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Second-line Treatment for Recurrent or Progressive GEC

Panelists: Johanna C. Bendell, MD, Sarah Cannon Research Institute; Peter C. Enzinger, MD, Dana-Farber Cancer Institute; Yelena Y. Janjigian, MD, Memorial Sloan Kettering Cancer Center; Kohei Shitara, MD, National Cancer Center Hospital East; Eric Van Cutsem, MD, PhD, University of Leuven
Published: Wednesday, Aug 15, 2018



Transcript: 

Johanna C. Bendell, MD: Now, Yelena, let’s say in New York, I got my 6 months of treatment, and I’m done. I want to go down to Florida. I don’t want any more chemotherapy. So, do you bring in treatment breaks? Do you change treatment intensity for your first-line patients?

Yelena Y. Janjigian, MD: There are no data to support our recommendation in gastric, but extrapolating from other solid tumors, it’s colon cancer and lung. Gastric cancer is a very aggressive disease, and if you turn your back on it, it’s going to grow. So, that’s what I tell my patients. We generally scale back, and I think the important message to get across there is that this is a marathon, not a sprint. You have to plan ahead for toxicities and dose reduction early on, as needed for symptom management, but don’t stop. If you discontinue chemotherapy, patients tend to then decompensate, and then there’s less of a chance to get them to second-line therapy. We tend to continue 5-FU. If the patient’s really fit and is able to swallow pills, capecitabine is also an option, because that gives them more freedom from the 5-FU infuser—but those are the recommendations.

Johanna C. Bendell, MD: They even crush capecitabine and put it in a tube if you need to—a feeding tube, right?

Peter C. Enzinger, MD: It’s not indicated, but you could.

Johanna C. Bendell, MD: You could, yes. So, Yelena, Eric alluded to this HER2 study in second line, which showed that we probably shouldn’t continue trastuzumab beyond progression in the first line into the second line. We were talking earlier, and you made some comments about HER2 status changing as the patient’s disease evolved. Tell us a little bit about that data, but also, if the HER2 status changes, would anything else change in a patient who has progressed on first-line therapy? Would you ever consider to rebiopsy the patient to look for alternate mutations or translocations?

Yelena Y. Janjigian, MD: You brought up a great point earlier. In trastuzumab therapy and HER2-directed therapy in gastric, it is different than it is in breast. I have a big interest in HER2 and do a lot of research in that field, but I hear it over and over again from colleagues and collaborators: “Well, HER2 in gastric is just not as important. It’s not a driver; you’re barking up the wrong tree.” It’s just as important as in breast cancer. What I would argue is that in gastric cancer, because of this heterogeneity that Eric brought up earlier—these patients with very focal HER2 expression—that you have to get 8 biopsies to find it; those tumors are really not all that HER2 driven. In those patients, the benefit from HER2-directed therapy is minimal. They are the patients who are bringing down the survival curves on these studies.

What we find is in gastric patients with low level of amplification due to this focal activity, and co-curing alterations such as RAS, PI3-kinase—which happens in gastric, as it is a GI-2 tumor, a lot more often than in breast—those patients are not truly HER2 driven. Moreover, if the tumor has focal amplifications, but it’s not a high enough level where you can’t even pick it up on NGS (next-generation sequencing), those patients behave as if they were not even HER2-positive.

So, gastric, that’s a caveat in first-line setting, and what we found on our rebiopsy studies in second-line settings is that what you see is a mechanism of primary resistance that just becomes amplified once the tumor becomes trastuzumab-refractory. Those studies that continue the patients beyond progression, I think, applied mostly to the general population. But if you have a patient where the tumor is truly HER2 driven, and you saw high-level amplification that persisted at the time of progression, I would rethink that and perhaps either seek out a HER2-specific study for that patient or consider using trastuzumab beyond progression, perhaps with a different backbone.

Johanna C. Bendell, MD: What is your second-line treatment option? What would you do?

Yelena Y. Janjigian, MD: Right now, the majority of our patients outside of a trial go on a combination of paclitaxel plus ramucirumab with a VEGFR-2 inhibitor. That’s the standard regimen, and it’s well tolerated. Most of our patients do not get taxanes in the first-line setting, and I think it’s very important that NCCN tighten their guidelines. Remember, a majority of the folks out there are not gastric cancer experts, so they need a go-to place. If you make it too open and put every New England Journal of Medicine paper on the NCCN Guidelines, then practitioners don’t know which paper to follow. Clearly stating that epirubicin is out, FOLFOX is in, is really important. So, the majority of our patients then in second line get paclitaxel plus ramucirumab.

