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Drug Development and Final Thoughts

Panelists: Johanna C Bendell, MD, Sarah Cannon Research Institute ; David H Ilson, MD, PhD, Memorial Sloan Kettering Cancer Center; Manish A Shah, MD, Weill Cornell Medicine; Kohei Shitara, MD, National Cancer Center Hospital East
Published: Friday, Sep 06, 2019



Transcript:

Johanna C. Bendell, MD:
Manish, what about drug development outside the holy grail, immunotherapy? Certainly, we’re looking at other things we talked about, other targeted agents. Talk to us about some of these FGFR agents. What’s the stemness inhibitor?

Manish A. Shah, MD: So we have BBI608, which is a stemness phenotype inhibitor. We examined that in gastric cancer in the second-line setting. Unfortunately, that was a negative study. The mechanism of action is actually curious. It targets STAT3, which actually affects stem cells, but it also affects the tumor microenvironment. There was hope of that actually augmenting immunotherapy or working like that.

We also did a phase II study of the drug BBI608 with immunotherapy. We haven’t seen much effect. Another drug that was actually a negative study was the MMP9 inhibitor, which also targets the immune microenvironment. That was a first-line study. We also combined that drug with immunotherapy in the second-line setting, and we’re doing a lot of pharmacodynamic markers to see how we can understand the immune microenvironment.

Johanna C. Bendell, MD: What about FGFR inhibitors and FGFR translocations, or fusions?

Manish A. Shah, MD: Fusions, yes. We know of a very nice drug that targets FGFR3. That study has shown some activity in these tumors that are overexpressing FGFR3. We actually participated in that study. Although it was explored in the advanced setting, the expression of FGFR3 is not as prevalent. But in earlier-line settings, it can be quite high—20%, 30%. They’ve actually embarked on a phase III study examining that.

Johanna C. Bendell, MD: The other thing that was big news at ASCO [American Society of Clinical Oncology Annual Meeting] was a plenary session looking at patients with BRCA mutations for pancreas cancer, looking at the use of PARP inhibitors. Certainly, the DDR phenotype is being evaluated in gastric cancer. David, is it something people have looked at or are continuing to look at? Tell us a little more about these patients.

David H. Ilson, MD, PhD: I think it’s a work in progress. We sometimes have somatic BRCA mutations. And from our experience, you really have to have loss of heterozygosity to see platinum sensitivity. Just having a somatic BRCA mutation in isolation may not convey that sensitivity to platinum agents. The PARP inhibitor experience was a bit disappointing. The trial combining paclitaxel with olaparib versus paclitaxel alone, even in a potential biomarker-enriched population, didn’t show a clear survival benefit. There were patients who were ATM deficient, who might do better with PARP inhibitors. But even with an enriched population, the trial was negative. There was a trend. They set the bar very high in that trial for a large improvement. Also, the ATM population was relatively small in that trial. But there is not a clear signal yet for a PARP inhibitor in esophageal cancer. Ongoing trials are looking at combinations of these agents with checkpoint inhibitors and TKIs to see whether we can build on what looks like some signal.

Kohei Shitara, MD: On the point that the goal of this trial is a combination, that means a lower dose of olaparib. That may be 1 reason why any subgroup did not show the benefit. But this kind of PARP inhibitor may have an impact in overall survival. In pancreatic cancer, it did not show the benefit in overall survival. Some studies have suggested the acquired BRCA mutation.… And I suspect this may contribute to the overall survival. Maybe we need more data to confirm a survival benefit.

Another very important target for gastric cancer is a claudin 18.2. This is a tight-junction protein that is usually expressed in normal stomach cells. But after cancer cells, especially the extensive diffuse type, show their high expression of claudin, it made a good target for a monoclonal antibody. The previous trial that was mainly conducted in Germany showed a good benefit in combination with a first-line therapy. Currently, this has been investigated in a phase III trial. At this ASCO meeting, CAR T therapy for claudin 18.2 was also reported. They are very exciting data.

Johanna C. Bendell, MD: Yeah, it’s interesting. Just like with all the other tumor types we have, we’re starting to divide gastric cancer into very specific populations that might have different treatment options, particularly in the research setting.

This has been great. Before we part ways, I’d like to ask each of our panelists for some final thoughts regarding today’s discussion. Kohei, give us some final thoughts.

