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Checkpoint Inhibitors: Emerging Role in GE Cancer

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: Friday, Aug 31, 2018



Transcript: 

Johanna C. Bendell, MD: Well, then let’s get happy and start looking towards the future in new and emerging things that are happening. Yelena, you have had quite a splash with combination data with nivolumab and ipilimumab for patients with gastric cancer.

Yelena Y. Janjigian, MD: Right. CheckMate-032 was started as a basket study where they picked the winners for different solid tumors in gastric cancer; showed a lot of activity. This paper will be published in the Journal of Clinical Oncology this month. We looked at higher doses, lower doses of ipilimumab in combination with nivolumab. In gastric, similar to melanoma and small-cell lung cancer, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg is the preferred regimen.

The grade 3/4 toxicity rate is quite high with that regimen, and ipilimumab really drives this toxicity profile. Patients generally develop liver function test abnormalities, diarrhea, toxicities that are reversible with high-dose steroids; but you really have to know what you’re observing and not minimize the side effects. That being said, in patients that are fit, combination therapies—and that’s sort of the lesson we learned in gastric cancer—2 drugs are usually better than 1, particularly for the immune checkpoint inhibitors. Although the ATTRACTION data, and the KEYNOTE data show that gastric cancer is a lukewarm tumor; it’s not a cold tumor, but it’s not a hot tumor. We have to make it more immunogenic with addition of CTLA-4, so, the hypothesis was that if you start earlier on while the patients are fitter, perhaps you can get them through more of the combination therapy. That’s the genesis behind the CheckMate-649 study, that’s actually looking at combination therapies in first-line metastatic gastric cancer and comparing it to chemotherapy.

Johanna C. Bendell, MD: You’re also doing other combinations as well, bringing the anti-angiogenesis drugs in combination with a checkpoint inhibitor. Why do we think that would work?

Yelena Y. Janjigian, MD: The idea is that, in gastric cancer, there is not a single pathognomonic driver because the epithelium has been exposed to so many insults over the patient’s years, and DNA damage. It’s not the one driver, one drug approach. To do combination therapies with immune checkpoint inhibitors, but also VEGFR-2 inhibitors, makes the tumor more immunogenic, brings in theoretically more T cells, and makes the immunotherapy work better. It’s all in hypothesis state. Some of the studies, although they looked promising to begin with, don’t look as good as we had hoped. But I think there is something there for the idea that we just need to try harder.

Johanna C. Bendell, MD: We’re seeing both pembrolizumab plus ramucirumab, as well as nivolumab plus ramucirumab. We’ve seen some readout of the pembrolizumab plus ramucirumab data. We’ll see what the nivolumab plus ramucirumab shows, to see if we have any differences there. Then, if immunotherapy helps for patients with advanced disease, why don’t we bring it into the adjuvant setting? We’ve seen this tactic across multiple different tumor types where immunotherapy works with success. So, Eric, tell us a little bit about KEYNOTE-585 for the treatment of locally advanced.

Eric Van Cutsem, MD, PhD: KEYNOTE-585 is a study where we start with the concept that perioperative chemotherapy is of benefit for patients. We have seen the FLOT data being presented last year. The FLOT first, is a doublet chemotherapy versus FOLFOX showing an improved outcome. In that concept, it’s 2 months of FLOT regimen. The concept now is to try to improve on that. There was this case study with perioperative chemotherapy plus or minus bevacizumab, which failed; it did not show any benefit. Now, of course, with the emerging data of checkpoint inhibitors in metastatic disease, it’s logical to look at this strategy, also of a combination of chemotherapy plus a checkpoint inhibitor, to try to improve the survival and to reduce recurrences; and that’s the basis of KEYNOTE-585.
For patients with locally advanced disease, patients are then randomized between 2 months of FLOT or PX (capecitabine/cisplatin); you can choose the doublet, followed by surgery, followed by 2 months of postoperative chemotherapy FLOT, with or without pembrolizumab in this study. To prove the outcome, there are big results on translation research to try to understand which subgroups of patients may benefit more in this situation, and that’s an important aspect.