Transcript Edited for Clarity 

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Transcript: 

Johanna C. Bendell, MD: Now, Yelena, let’s say in New York, I got my 6 months of treatment, and I’m done. I want to go down to Florida. I don’t want any more chemotherapy. So, do you bring in treatment breaks? Do you change treatment intensity for your first-line patients?

Yelena Y. Janjigian, MD: There are no data to support our recommendation in gastric, but extrapolating from other solid tumors, it’s colon cancer and lung. Gastric cancer is a very aggressive disease, and if you turn your back on it, it’s going to grow. So, that’s what I tell my patients. We generally scale back, and I think the important message to get across there is that this is a marathon, not a sprint. You have to plan ahead for toxicities and dose reduction early on, as needed for symptom management, but don’t stop. If you discontinue chemotherapy, patients tend to then decompensate, and then there’s less of a chance to get them to second-line therapy. We tend to continue 5-FU. If the patient’s really fit and is able to swallow pills, capecitabine is also an option, because that gives them more freedom from the 5-FU infuser—but those are the recommendations.

Johanna C. Bendell, MD: They even crush capecitabine and put it in a tube if you need to—a feeding tube, right?

Peter C. Enzinger, MD: It’s not indicated, but you could.

Johanna C. Bendell, MD: You could, yes. So, Yelena, Eric alluded to this HER2 study in second line, which showed that we probably shouldn’t continue trastuzumab beyond progression in the first line into the second line. We were talking earlier, and you made some comments about HER2 status changing as the patient’s disease evolved. Tell us a little bit about that data, but also, if the HER2 status changes, would anything else change in a patient who has progressed on first-line therapy? Would you ever consider to rebiopsy the patient to look for alternate mutations or translocations?

Yelena Y. Janjigian, MD: You brought up a great point earlier. In trastuzumab therapy and HER2-directed therapy in gastric, it is different than it is in breast. I have a big interest in HER2 and do a lot of research in that field, but I hear it over and over again from colleagues and collaborators: “Well, HER2 in gastric is just not as important. It’s not a driver; you’re barking up the wrong tree.” It’s just as important as in breast cancer. What I would argue is that in gastric cancer, because of this heterogeneity that Eric brought up earlier—these patients with very focal HER2 expression—that you have to get 8 biopsies to find it; those tumors are really not all that HER2 driven. In those patients, the benefit from HER2-directed therapy is minimal. They are the patients who are bringing down the survival curves on these studies.

What we find is in gastric patients with low level of amplification due to this focal activity, and co-curing alterations such as RAS, PI3-kinase—which happens in gastric, as it is a GI-2 tumor, a lot more often than in breast—those patients are not truly HER2 driven. Moreover, if the tumor has focal amplifications, but it’s not a high enough level where you can’t even pick it up on NGS (next-generation sequencing), those patients behave as if they were not even HER2-positive.

So, gastric, that’s a caveat in first-line setting, and what we found on our rebiopsy studies in second-line settings is that what you see is a mechanism of primary resistance that just becomes amplified once the tumor becomes trastuzumab-refractory. Those studies that continue the patients beyond progression, I think, applied mostly to the general population. But if you have a patient where the tumor is truly HER2 driven, and you saw high-level amplification that persisted at the time of progression, I would rethink that and perhaps either seek out a HER2-specific study for that patient or consider using trastuzumab beyond progression, perhaps with a different backbone.

Johanna C. Bendell, MD: What is your second-line treatment option? What would you do?

Yelena Y. Janjigian, MD: Right now, the majority of our patients outside of a trial go on a combination of paclitaxel plus ramucirumab with a VEGFR-2 inhibitor. That’s the standard regimen, and it’s well tolerated. Most of our patients do not get taxanes in the first-line setting, and I think it’s very important that NCCN tighten their guidelines. Remember, a majority of the folks out there are not gastric cancer experts, so they need a go-to place. If you make it too open and put every New England Journal of Medicine paper on the NCCN Guidelines, then practitioners don’t know which paper to follow. Clearly stating that epirubicin is out, FOLFOX is in, is really important. So, the majority of our patients then in second line get paclitaxel plus ramucirumab.

Transcript Edited for Clarity 
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