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Antiangiogenesis in Gastric/GEJ Cancers: A Global View

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: Wednesday, Jul 26, 2017



Transcript:

Johanna C. Bendell, MD:
I want to come back to antiangiogenic therapy. I’m going to take advantage of this global portfolio of people that we have here. And so, Ian, can you tell us a little bit about the ramucirumab trials? We’ve talked about and alluded to the ramucirumab trials, what they showed, and what kind of patient population that they enrolled.

Ian Chau, MD: So, there are the 2 pivotal studies for ramucirumab. The first study is the REGARD study, where there were 355 patients randomized to ramucirumab or placebo. This is single-agent ramucirumab, and these are patients who don’t actually have to have a doublet first-line. They can have either platinum or fluoropyrimidine, so, therefore, only 75% of the patients actually have the doublet first-line. Then they were randomized in a 2:1 fashion and showed a significant survival benefit in favor of ramucirumab. As I mentioned before, with ramucirumab on its own, the safety profile is very favorable, almost the same as placebo.
The second study is the RAINBOW trial, which we already heard quite a bit about. It is a larger study—again, conducted globally—where paclitaxel/placebo is the control arm, and then the experimental arm is paclitaxel/ramucirumab. Again, it showed a significant survival benefit in overall survival, progression-free survival, and response rate. And I think really, based on these 2 studies, we’re able to conclude, and I think the majority of the world actually accept, that paclitaxel/ramucirumab has become a standard of care.

And this, of course, is in contrast to some data we’ve seen with bevacizumab. A lot of us are aware of the AVAGAST study using, in first-line, either cisplatin/fluoropyrimidine with or without bevacizumab, which did not improve overall survival, although there was an improvement in response rate and progression-free survival. But perhaps the second, big randomized study of bevacizumab—which was recently published by my colleague, David Cunningham, in Lancet Oncologyis in the perioperative setting of using ECX [epirubicin/cisplatin/capecitabine] with or without bevacizumab. And yet again, in that very large study—which is close to 1100 patients randomized—there was no significant benefit of adding bevacizumab to chemotherapy. Interestingly, that study, although it was right at the end of recruitment, was actually stopped by DMC, or the Data Monitoring Committee, because they noticed that there was an increased risk of anastomotic leak in that group who was randomized to bevacizumab. But those were mainly in the patients with gastroesophageal junction adenocarcinoma, not those who have to undergo gastrectomy. It looks like those who need to do gastrectomy were compromised by having bevacizumab.

So, I think it’s interesting. Here we are, we’ve got 2 large phase III studies with bevacizumab that did not seem to provide a benefit, but the 2 studies with ramucirumab seem to provide benefit. And whether people truly believe there really is a difference in mechanism of action—one targeted in the receptor, then one targeted in the ligand—actually makes that difference in gastric cancer. We already heard that for different diseases, the same targets can have different effects, and the same targets of a different compound can have different effects.

Johanna C. Bendell, MD: And in different parts of the world, right?

Ian Chau, MD: Yes.

Johanna C. Bendell, MD: So, wasn’t their controversy the fact that one of the reasons we thought AVAGAST was negative was because of the Asian population? But yet, with the ramucirumab studies we saw something different. Tell us a little bit about antiangiogenic use in Asia.

Kohei Shitara, MD: For the RAINBOW study, we enrolled 140 patients in the study. I already reported a subgroup analysis in a Japanese subset. It clearly showed their improvement in response rate and progression-free survival, almost a doubling. Overall survival hazard ratio was 0.87, so there is some trend of improvement, but the control arm has very good outcomes. So, it might have been dire to the difference in survival. But this was clearly different from the previous AVAGAST trial, which showed no trend of improvement in terms of PFS response. I’m not sure what the reason is—difference of the drug, time of the treatment, or in combination.

Yelena Y. Janjigian, MD: Or patient selection, because the bevacizumab studies involved first-line and perioperative settings. If the patients make it to second-line and then you select for patients with low-volume disease, no peritoneal carcinomatosis, no bleeding, normal albumin, etc, then you’re selecting a very select patient population.

Johanna C. Bendell, MD: Yes. And we’ve seen also apatinib and regorafenib.

Yelena Y. Janjigian, MD: Again, these are small molecule inhibitors targeting the receptor tyrosine kinase inside the cell, and regorafenib has other off-target effects on PDGF and FGFR, pathways that are parallel pathways that are potentially important to cancer cell growth. And, once again, if you get to the second- and third-line settings, yes, you’re obviously at a higher risk for toxicity and other morbidities—mortality—but you also have a disease that is specific, very particular of disease biology. So, perhaps you’re more dependent on VEGF for growth, or as your disease is progressing, your VEGF dependence is increasing. In the first-line setting, and I always tell this to my patients, we won’t know how you do until we start chemotherapy. And so, in the first-line trial, there’s no way to predict if this particular patient and tumor will be chemotherapy-refractory. And, in that case, if they’re chemotherapy-refractory, adding a VEGF inhibitor is not going to make it or break their response if there’s no biomarker and you’re not enriching patients. And so, I think that’s why I would be careful to compare a second-line and a first-line study and efficacy of agents.

Kohei Shitara, MD: So, we should wait for the results of RAINFALL.

Johanna C. Bendell, MD: Yes, we eagerly await the results of RAINFALL.

