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HER2+ Gastric 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, Jan 05, 2017


Transcript:

Johanna Bendell, MD:
There is lots of development going on within the gastric field. Antiangiogenic agents, we saw this study from China about apatinib.

Manish Shah, MD: Yes. I was going to come back to that. We mentioned the AVAGAST study, which was a first-line study. RAINBOW and REGARD were second-line studies, and there was obviously a benefit. Also, the proportion of patients from Asia were limited in those studies. But, then, we have this study of apatinib which is a tyrosine kinase inhibitor that inhibits VEGFR2, the same receptor that is inhibited by ramucirumab and the results were positive in the third-line setting from an Asian country, China. I think Asia versus non-Asia antiangiogenic therapy is very complicated, but beyond that, I think this is actually a proven target in gastroesophageal cancers. Antiangiogenic therapies, they do work, sometimes as monotherapy, often in combination. And, I think, looking out for the RAINFALL study and that result in the next year or so will be very exciting!

Johanna Bendell, MD: Like you’re alluding to, I think we’re seeing more and more gastric patients, particularly in the west, that are getting to third-line and potentially fourth-line therapies. I think there is the importance of getting all the agents in there. If you use a fluoropyrimidine and a platinum, then a taxane, you’re using your antiangiogenic agents, and then you also have irinotecan to use. So, definitely options for these patients.

Manish Shah, MD: Yes, and possibly a PD-1 inhibitor.

Johanna Bendell, MD: Exactly.

Yelena Janjigian, MD: For patients with small-volume disease, I think antiangiogenic therapy alone may be the answer to give them an opportunity to breathe without chemotherapy toxicity. For second-line data, progression-free survival for single-agent docetaxel compared to single-agent ramucirumab, the historic data are pretty much right on point. This way you avoid alopecia, neuropathy, neutropenia, and others. We do scan our patients and monitor them closely, and so with small-volume progression that’s asymptomatic, it’s small liver lesion or lung lesion, you will have time to rescue them from any symptoms; single-agent antiangiogenics, such as ramucirumab, are a great option.

Johanna Bendell, MD: Yelena, you alluded a little bit earlier to looking at trastuzumab plus a PD-1 inhibitor with your clinical trial. So, a question I get a lot, and I’m sure you guys get this a lot: I have an HER2-positive patient, they’ve progressed on FOLFOX plus trastuzumab first-line. Do I move them to ramucirumab plus paclitaxel second-line or do I continue the trastuzumab with chemotherapy or without?

Yelena Janjigian, MD: It’s a great question. At the time of trastuzumab progression, actually, the data suggest from repeat biopsies that up to 20% of tumors lose HER2 expression in gastric cancer, which is a pretty substantial proportion of patients. So, I think it’s important to understand the tumor biology at the time of progression and it’s increasingly important to biopsy these tumors to understand what you’re targeting. Because if the target is not there, certainly trastuzumab will do nothing and it would be that much more important to switch to ramucirumab or another experimental therapy. Let’s make the problem more complicated. Let’s say the tumor is still HER2-positive. What are the data to support trastuzumab beyond progression?

And, I would say, before the GATSBY study came out, the T-DM1 data came out. I was more in favor of continuing trastuzumab beyond progression, again, extrapolating from the breast cancer data. But, the T-DM1 data suggest that in second-line, T-DM1 was not any better than single-agent paclitaxel. And T-DM1, as you know, is a trastuzumab bound to another DNA damaging agent, a cross-linker. So, this is suggesting that perhaps in second line it would be okay to switch from trastuzumab to ramucirumab. This is generally decided on a case by case basis on the degree of response to trastuzumab in the first line, how long the patients stay on it, and how convinced I am that the tumor biology is dependent on HER2 signaling.

Ian Chau, MD: And a recent paper from REGARD had showed there’s no differential effect of ramucirumab whether it’s HER2-positive or HER2-negative. So, I think at least there is some reassurance that using a ramucirumab-based treatment is actually a reasonable thing in the HER2-positive gastric cancer beyond trastuzumab.

