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Ongoing Research in Gastric Cancer; Antiangiogenic Therapy Upfront and Immunotherapy

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: Tuesday, Jan 03, 2017


Transcript:

Johanna Bendell, MD:
So, ramucirumab seems to help consistently across all populations alone and with chemotherapy. Manish, you were very involved in the bevacizumab development. Ramucirumab, it only makes sense now to look at the first-line treatment of patients with ramucirumab plus chemotherapy. Can you give us your thoughts on where is that going and about this dosing I hear about ramucirumab?

Manish Shah, MD: The dosing is a very interesting issue. This was actually first thought of in the ToGA study with another antibody, and the feeling was that in the ToGA study, which is a first-line gastric study with or without Herceptin (trastuzumab), about a third of patients seem to have a very low trough level, meaning that they were underdosed compared to a breast counterpart. So, there was a follow-up study to look at higher dosing of trastuzumab in gastric study. That was the HELOISE study, and that, unfortunately, was negative, but it actually established the correct dose of trastuzumab. Similarly, in the REGARD and RAINBOW studies, there was an idea that the patients who had the lowest quartile of ramucirumab levels at the end of their cycle, those patients did the worst in terms of survival.

So, with very sophisticated modeling that was done, the ramucirumab dose was modified to, instead of a single dose every other week, week 1 and week 3, it’s actually 2 out of 3 weeks giving ramucirumab in the RAINFALL study. And, with that modeling at a higher dose, the idea is that more patients will actually be above that threshold where they may actually achieve benefit. And, there’s also a second study, a second-line study of Taxol with 2 different dose levels of ramucirumab, which will also be supportive evidence of that.

Johanna Bendell, MD: So, we might even get better data.

Manish Shah, MD: We might get better data, yes.

Johanna Bendell, MD: If we can get everybody’s serum levels high enough. That would be very exciting. And, I think, we’re seeing now this consistent effect of antiangiogenic agents being useful for patients with gastroesophageal cancers. Yelena, there are other agents that we’ve seen now, as well.

Yelena Janjigian, MD: Sure, of course. Probably the biggest interest right now is immuno-oncology and the use of checkpoint inhibitors. Gastric cancer, by exposure to a lot of insults in the mucosa, H. pylori, chronic inflammation, is prone to quite a bit of DNA damage. And so, some of these tumors are hypermutated, and, if you look at the mutational burden of the tumors that have been historically studied and targeted with checkpoint inhibitors, such as melanoma and subtypes of lung cancer, gastric cancer is actually very close to the mutational burden on that spectrum. The clinical data support that there are subtypes of gastric cancer that profoundly benefit from PD-1 and PD-L1 inhibition. And, particularly, there are a number of drugs on the market. And, in subtypes of gastric cancer, single-agent PD-1 inhibitors such as nivolumab or pembrolizumab are likely sufficient. And, that subtype is likely MSI subtype or EBV subtype. The data are still uncertain about whether or not PD-L1 immunohistochemistry is an important biomarker. In short, it probably is part of the puzzle of enrichment for the study, but it is a biomarker that is fraught with difficulty because of the methodology and the preparation and the different antibodies that are used. And, certainly, certain PD-L1–negative patients also respond.

In the majority of our patients, the benefit is very small and I would say that in an unselected patient population, 8% to 10% of the tumors respond to single-agent PD-1 inhibitors. It appears that dual inhibition with PD-1 and anti-CTLA4 blockade—so anti-CTLA4, sort of you take the brakes off the immune system and with the PD-1 antibodies, you uncloak the tumor and let the immune system see the tumor. And so, in that sense, dual inhibition has a higher response rate. The CheckMate-032 study looked at this in a nivolumab 1 mg/kg, ipilimumab 3 mg/kg combination; the response rate was 26%. But, as you may expect, it comes with a cost of toxicity. So, grade 3/4 toxicities or potential autoimmune hepatitis and autoimmune processes, which most of them are reversible. There wasn’t any colitis or other dangerous problems like that. Nonetheless, a 46% toxicity rate, which, actually, if you look at first-line 5-FU/platinum, is very similar.

Manish Shah, MD: It compares favorably.

Yelena Janjigian, MD: Right! It’s just different toxicities. Instead of febrile neutropenia and neuropathy, these folks get potentially life-threatening immune processes. In second- and third-line settings, immuno-oncology has a strong presence, at least in clinical trial development. And next-generation PD-L1 inhibitors are out there, and now we’re trying to move us into the first-line setting, and there are a number of first-line studies looking at this. Again, not prime time yet, but hopefully coming shortly.

Johanna Bendell, MD: Yes. So, it’s certainly exciting, this whole concept of immunotherapy where you get your own immune system to attack the tumor. We’ve seen these responses for patients with gastric, and even esophageal cancers, where the people who respond have, and this is what I think impresses everybody, the most durable responses that can even go on for years, and they do very well with them. A huge, clinical trial development area with combinations, and even, I think, they’re looking in the adjuvant setting now to see if we can improve survival. I’m actually working on this trial with Ian, and he keeps stealing all the slots from me. Going back to the antiangiogenic combinations with immunotherapy, can you tell us a little bit about the clinical trial we have of ramucirumab plus a PD-1 inhibitor?

