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Analyzing Potential Therapies in Gastric/GEJ Cancer

Insights From: David Ilson, MD PhD, Memorial Sloan Kettering Cancer Center; Minaxi Jhawer, MD, Englewood Hospital and Medical Center
Published: Friday, Aug 10, 2018



Transcript: 

David Ilson, MD, PhD: What’s new and ongoing in the research of esophagogastric cancer is really trying to build on the signals of activity we’ve seen for immunotherapy and other potential targets like HER2, VEGF, and other new mutations or DNA repair mechanisms. Currently, there are a lot of ongoing phase I and II trials. We have had some disappointing results with some and encouragement with others. I think we anxiously await the results of first-line immunotherapy trials. There also are some other novel targets. For the claudin protein, which is a gap junction protein that’s overexpressed in most gastric cancers, there is an antibody targeting that protein that may lead to immune enhancement and recruitment. There were some very promising phase II data.

A monoclonal antibody that targets claudin combined with chemotherapy in high expressers of claudin translated into improved response in progression-free and overall survival. Based on that observation, that drug is going to go to a phase III trial in claudin high-expressing patients. The use of PARP inhibitors has been a little bit disappointing. There was a randomized trial, called the GOLD trial, combining PARP inhibitors with paclitaxel, that didn’t meet its primary endpoint. There was a trend in biomarker-selected patients that there might be a benefit, so that remains a work-in-progress.

There’s obviously interest in studying ramucirumab in combination with other targeted agents, but that’s a strategy that’s in development. We talked earlier about novel immunomodulatory agents combined with immunotherapy that may potentially enhance the effectiveness of those drugs. There have been some disappointing trials. There was a second-line trial of an oral taxane versus an IV [intravenous] taxane, which was a negative trial. There also was a negative trial of a STAT inhibitor, which potentially targeted stem cells. Paclitaxel alone with or without a STAT inhibitor was reported in a press release as a negative trial. Another EGFR drug failed first line. There was a trial from Asia looking at a drug called nimotuzumab combined with chemotherapy versus chemotherapy alone, which was also a negative trial.

I think right now, the excitement is going to be in looking at some novel targets, like claudin, and developing the immunotherapy space, potentially looking at ramucirumab or other VEGF inhibitor combinations. There are some late-line trials of VEGF-targeted drugs, randomized trials. There’s a randomized trial ongoing of regorafenib versus supportive care, given some promising phase II data. We’re about to hear results in refractory gastric cancer of a novel antimetabolite, TAS-102, versus best supportive care in refractory gastric cancer. That trial was based on the promising results in phase II and the positive phase III trial for TAS-102 in colorectal cancer.

Minaxi Jhawer, MD: As we move forward with gastric cancer and an understanding of the biology, we have molecular panels that we can use. The question is whether you use dedicated panels. What gives us the most information, the most valued information, to impact the care of our patients? What is the true sequencing of the drugs? Can we do better? Can we sensitize some of the disease so that the next line of therapy would work better? What would be the strategy? That’s really based on more biological understandings of the disease. We do understand that there’s a limited role of radiation in pure gastric cancer, but we are clearly defining if there is truly any role in this time.

As we have a better understanding of perioperative chemotherapy in gastric cancer, we see that only 50% of patients in postoperative therapy actually receive the full planned doses, which really limits the chemotherapy they’re getting during that period. The question is, can we move all of their chemotherapy up front to total neoadjuvant therapy models that we’ve seen in some of the diseases like colon cancer? Would that then improve the patient’s survival and resection rates, giving them better outcomes in the long run? I think that seems to be the direction that we need to take in the future.

David Ilson, MD, PhD: In the last few decades, we have identified strategies that have improved outcomes in the management of esophagogastric cancer. It’s clear that neoadjuvant strategies have improved survival. Neoadjuvant chemotherapy and radiation added to surgery for esophagus and GE [gastroesophageal] junction cancers, perioperative chemotherapy added to gastric cancer, improves outcomes. We now know that HER2-targeted agents improve outcomes in first-line treatment of metastatic disease. VEGF-targeted drugs improve outcomes in the second line, and we have a role now for immunotherapy agents in chemotherapy-refractory disease. The hope now is to move targeted strategy forward, building on the observations that we have; identifying novel strategies looking at the validated pathways, such as HER2, VEGF, and immunotherapy approaches; and hoping that our characterization of cancers will result in new hypotheses or new strategies to overcome resistance and develop new drugs and new targets.

Minaxi Jhawer, MD: It’s been an exciting evolution to see multiple drugs develop in gastric cancer. We’ve clearly paved the way to improving survival by small numbers, but we really think we have a lot more to do. We’ve been fortunate to have trastuzumab, pembrolizumab, and ramucirumab, all the great biological drugs, but when you start moving them around to first line and seeing if they can be used in the different combinations, the data are not panning out as positively. It would be really good to have a deeper understanding of the disease, the biology, so that we can come up with better strategies to use these combinations in and come up with newer drugs that would really make a significant difference in this disease.