Transcript Edited for Clarity

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Transcript:

Johanna C. Bendell, MD:
I want to come back to antiangiogenic therapy. I’m going to take advantage of this global portfolio of people that we have here. And so, Ian, can you tell us a little bit about the ramucirumab trials? We’ve talked about and alluded to the ramucirumab trials, what they showed, and what kind of patient population that they enrolled.

Ian Chau, MD: So, there are the 2 pivotal studies for ramucirumab. The first study is the REGARD study, where there were 355 patients randomized to ramucirumab or placebo. This is single-agent ramucirumab, and these are patients who don’t actually have to have a doublet first-line. They can have either platinum or fluoropyrimidine, so, therefore, only 75% of the patients actually have the doublet first-line. Then they were randomized in a 2:1 fashion and showed a significant survival benefit in favor of ramucirumab. As I mentioned before, with ramucirumab on its own, the safety profile is very favorable, almost the same as placebo.
The second study is the RAINBOW trial, which we already heard quite a bit about. It is a larger study—again, conducted globally—where paclitaxel/placebo is the control arm, and then the experimental arm is paclitaxel/ramucirumab. Again, it showed a significant survival benefit in overall survival, progression-free survival, and response rate. And I think really, based on these 2 studies, we’re able to conclude, and I think the majority of the world actually accept, that paclitaxel/ramucirumab has become a standard of care.

And this, of course, is in contrast to some data we’ve seen with bevacizumab. A lot of us are aware of the AVAGAST study using, in first-line, either cisplatin/fluoropyrimidine with or without bevacizumab, which did not improve overall survival, although there was an improvement in response rate and progression-free survival. But perhaps the second, big randomized study of bevacizumab—which was recently published by my colleague, David Cunningham, in Lancet Oncologyis in the perioperative setting of using ECX [epirubicin/cisplatin/capecitabine] with or without bevacizumab. And yet again, in that very large study—which is close to 1100 patients randomized—there was no significant benefit of adding bevacizumab to chemotherapy. Interestingly, that study, although it was right at the end of recruitment, was actually stopped by DMC, or the Data Monitoring Committee, because they noticed that there was an increased risk of anastomotic leak in that group who was randomized to bevacizumab. But those were mainly in the patients with gastroesophageal junction adenocarcinoma, not those who have to undergo gastrectomy. It looks like those who need to do gastrectomy were compromised by having bevacizumab.

So, I think it’s interesting. Here we are, we’ve got 2 large phase III studies with bevacizumab that did not seem to provide a benefit, but the 2 studies with ramucirumab seem to provide benefit. And whether people truly believe there really is a difference in mechanism of action—one targeted in the receptor, then one targeted in the ligand—actually makes that difference in gastric cancer. We already heard that for different diseases, the same targets can have different effects, and the same targets of a different compound can have different effects.

Johanna C. Bendell, MD: And in different parts of the world, right?

Ian Chau, MD: Yes.

Johanna C. Bendell, MD: So, wasn’t their controversy the fact that one of the reasons we thought AVAGAST was negative was because of the Asian population? But yet, with the ramucirumab studies we saw something different. Tell us a little bit about antiangiogenic use in Asia.

Kohei Shitara, MD: For the RAINBOW study, we enrolled 140 patients in the study. I already reported a subgroup analysis in a Japanese subset. It clearly showed their improvement in response rate and progression-free survival, almost a doubling. Overall survival hazard ratio was 0.87, so there is some trend of improvement, but the control arm has very good outcomes. So, it might have been dire to the difference in survival. But this was clearly different from the previous AVAGAST trial, which showed no trend of improvement in terms of PFS response. I’m not sure what the reason is—difference of the drug, time of the treatment, or in combination.

Yelena Y. Janjigian, MD: Or patient selection, because the bevacizumab studies involved first-line and perioperative settings. If the patients make it to second-line and then you select for patients with low-volume disease, no peritoneal carcinomatosis, no bleeding, normal albumin, etc, then you’re selecting a very select patient population.

Johanna C. Bendell, MD: Yes. And we’ve seen also apatinib and regorafenib.

Yelena Y. Janjigian, MD: Again, these are small molecule inhibitors targeting the receptor tyrosine kinase inside the cell, and regorafenib has other off-target effects on PDGF and FGFR, pathways that are parallel pathways that are potentially important to cancer cell growth. And, once again, if you get to the second- and third-line settings, yes, you’re obviously at a higher risk for toxicity and other morbidities—mortality—but you also have a disease that is specific, very particular of disease biology. So, perhaps you’re more dependent on VEGF for growth, or as your disease is progressing, your VEGF dependence is increasing. In the first-line setting, and I always tell this to my patients, we won’t know how you do until we start chemotherapy. And so, in the first-line trial, there’s no way to predict if this particular patient and tumor will be chemotherapy-refractory. And, in that case, if they’re chemotherapy-refractory, adding a VEGF inhibitor is not going to make it or break their response if there’s no biomarker and you’re not enriching patients. And so, I think that’s why I would be careful to compare a second-line and a first-line study and efficacy of agents.

Kohei Shitara, MD: So, we should wait for the results of RAINFALL.

Johanna C. Bendell, MD: Yes, we eagerly await the results of RAINFALL.

Transcript Edited for Clarity
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