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Treatment for Recurrent 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: Thursday, Dec 29, 2016


Transcript:

Johanna Bendell, MD:
Let’s talk about recurrence. We’ve gotten through first-line therapy and now the cancer has come back. What do you guys use for second-line therapy, and why?

Manish Shah, MD: The data with Taxol/ramucirumab is level-1 evidence that it’s superior to Taxol alone. So, that’s a standard that we use. There are also data that a doublet using a platinum and S1 versus S1 alone, in the second-line setting, actually has no difference in survival. So, I’m not sure that a doublet makes a lot of sense in the second- or third-line setting. It’s mostly monotherapy treatment or Taxol with Cyramza.

Johanna Bendell, MD: Ian, you don’t have access to ramucirumab in the UK.

Ian Chau, MD: We don’t have routine access to it because this is not funded by the government. So, for patients who have access to it, then like what Manish said, that would be our preferred standard to give the paclitaxel plus ramucirumab. And, of course, finding the appropriate clinical trial for them would be a very essential goal. There have been a lot of studies on immuno-oncology compounds, although those trials obviously open and close. So, off study, we do consider weekly paclitaxel on its own, which obviously, we have good results. That itself is a good treatment, but, if we do have access to ramucirumab, we do generally like to add on ramucirumab. I think when we think about the whole patient journey, it’s how much neuropathy does the patient have. And in the way I talked about earlier on, we try to avert oxaliplatin for that reason. But, equally, I think how I interpret both RAINBOW and REGARD is that ramucirumab have single activity. So, if people are running into neuropathy, I do actually have confidence to maybe take the paclitaxel off and run them on ramucirumab.

Johanna Bendell, MD: Let me pause you there. Can we refresh our audience on RAINBOW and REGARD and what we saw, why even in the UK if you can get it, you’re going to give a patient ramucirumab?

Ian Chau, MD: Those are 2 randomized controlled trials. REGARD is single-agent ramucirumab, placebo-controlled. So, therefore, the control group had best supportive care and no other active cancer treatment. It is a 350-patient trial done in multiple countries and what it showed is that single-agent ramucirumab had a significant survival advantage over placebo alone. And this is actually the first randomized controlled trial that shows an antibody against VEGF to have a survival advantage. Because, remember, all the data with bevacizumab are in conjunction with either chemotherapy or interferon or whatever they were using in the tumor types.

And, also, we do know that the safety profile for single-agent ramucirumab is extremely favorable. Certainly, when we were doing the study, we don’t know who’s on placebo, who’s on drug. And, now, that the data are out, we can see that compared to placebo, in fact, the side effects are almost the same. I think the main difference probably is hypertension, and hypertension is managed quite adequately by antihypertensive medications.

Almost in parallel, although perhaps slightly later, the RAINBOW study was conducted, again in many countries. Of course in many countries, giving chemotherapy is a standard of care. So, in that study, the chemotherapy backbone is weekly paclitaxel, and then the experimental arm had the addition of ramucirumab, again placebo controlled. Again, this is actually a bigger study, over 600 patients recruited in the study and, again, show a significant survival advantage. Now, if you look across the board, you actually go from having a best standard of care in that setting with only a median survival of about 3.6 months, and now almost triple the survival when you add paclitaxel plus ramucirumab to over nine months. So, therefore, I think if one has access to it, I would say it is a valuable treatment to have. As I said, if one runs into either neuropathy or really problematic neutropenia, then maybe stopping paclitaxel for a while and with monotherapy ramucirumab is also an option.

Johanna Bendell, MD: It’s really interesting. One of the reasons that bevacizumab, in the AVAGAST study, which was a first-line bevacizumab study, came into controversy was because it was done across the world. And we talked a little bit earlier about that whether there some sort of biologic and probably multifactorial, but probably underlying biologic difference between the Asian and the rest-of-the-world populations. Because in AVAGAST we did not see any benefit to bevacizumab added to chemotherapy. What did we see for RAINBOW in the Asian populations?

Ian Chau, MD: I think, first of all, what we saw in AVAGAST is that, as you said, the Asians really don’t seem to derive any benefit from bevacizumab either in progression-free survival or overall survival. Whereas, the Pan-Americans seem to have some benefits. Because if you only see no difference in overall survival but you do see a progression-free survival, you might say, well, maybe because the Asians are getting second-line, third-line, fourth-line treatment, and, therefore, you just diluted out the overall survival.

As I said, in the AVAGAST, and Manish, please correct me if I’m wrong, the PFS was also not in favor in the Asian population for bevacizumab. For RAINBOW, again, yes, it is a sub-group analysis looking at the Japanese versus the western populations. But, there they actually showed a progression-free survival advantage for ramucirumab in the Japanese, as well as in the western population. Although, for the overall survival, yes, they were seen in the western population and not so in the Japanese. But, I think there we know that 75% of the Japanese population actually had post-progression therapy in that study. So, three-quarters of them were getting third-line, fourth-line, fifth-line, whereas the western population had only about one-third of the patients getting subsequent lines therapy. I think there, really perhaps the lack of overall survival benefit in the Japanese is probably the cause of subsequent-line therapy. But, the biological effect is there. So, I think, therefore, ramucirumab is well-accepted in the Japanese oncological community.

