat locally advanced disease much through collaboration. And I think what I love about this overall theme and the overall theme of everybody’s comments was the importance that we’re all seeing a coming together and a collaboration globally to change the lives of patients throughout the world. This was a great discussion, and thank you on behalf of our panel, and we thank you for joining us.

Transcript Edited for Clarity
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