Johanna C. Bendell, MD: Absolutely. And of course, nivolumab can’t be left out. So, Peter, we have CheckMate-577. Now the numbers are getting too close to each other.

Peter C. Enzinger, MD: It’s getting very complicated to remember all of these. But CheckMate-577 is the counterpart to this study in esophageal cancer. Really, the global standard right now is the CROSS regimen for preoperative treatment of esophageal cancer. What this study does is it basically says, “Okay, you get CROSS frontline, you get your usual surgery, and, as long as you’ve had an R0 resection and you have some residual disease, you can enroll in this particular study.” Basically, the idea is simply to give postoperative nivolumab, initially every 2 weeks, and then after a set period, it goes to once every 4 weeks for a total of 1 year. Again, the idea is to see if we can move the bar on survival in these patients. It’s a very simple idea; it’s moving along, and we’ll see how it goes.

Johanna C. Bendell, MD: Other new agents that we have, and emerging data coming from a study that you have done, Kohei. You can’t tell us very much about it, but it’s using TAS-102 for patients with gastric cancer?

Kohei Shitara, MD: Yes. TAS-102 is already an approved drug for colorectal cancer. We previously investigated this TAS-102 for heavily pretreated gastric cancer patients in a Japanese phase II trial, and it showed approximately 50% disease control, and median overall survival exceeded 8 months in third-line, or later-line treatment. That’s why a global study of TAS-102 was conducted to compare placebo plus best supportive care for heavily pretreated gastric cancer patients. Once the analysis was finished and the top-line data are out, which says it was positive or the pharmaceutical company released the results. I’m very happy about it. The details of the data will be presented in the upcoming scientific meeting, ESMO GI.

Johanna C. Bendell, MD: Yes, so we’re very excited. I tell you, there’s more and more data that are coming out now; big data at ESMO GI; so pleased stay tuned to see that positive data.

Transcript Edited for Clarity 

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Transcript: 

Johanna C. Bendell, MD: Well, then let’s get happy and start looking towards the future in new and emerging things that are happening. Yelena, you have had quite a splash with combination data with nivolumab and ipilimumab for patients with gastric cancer.

Yelena Y. Janjigian, MD: Right. CheckMate-032 was started as a basket study where they picked the winners for different solid tumors in gastric cancer; showed a lot of activity. This paper will be published in the Journal of Clinical Oncology this month. We looked at higher doses, lower doses of ipilimumab in combination with nivolumab. In gastric, similar to melanoma and small-cell lung cancer, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg is the preferred regimen.

The grade 3/4 toxicity rate is quite high with that regimen, and ipilimumab really drives this toxicity profile. Patients generally develop liver function test abnormalities, diarrhea, toxicities that are reversible with high-dose steroids; but you really have to know what you’re observing and not minimize the side effects. That being said, in patients that are fit, combination therapies—and that’s sort of the lesson we learned in gastric cancer—2 drugs are usually better than 1, particularly for the immune checkpoint inhibitors. Although the ATTRACTION data, and the KEYNOTE data show that gastric cancer is a lukewarm tumor; it’s not a cold tumor, but it’s not a hot tumor. We have to make it more immunogenic with addition of CTLA-4, so, the hypothesis was that if you start earlier on while the patients are fitter, perhaps you can get them through more of the combination therapy. That’s the genesis behind the CheckMate-649 study, that’s actually looking at combination therapies in first-line metastatic gastric cancer and comparing it to chemotherapy.

Johanna C. Bendell, MD: You’re also doing other combinations as well, bringing the anti-angiogenesis drugs in combination with a checkpoint inhibitor. Why do we think that would work?