Transcript Edited for Clarity
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Transcript:

Johanna Bendell, MD:
Let’s talk about recurrence. We’ve gotten through first-line therapy and now the cancer has come back. What do you guys use for second-line therapy, and why?

Manish Shah, MD: The data with Taxol/ramucirumab is level-1 evidence that it’s superior to Taxol alone. So, that’s a standard that we use. There are also data that a doublet using a platinum and S1 versus S1 alone, in the second-line setting, actually has no difference in survival. So, I’m not sure that a doublet makes a lot of sense in the second- or third-line setting. It’s mostly monotherapy treatment or Taxol with Cyramza.

Johanna Bendell, MD: Ian, you don’t have access to ramucirumab in the UK.

Ian Chau, MD: We don’t have routine access to it because this is not funded by the government. So, for patients who have access to it, then like what Manish said, that would be our preferred standard to give the paclitaxel plus ramucirumab. And, of course, finding the appropriate clinical trial for them would be a very essential goal. There have been a lot of studies on immuno-oncology compounds, although those trials obviously open and close. So, off study, we do consider weekly paclitaxel on its own, which obviously, we have good results. That itself is a good treatment, but, if we do have access to ramucirumab, we do generally like to add on ramucirumab. I think when we think about the whole patient journey, it’s how much neuropathy does the patient have. And in the way I talked about earlier on, we try to avert oxaliplatin for that reason. But, equally, I think how I interpret both RAINBOW and REGARD is that ramucirumab have single activity. So, if people are running into neuropathy, I do actually have confidence to maybe take the paclitaxel off and run them on ramucirumab.

Johanna Bendell, MD: Let me pause you there. Can we refresh our audience on RAINBOW and REGARD and what we saw, why even in the UK if you can get it, you’re going to give a patient ramucirumab?

Ian Chau, MD: Those are 2 randomized controlled trials. REGARD is single-agent ramucirumab, placebo-controlled. So, therefore, the control group had best supportive care and no other active cancer treatment. It is a 350-patient trial done in multiple countries and what it showed is that single-agent ramucirumab had a significant survival advantage over placebo alone. And this is actually the first randomized controlled trial that shows an antibody against VEGF to have a survival advantage. Because, remember, all the data with bevacizumab are in conjunction with either chemotherapy or interferon or whatever they were using in the tumor types.

And, also, we do know that the safety profile for single-agent ramucirumab is extremely favorable. Certainly, when we were doing the study, we don’t know who’s on placebo, who’s on drug. And, now, that the data are out, we can see that compared to placebo, in fact, the side effects are almost the same. I think the main difference probably is hypertension, and hypertension is managed quite adequately by antihypertensive medications.

Almost in parallel, although perhaps slightly later, the RAINBOW study was conducted, again in many countries. Of course in many countries, giving chemotherapy is a standard of care. So, in that study, the chemotherapy backbone is weekly paclitaxel, and then the experimental arm had the addition of ramucirumab, again placebo controlled. Again, this is actually a bigger study, over 600 patients recruited in the study and, again, show a significant survival advantage. Now, if you look across the board, you actually go from having a best standard of care in that setting with only a median survival of about 3.6 months, and now almost triple the survival when you add paclitaxel plus ramucirumab to over nine months. So, therefore, I think if one has access to it, I would say it is a valuable treatment to have. As I said, if one runs into either neuropathy or really problematic neutropenia, then maybe stopping paclitaxel for a while and with monotherapy ramucirumab is also an option.

Johanna Bendell, MD: It’s really interesting. One of the reasons that bevacizumab, in the AVAGAST study, which was a first-line bevacizumab study, came into controversy was because it was done across the world. And we talked a little bit earlier about that whether there some sort of biologic and probably multifactorial, but probably underlying biologic difference between the Asian and the rest-of-the-world populations. Because in AVAGAST we did not see any benefit to bevacizumab added to chemotherapy. What did we see for RAINBOW in the Asian populations?

Ian Chau, MD: I think, first of all, what we saw in AVAGAST is that, as you said, the Asians really don’t seem to derive any benefit from bevacizumab either in progression-free survival or overall survival. Whereas, the Pan-Americans seem to have some benefits. Because if you only see no difference in overall survival but you do see a progression-free survival, you might say, well, maybe because the Asians are getting second-line, third-line, fourth-line treatment, and, therefore, you just diluted out the overall survival.

As I said, in the AVAGAST, and Manish, please correct me if I’m wrong, the PFS was also not in favor in the Asian population for bevacizumab. For RAINBOW, again, yes, it is a sub-group analysis looking at the Japanese versus the western populations. But, there they actually showed a progression-free survival advantage for ramucirumab in the Japanese, as well as in the western population. Although, for the overall survival, yes, they were seen in the western population and not so in the Japanese. But, I think there we know that 75% of the Japanese population actually had post-progression therapy in that study. So, three-quarters of them were getting third-line, fourth-line, fifth-line, whereas the western population had only about one-third of the patients getting subsequent lines therapy. I think there, really perhaps the lack of overall survival benefit in the Japanese is probably the cause of subsequent-line therapy. But, the biological effect is there. So, I think, therefore, ramucirumab is well-accepted in the Japanese oncological community.

Transcript Edited for Clarity
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