Ian Chau, MD: I would never steal any slots from you. You’re just too slow. There was an initial phase I with an expanded cohort of combining ramucirumab with pembrolizumab because there is preclinical evidence to say that if you give a tumor some low-dose antiangiogenic therapy, you actually change it from an immunosuppressive environment to be a much more immuno-supportive environment. There are also synergistic effects seen in preclinical models of adding PD-L1 with VEGFR2 antibodies. So, based on that, they have conducted a phase I study combining the two. The safety results were actually reported at ASCO, and certainly the two drugs by themselves are very, very safe, with hardly any grade 3/4 toxicity or even grade 2 toxicities. But, they have done it in different cohorts.

For gastric cancer, they’ve actually done it in two dose-scheduled cohorts, initially, because they did what Manish said, with the higher PK cohort, so day 1 and day 8 ramucirumab in conjunction with pembrolizumab given every three weeks. And, then, they have a lower-dose ramucirumab cohort to try to take into account the preclinical evidence of lower-dose antiangiogenic antibody with pembrolizumab. So, for those 2 cohorts, there are 40 patients recruited. We’ve got some safety data, as I said, from ASCO, and hopefully the efficacy data will be presented early next year.

They now actually opened new cohorts in gastric cancer in people who have chemo-naïve metastatic gastric cancer. These are, in a way, doing what some other companies are doing with dual checkpoint inhibition. So, they are giving that to patients who are naïve to cytotoxic chemotherapy and you give them the combination. But, I think, probably, Yelena, then Manish, and you can probably echo that. You do need to select your patients carefully to whom you want to give immuno-oncology compounds because I don’t think they’re really suitable for everyone, and it’s not really just about the biomarker, as you say. You really have to look at the patient in front of you, the physical condition, and decide whether this is someone in whom you can wait for I-O compounds to work. And I don’t know whether you want to comment a bit on that, as well.

Yelena Janjigian, MD: Absolutely. The time to response for these patients can be six, 12 weeks. So, in the patient who is symptomatic, presenting with obstructive symptoms or peritoneal carcinomatosis, it’s probably not an ideal option. But, the future is the combination therapies. In fact, we’re doing a trial for the combination of trastuzumab with PD-1 inhibitor, and, hopefully, as we build on the complex biology of gastric cancer, the responses and the time to response for some of these immuno-oncology drugs will improve.

Transcript Edited for Clarity
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Transcript:

Johanna Bendell, MD:
So, ramucirumab seems to help consistently across all populations alone and with chemotherapy. Manish, you were very involved in the bevacizumab development. Ramucirumab, it only makes sense now to look at the first-line treatment of patients with ramucirumab plus chemotherapy. Can you give us your thoughts on where is that going and about this dosing I hear about ramucirumab?

Manish Shah, MD: The dosing is a very interesting issue. This was actually first thought of in the ToGA study with another antibody, and the feeling was that in the ToGA study, which is a first-line gastric study with or without Herceptin (trastuzumab), about a third of patients seem to have a very low trough level, meaning that they were underdosed compared to a breast counterpart. So, there was a follow-up study to look at higher dosing of trastuzumab in gastric study. That was the HELOISE study, and that, unfortunately, was negative, but it actually established the correct dose of trastuzumab. Similarly, in the REGARD and RAINBOW studies, there was an idea that the patients who had the lowest quartile of ramucirumab levels at the end of their cycle, those patients did the worst in terms of survival.

So, with very sophisticated modeling that was done, the ramucirumab dose was modified to, instead of a single dose every other week, week 1 and week 3, it’s actually 2 out of 3 weeks giving ramucirumab in the RAINFALL study. And, with that modeling at a higher dose, the idea is that more patients will actually be above that threshold where they may actually achieve benefit. And, there’s also a second study, a second-line study of Taxol with 2 different dose levels of ramucirumab, which will also be supportive evidence of that.

Johanna Bendell, MD: So, we might even get better data.

Manish Shah, MD: We might get better data, yes.

Johanna Bendell, MD: If we can get everybody’s serum levels high enough. That would be very exciting. And, I think, we’re seeing now this consistent effect of antiangiogenic agents being useful for patients with gastroesophageal cancers. Yelena, there are other agents that we’ve seen now, as well.