Kohei Shitara, MD: Yes, recently an immunotherapy trial showed us some disappointing results, but it still may give us some important information. Clearly, gastric cancer is not 1 disease, in terms of response to a checkpoint inhibitor. Maybe in the future we should stratify patients into several subgroups—not only MSI [microsatellite instability]–high, but also PD-L1 [programmed death-ligand 1] or other molecules. A small study may give us some more insight. For this small subgroup, to do a randomized trial in 1 country is very difficult. I still believe drug development for gastric cancer should be done as a global collaboration.

Johanna C. Bendell, MD: Yeah, I agree. Manish?

Manish A. Shah, MD: I agree with what Kohei said. Although gastric cancer is a heterogeneous disease and is prevalent, drug development is best in the global setting. Then you can capture that heterogeneity. I think the errors that have been made in the past are that perhaps studies were too small to capture that heterogeneity, and that may reflect some of the challenges we’ve had. In the last 10 years, 10,000 patients have actually been enrolled on clinical trials in gastric cancer. That’s very different from when I started years before that. So there is hope. There are new drugs, and I think with the combination of immunotherapy and targeted agents, we’re going to redefine how we treat this disease.

Johanna C. Bendell, MD: David, take us home.

David H. Ilson, MD, PhD: It’s important to stress that we now have a global consensus about treatment approaches. That adjuvant therapy [and] neoadjuvant therapy work in gastric cancer. Certainly, perioperative FLOT [docetaxel, oxaliplatin, leucovorin, 5-fluorouracil] in the West, postoperative combination chemotherapy in Asia without radiation. GE [gastroesophageal] junction [and] esophagus chemotherapy radiation is still the more dominant approach in the West. In terms of new drug development, immunotherapy drugs, at least at the current time, have a role in later-line treatment. It does not have a clearly defined role in early line treatment. We are hopeful for ongoing trials looking at the FGF receptor as well as the claudin molecule, which are very promising signals from phase II trials, as well as a whole host of other targets and approaches in that are in development in later-line therapy. But there is a global consensus, and I agree with Kohei. We need to work together. This is a disease in Asia, where trials can be done more efficiently, and I think there’s more agreement than disagreement now about how to treat patients.

Johanna C. Bendell, MD: On behalf of our panel, we thank you for joining us today and hope you found this OncLive Peer Exchange® discussion to be useful and informative.


Transcript Edited for Clarity

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Transcript:

Johanna C. Bendell, MD:
Manish, what about drug development outside the holy grail, immunotherapy? Certainly, we’re looking at other things we talked about, other targeted agents. Talk to us about some of these FGFR agents. What’s the stemness inhibitor?

Manish A. Shah, MD: So we have BBI608, which is a stemness phenotype inhibitor. We examined that in gastric cancer in the second-line setting. Unfortunately, that was a negative study. The mechanism of action is actually curious. It targets STAT3, which actually affects stem cells, but it also affects the tumor microenvironment. There was hope of that actually augmenting immunotherapy or working like that.

We also did a phase II study of the drug BBI608 with immunotherapy. We haven’t seen much effect. Another drug that was actually a negative study was the MMP9 inhibitor, which also targets the immune microenvironment. That was a first-line study. We also combined that drug with immunotherapy in the second-line setting, and we’re doing a lot of pharmacodynamic markers to see how we can understand the immune microenvironment.

Johanna C. Bendell, MD: What about FGFR inhibitors and FGFR translocations, or fusions?

Manish A. Shah, MD: Fusions, yes. We know of a very nice drug that targets FGFR3. That study has shown some activity in these tumors that are overexpressing FGFR3. We actually participated in that study. Although it was explored in the advanced setting, the expression of FGFR3 is not as prevalent. But in earlier-line settings, it can be quite high—20%, 30%. They’ve actually embarked on a phase III study examining that.

Johanna C. Bendell, MD: The other thing that was big news at ASCO [American Society of Clinical Oncology Annual Meeting] was a plenary session looking at patients with BRCA mutations for pancreas cancer, looking at the use of PARP inhibitors. Certainly, the DDR phenotype is being evaluated in gastric cancer. David, is it something people have looked at or are continuing to look at? Tell us a little more about these patients.