Yelena Y. Janjigian, MD: The idea is that, in gastric cancer, there is not a single pathognomonic driver because the epithelium has been exposed to so many insults over the patient’s years, and DNA damage. It’s not the one driver, one drug approach. To do combination therapies with immune checkpoint inhibitors, but also VEGFR-2 inhibitors, makes the tumor more immunogenic, brings in theoretically more T cells, and makes the immunotherapy work better. It’s all in hypothesis state. Some of the studies, although they looked promising to begin with, don’t look as good as we had hoped. But I think there is something there for the idea that we just need to try harder.

Johanna C. Bendell, MD: We’re seeing both pembrolizumab plus ramucirumab, as well as nivolumab plus ramucirumab. We’ve seen some readout of the pembrolizumab plus ramucirumab data. We’ll see what the nivolumab plus ramucirumab shows, to see if we have any differences there. Then, if immunotherapy helps for patients with advanced disease, why don’t we bring it into the adjuvant setting? We’ve seen this tactic across multiple different tumor types where immunotherapy works with success. So, Eric, tell us a little bit about KEYNOTE-585 for the treatment of locally advanced.

Eric Van Cutsem, MD, PhD: KEYNOTE-585 is a study where we start with the concept that perioperative chemotherapy is of benefit for patients. We have seen the FLOT data being presented last year. The FLOT first, is a doublet chemotherapy versus FOLFOX showing an improved outcome. In that concept, it’s 2 months of FLOT regimen. The concept now is to try to improve on that. There was this case study with perioperative chemotherapy plus or minus bevacizumab, which failed; it did not show any benefit. Now, of course, with the emerging data of checkpoint inhibitors in metastatic disease, it’s logical to look at this strategy, also of a combination of chemotherapy plus a checkpoint inhibitor, to try to improve the survival and to reduce recurrences; and that’s the basis of KEYNOTE-585.
For patients with locally advanced disease, patients are then randomized between 2 months of FLOT or PX (capecitabine/cisplatin); you can choose the doublet, followed by surgery, followed by 2 months of postoperative chemotherapy FLOT, with or without pembrolizumab in this study. To prove the outcome, there are big results on translation research to try to understand which subgroups of patients may benefit more in this situation, and that’s an important aspect.

Johanna C. Bendell, MD: Absolutely. And of course, nivolumab can’t be left out. So, Peter, we have CheckMate-577. Now the numbers are getting too close to each other.

Peter C. Enzinger, MD: It’s getting very complicated to remember all of these. But CheckMate-577 is the counterpart to this study in esophageal cancer. Really, the global standard right now is the CROSS regimen for preoperative treatment of esophageal cancer. What this study does is it basically says, “Okay, you get CROSS frontline, you get your usual surgery, and, as long as you’ve had an R0 resection and you have some residual disease, you can enroll in this particular study.” Basically, the idea is simply to give postoperative nivolumab, initially every 2 weeks, and then after a set period, it goes to once every 4 weeks for a total of 1 year. Again, the idea is to see if we can move the bar on survival in these patients. It’s a very simple idea; it’s moving along, and we’ll see how it goes.

Johanna C. Bendell, MD: Other new agents that we have, and emerging data coming from a study that you have done, Kohei. You can’t tell us very much about it, but it’s using TAS-102 for patients with gastric cancer?

Kohei Shitara, MD: Yes. TAS-102 is already an approved drug for colorectal cancer. We previously investigated this TAS-102 for heavily pretreated gastric cancer patients in a Japanese phase II trial, and it showed approximately 50% disease control, and median overall survival exceeded 8 months in third-line, or later-line treatment. That’s why a global study of TAS-102 was conducted to compare placebo plus best supportive care for heavily pretreated gastric cancer patients. Once the analysis was finished and the top-line data are out, which says it was positive or the pharmaceutical company released the results. I’m very happy about it. The details of the data will be presented in the upcoming scientific meeting, ESMO GI.

Johanna C. Bendell, MD: Yes, so we’re very excited. I tell you, there’s more and more data that are coming out now; big data at ESMO GI; so pleased stay tuned to see that positive data.

Transcript Edited for Clarity 
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