Yelena Janjigian, MD: Sure, of course. Probably the biggest interest right now is immuno-oncology and the use of checkpoint inhibitors. Gastric cancer, by exposure to a lot of insults in the mucosa, H. pylori, chronic inflammation, is prone to quite a bit of DNA damage. And so, some of these tumors are hypermutated, and, if you look at the mutational burden of the tumors that have been historically studied and targeted with checkpoint inhibitors, such as melanoma and subtypes of lung cancer, gastric cancer is actually very close to the mutational burden on that spectrum. The clinical data support that there are subtypes of gastric cancer that profoundly benefit from PD-1 and PD-L1 inhibition. And, particularly, there are a number of drugs on the market. And, in subtypes of gastric cancer, single-agent PD-1 inhibitors such as nivolumab or pembrolizumab are likely sufficient. And, that subtype is likely MSI subtype or EBV subtype. The data are still uncertain about whether or not PD-L1 immunohistochemistry is an important biomarker. In short, it probably is part of the puzzle of enrichment for the study, but it is a biomarker that is fraught with difficulty because of the methodology and the preparation and the different antibodies that are used. And, certainly, certain PD-L1–negative patients also respond.

In the majority of our patients, the benefit is very small and I would say that in an unselected patient population, 8% to 10% of the tumors respond to single-agent PD-1 inhibitors. It appears that dual inhibition with PD-1 and anti-CTLA4 blockade—so anti-CTLA4, sort of you take the brakes off the immune system and with the PD-1 antibodies, you uncloak the tumor and let the immune system see the tumor. And so, in that sense, dual inhibition has a higher response rate. The CheckMate-032 study looked at this in a nivolumab 1 mg/kg, ipilimumab 3 mg/kg combination; the response rate was 26%. But, as you may expect, it comes with a cost of toxicity. So, grade 3/4 toxicities or potential autoimmune hepatitis and autoimmune processes, which most of them are reversible. There wasn’t any colitis or other dangerous problems like that. Nonetheless, a 46% toxicity rate, which, actually, if you look at first-line 5-FU/platinum, is very similar.

Manish Shah, MD: It compares favorably.

Yelena Janjigian, MD: Right! It’s just different toxicities. Instead of febrile neutropenia and neuropathy, these folks get potentially life-threatening immune processes. In second- and third-line settings, immuno-oncology has a strong presence, at least in clinical trial development. And next-generation PD-L1 inhibitors are out there, and now we’re trying to move us into the first-line setting, and there are a number of first-line studies looking at this. Again, not prime time yet, but hopefully coming shortly.

Johanna Bendell, MD: Yes. So, it’s certainly exciting, this whole concept of immunotherapy where you get your own immune system to attack the tumor. We’ve seen these responses for patients with gastric, and even esophageal cancers, where the people who respond have, and this is what I think impresses everybody, the most durable responses that can even go on for years, and they do very well with them. A huge, clinical trial development area with combinations, and even, I think, they’re looking in the adjuvant setting now to see if we can improve survival. I’m actually working on this trial with Ian, and he keeps stealing all the slots from me. Going back to the antiangiogenic combinations with immunotherapy, can you tell us a little bit about the clinical trial we have of ramucirumab plus a PD-1 inhibitor?

Ian Chau, MD: I would never steal any slots from you. You’re just too slow. There was an initial phase I with an expanded cohort of combining ramucirumab with pembrolizumab because there is preclinical evidence to say that if you give a tumor some low-dose antiangiogenic therapy, you actually change it from an immunosuppressive environment to be a much more immuno-supportive environment. There are also synergistic effects seen in preclinical models of adding PD-L1 with VEGFR2 antibodies. So, based on that, they have conducted a phase I study combining the two. The safety results were actually reported at ASCO, and certainly the two drugs by themselves are very, very safe, with hardly any grade 3/4 toxicity or even grade 2 toxicities. But, they have done it in different cohorts.

For gastric cancer, they’ve actually done it in two dose-scheduled cohorts, initially, because they did what Manish said, with the higher PK cohort, so day 1 and day 8 ramucirumab in conjunction with pembrolizumab given every three weeks. And, then, they have a lower-dose ramucirumab cohort to try to take into account the preclinical evidence of lower-dose antiangiogenic antibody with pembrolizumab. So, for those 2 cohorts, there are 40 patients recruited. We’ve got some safety data, as I said, from ASCO, and hopefully the efficacy data will be presented early next year.

They now actually opened new cohorts in gastric cancer in people who have chemo-naïve metastatic gastric cancer. These are, in a way, doing what some other companies are doing with dual checkpoint inhibition. So, they are giving that to patients who are naïve to cytotoxic chemotherapy and you give them the combination. But, I think, probably, Yelena, then Manish, and you can probably echo that. You do need to select your patients carefully to whom you want to give immuno-oncology compounds because I don’t think they’re really suitable for everyone, and it’s not really just about the biomarker, as you say. You really have to look at the patient in front of you, the physical condition, and decide whether this is someone in whom you can wait for I-O compounds to work. And I don’t know whether you want to comment a bit on that, as well.

Yelena Janjigian, MD: Absolutely. The time to response for these patients can be six, 12 weeks. So, in the patient who is symptomatic, presenting with obstructive symptoms or peritoneal carcinomatosis, it’s probably not an ideal option. But, the future is the combination therapies. In fact, we’re doing a trial for the combination of trastuzumab with PD-1 inhibitor, and, hopefully, as we build on the complex biology of gastric cancer, the responses and the time to response for some of these immuno-oncology drugs will improve.

Transcript Edited for Clarity
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