Transcript Edited for Clarity 
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Transcript: 

David Ilson, MD, PhD: What’s new and ongoing in the research of esophagogastric cancer is really trying to build on the signals of activity we’ve seen for immunotherapy and other potential targets like HER2, VEGF, and other new mutations or DNA repair mechanisms. Currently, there are a lot of ongoing phase I and II trials. We have had some disappointing results with some and encouragement with others. I think we anxiously await the results of first-line immunotherapy trials. There also are some other novel targets. For the claudin protein, which is a gap junction protein that’s overexpressed in most gastric cancers, there is an antibody targeting that protein that may lead to immune enhancement and recruitment. There were some very promising phase II data.

A monoclonal antibody that targets claudin combined with chemotherapy in high expressers of claudin translated into improved response in progression-free and overall survival. Based on that observation, that drug is going to go to a phase III trial in claudin high-expressing patients. The use of PARP inhibitors has been a little bit disappointing. There was a randomized trial, called the GOLD trial, combining PARP inhibitors with paclitaxel, that didn’t meet its primary endpoint. There was a trend in biomarker-selected patients that there might be a benefit, so that remains a work-in-progress.

There’s obviously interest in studying ramucirumab in combination with other targeted agents, but that’s a strategy that’s in development. We talked earlier about novel immunomodulatory agents combined with immunotherapy that may potentially enhance the effectiveness of those drugs. There have been some disappointing trials. There was a second-line trial of an oral taxane versus an IV [intravenous] taxane, which was a negative trial. There also was a negative trial of a STAT inhibitor, which potentially targeted stem cells. Paclitaxel alone with or without a STAT inhibitor was reported in a press release as a negative trial. Another EGFR drug failed first line. There was a trial from Asia looking at a drug called nimotuzumab combined with chemotherapy versus chemotherapy alone, which was also a negative trial.

I think right now, the excitement is going to be in looking at some novel targets, like claudin, and developing the immunotherapy space, potentially looking at ramucirumab or other VEGF inhibitor combinations. There are some late-line trials of VEGF-targeted drugs, randomized trials. There’s a randomized trial ongoing of regorafenib versus supportive care, given some promising phase II data. We’re about to hear results in refractory gastric cancer of a novel antimetabolite, TAS-102, versus best supportive care in refractory gastric cancer. That trial was based on the promising results in phase II and the positive phase III trial for TAS-102 in colorectal cancer.

Minaxi Jhawer, MD: As we move forward with gastric cancer and an understanding of the biology, we have molecular panels that we can use. The question is whether you use dedicated panels. What gives us the most information, the most valued information, to impact the care of our patients? What is the true sequencing of the drugs? Can we do better? Can we sensitize some of the disease so that the next line of therapy would work better? What would be the strategy? That’s really based on more biological understandings of the disease. We do understand that there’s a limited role of radiation in pure gastric cancer, but we are clearly defining if there is truly any role in this time.

As we have a better understanding of perioperative chemotherapy in gastric cancer, we see that only 50% of patients in postoperative therapy actually receive the full planned doses, which really limits the chemotherapy they’re getting during that period. The question is, can we move all of their chemotherapy up front to total neoadjuvant therapy models that we’ve seen in some of the diseases like colon cancer? Would that then improve the patient’s survival and resection rates, giving them better outcomes in the long run? I think that seems to be the direction that we need to take in the future.

David Ilson, MD, PhD: In the last few decades, we have identified strategies that have improved outcomes in the management of esophagogastric cancer. It’s clear that neoadjuvant strategies have improved survival. Neoadjuvant chemotherapy and radiation added to surgery for esophagus and GE [gastroesophageal] junction cancers, perioperative chemotherapy added to gastric cancer, improves outcomes. We now know that HER2-targeted agents improve outcomes in first-line treatment of metastatic disease. VEGF-targeted drugs improve outcomes in the second line, and we have a role now for immunotherapy agents in chemotherapy-refractory disease. The hope now is to move targeted strategy forward, building on the observations that we have; identifying novel strategies looking at the validated pathways, such as HER2, VEGF, and immunotherapy approaches; and hoping that our characterization of cancers will result in new hypotheses or new strategies to overcome resistance and develop new drugs and new targets.

Minaxi Jhawer, MD: It’s been an exciting evolution to see multiple drugs develop in gastric cancer. We’ve clearly paved the way to improving survival by small numbers, but we really think we have a lot more to do. We’ve been fortunate to have trastuzumab, pembrolizumab, and ramucirumab, all the great biological drugs, but when you start moving them around to first line and seeing if they can be used in the different combinations, the data are not panning out as positively. It would be really good to have a deeper understanding of the disease, the biology, so that we can come up with better strategies to use these combinations in and come up with newer drugs that would really make a significant difference in this disease.

Transcript Edited for Clarity 
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