David H. Ilson, MD, PhD: I think it’s a work in progress. We sometimes have somatic BRCA mutations. And from our experience, you really have to have loss of heterozygosity to see platinum sensitivity. Just having a somatic BRCA mutation in isolation may not convey that sensitivity to platinum agents. The PARP inhibitor experience was a bit disappointing. The trial combining paclitaxel with olaparib versus paclitaxel alone, even in a potential biomarker-enriched population, didn’t show a clear survival benefit. There were patients who were ATM deficient, who might do better with PARP inhibitors. But even with an enriched population, the trial was negative. There was a trend. They set the bar very high in that trial for a large improvement. Also, the ATM population was relatively small in that trial. But there is not a clear signal yet for a PARP inhibitor in esophageal cancer. Ongoing trials are looking at combinations of these agents with checkpoint inhibitors and TKIs to see whether we can build on what looks like some signal.

Kohei Shitara, MD: On the point that the goal of this trial is a combination, that means a lower dose of olaparib. That may be 1 reason why any subgroup did not show the benefit. But this kind of PARP inhibitor may have an impact in overall survival. In pancreatic cancer, it did not show the benefit in overall survival. Some studies have suggested the acquired BRCA mutation.… And I suspect this may contribute to the overall survival. Maybe we need more data to confirm a survival benefit.

Another very important target for gastric cancer is a claudin 18.2. This is a tight-junction protein that is usually expressed in normal stomach cells. But after cancer cells, especially the extensive diffuse type, show their high expression of claudin, it made a good target for a monoclonal antibody. The previous trial that was mainly conducted in Germany showed a good benefit in combination with a first-line therapy. Currently, this has been investigated in a phase III trial. At this ASCO meeting, CAR T therapy for claudin 18.2 was also reported. They are very exciting data.

Johanna C. Bendell, MD: Yeah, it’s interesting. Just like with all the other tumor types we have, we’re starting to divide gastric cancer into very specific populations that might have different treatment options, particularly in the research setting.

This has been great. Before we part ways, I’d like to ask each of our panelists for some final thoughts regarding today’s discussion. Kohei, give us some final thoughts.

Kohei Shitara, MD: Yes, recently an immunotherapy trial showed us some disappointing results, but it still may give us some important information. Clearly, gastric cancer is not 1 disease, in terms of response to a checkpoint inhibitor. Maybe in the future we should stratify patients into several subgroups—not only MSI [microsatellite instability]–high, but also PD-L1 [programmed death-ligand 1] or other molecules. A small study may give us some more insight. For this small subgroup, to do a randomized trial in 1 country is very difficult. I still believe drug development for gastric cancer should be done as a global collaboration.

Johanna C. Bendell, MD: Yeah, I agree. Manish?

Manish A. Shah, MD: I agree with what Kohei said. Although gastric cancer is a heterogeneous disease and is prevalent, drug development is best in the global setting. Then you can capture that heterogeneity. I think the errors that have been made in the past are that perhaps studies were too small to capture that heterogeneity, and that may reflect some of the challenges we’ve had. In the last 10 years, 10,000 patients have actually been enrolled on clinical trials in gastric cancer. That’s very different from when I started years before that. So there is hope. There are new drugs, and I think with the combination of immunotherapy and targeted agents, we’re going to redefine how we treat this disease.

Johanna C. Bendell, MD: David, take us home.

David H. Ilson, MD, PhD: It’s important to stress that we now have a global consensus about treatment approaches. That adjuvant therapy [and] neoadjuvant therapy work in gastric cancer. Certainly, perioperative FLOT [docetaxel, oxaliplatin, leucovorin, 5-fluorouracil] in the West, postoperative combination chemotherapy in Asia without radiation. GE [gastroesophageal] junction [and] esophagus chemotherapy radiation is still the more dominant approach in the West. In terms of new drug development, immunotherapy drugs, at least at the current time, have a role in later-line treatment. It does not have a clearly defined role in early line treatment. We are hopeful for ongoing trials looking at the FGF receptor as well as the claudin molecule, which are very promising signals from phase II trials, as well as a whole host of other targets and approaches in that are in development in later-line therapy. But there is a global consensus, and I agree with Kohei. We need to work together. This is a disease in Asia, where trials can be done more efficiently, and I think there’s more agreement than disagreement now about how to treat patients.

Johanna C. Bendell, MD: On behalf of our panel, we thank you for joining us today and hope you found this OncLive Peer Exchange® discussion to be useful and informative.


Transcript Edited for Clarity
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