Transcript Edited for Clarity
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Transcript:

Johanna Bendell, MD:
There is lots of development going on within the gastric field. Antiangiogenic agents, we saw this study from China about apatinib.

Manish Shah, MD: Yes. I was going to come back to that. We mentioned the AVAGAST study, which was a first-line study. RAINBOW and REGARD were second-line studies, and there was obviously a benefit. Also, the proportion of patients from Asia were limited in those studies. But, then, we have this study of apatinib which is a tyrosine kinase inhibitor that inhibits VEGFR2, the same receptor that is inhibited by ramucirumab and the results were positive in the third-line setting from an Asian country, China. I think Asia versus non-Asia antiangiogenic therapy is very complicated, but beyond that, I think this is actually a proven target in gastroesophageal cancers. Antiangiogenic therapies, they do work, sometimes as monotherapy, often in combination. And, I think, looking out for the RAINFALL study and that result in the next year or so will be very exciting!

Johanna Bendell, MD: Like you’re alluding to, I think we’re seeing more and more gastric patients, particularly in the west, that are getting to third-line and potentially fourth-line therapies. I think there is the importance of getting all the agents in there. If you use a fluoropyrimidine and a platinum, then a taxane, you’re using your antiangiogenic agents, and then you also have irinotecan to use. So, definitely options for these patients.

Manish Shah, MD: Yes, and possibly a PD-1 inhibitor.

Johanna Bendell, MD: Exactly.

Yelena Janjigian, MD: For patients with small-volume disease, I think antiangiogenic therapy alone may be the answer to give them an opportunity to breathe without chemotherapy toxicity. For second-line data, progression-free survival for single-agent docetaxel compared to single-agent ramucirumab, the historic data are pretty much right on point. This way you avoid alopecia, neuropathy, neutropenia, and others. We do scan our patients and monitor them closely, and so with small-volume progression that’s asymptomatic, it’s small liver lesion or lung lesion, you will have time to rescue them from any symptoms; single-agent antiangiogenics, such as ramucirumab, are a great option.

Johanna Bendell, MD: Yelena, you alluded a little bit earlier to looking at trastuzumab plus a PD-1 inhibitor with your clinical trial. So, a question I get a lot, and I’m sure you guys get this a lot: I have an HER2-positive patient, they’ve progressed on FOLFOX plus trastuzumab first-line. Do I move them to ramucirumab plus paclitaxel second-line or do I continue the trastuzumab with chemotherapy or without?

Yelena Janjigian, MD: It’s a great question. At the time of trastuzumab progression, actually, the data suggest from repeat biopsies that up to 20% of tumors lose HER2 expression in gastric cancer, which is a pretty substantial proportion of patients. So, I think it’s important to understand the tumor biology at the time of progression and it’s increasingly important to biopsy these tumors to understand what you’re targeting. Because if the target is not there, certainly trastuzumab will do nothing and it would be that much more important to switch to ramucirumab or another experimental therapy. Let’s make the problem more complicated. Let’s say the tumor is still HER2-positive. What are the data to support trastuzumab beyond progression?

And, I would say, before the GATSBY study came out, the T-DM1 data came out. I was more in favor of continuing trastuzumab beyond progression, again, extrapolating from the breast cancer data. But, the T-DM1 data suggest that in second-line, T-DM1 was not any better than single-agent paclitaxel. And T-DM1, as you know, is a trastuzumab bound to another DNA damaging agent, a cross-linker. So, this is suggesting that perhaps in second line it would be okay to switch from trastuzumab to ramucirumab. This is generally decided on a case by case basis on the degree of response to trastuzumab in the first line, how long the patients stay on it, and how convinced I am that the tumor biology is dependent on HER2 signaling.

Ian Chau, MD: And a recent paper from REGARD had showed there’s no differential effect of ramucirumab whether it’s HER2-positive or HER2-negative. So, I think at least there is some reassurance that using a ramucirumab-based treatment is actually a reasonable thing in the HER2-positive gastric cancer beyond trastuzumab.

Transcript Edited for Clarity
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