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PEGPH20 in Advanced Pancreatic Cancer

Panelists: Johanna Bendell, MD, Sarah Cannon Research Institute; Eileen O’Reilly, MD, Memorial Sloan-Kettering Cancer Center; John Marshall, MD, Ruesch Cancer Center at the Lombardi Comprehensive Cancer Center; George Kim, MD, University of Florida Health Oncology; Caio Max S. Rocha Lima, MD, Gibbs Cancer Center
Published: Tuesday, Mar 28, 2017



Transcript:

Johanna Bendell, MD:
Now tell me, Caio, George keeps talking about the hyaluronidase data. He keeps calling it “PEGPH20.” What is he talking about?

Caio Max S. Rocha Lima, MD: He’s talking about using a brick to break concrete and trying to get chemotherapy to the tumor bed—I think that’s a good mimic. Hyaluronidase is an enzyme that breaks down hyaluronic acid, and it’s a component of the stroma in pancreatic cancer. The component is the concrete. And in preclinical animal models, in a combination with gemcitabine—that’s the first preclinical model done. It improves outcomes with the addition of the hyaluronidase to gemcitabine. This was a segue way into a phase I trial that showed promising results. This led to a randomized phase II trial, but the results are not as exciting as was felt in the beginning. But then, when they stratified the population based upon the immunohistochemistry expression of hyaluronic acid—2 plus or 3 plus—then there was really a widening of the survival, favoring the experimental arm with the addition of the PEGPH20 hyaluronidase to gemcitabine and nab-paclitaxel. And the randomized phase III trial is ongoing, and it is word-of-mouth that things are going in the right direction.

Johanna Bendell, MD: So, this is gemcitabine/nab-paclitaxel plus or minus the hyaluronidase.

Caio Max S. Rocha Lima, MD: One more issue here, and I think this is very important, is about quality control and watching the trial that the patients are going through. I remember being part of the randomized phase II trial when we got a call that the accrual was suspended. The Safety Monitoring Committee called it off because there was an excess of thromboembolic events. It’s already a phenomenon that is very prevalent in pancreatic cancer, but patients that are receiving the study drug had the higher incidence of thromboembolic events.

Initially, they used a low dose of low molecular weight heparin and enoxaparin at a fixed dose of 40 mg, and there was some improvement. There was a high incidence in the study arm and they actually had to go up 1 mg/kg per dose in order to really diminish the risk of thromboembolic events. So, if this agent makes it to our shelf, it’s going to be with a tag of enoxaparin. And this is interesting because there has been a trial done in the past with a low molecular weight heparin that did not improve survival. But it did decrease the incidence of thromboembolic events. That actually may impact that phenomenon in pancreatic cancer, in addition to improving outcomes.

John Marshall, MD: I’ve kind of always looked for an excuse to give it. I hate doing it to patients because it’s not fun, but this might give us our excuse.

Johanna Bendell, MD: For once, I can even get somebody to provide it, right?

John Marshall, MD: Yes.

George Kim, MD: They’re already doing their insulin injections and now you’re going to throw this in. But in the trials that were done with heparin-like compounds, unfortunately, the endpoints were clot, not survival. So, we’ll have to see what impact this really has; it will be interesting. But it’s what we said earlier: if this trial is positive, then it’s going to set the table for sequencing for us. It can simplify things, and hopefully, it’s a 9-month progression-free survival. So, that should translate into maybe a 15- or 14-month overall survival. That’s a whopper. That’s really good.

Eileen O’Reilly, MD: The other exciting thing, if this holds off, is that this is for a biomarker-selected population, right? And it may be the first truly validated biomarker that we have in this disease. So, we’ll see. I think, again, there’s an optimism that this may hold up. It’s exciting.

George Kim, MD: Optimism in pancreatic cancer?

Caio Max S. Rocha Lima, MD: Is there any other cancer where a stromal-targeted therapy is approved?

George Kim, MD: There are some breast subtypes that are stromal-associated.

Caio Max S. Rocha Lima, MD: I understand, but is there a target agent to the stroma? I think this is going to be the first.

Eileen O’Reilly, MD: Well, there are hedgehog inhibitors in basal cell carcinomas and medulloblastomas.

George Kim, MD: But it does simplify things. We’re hitting the stroma and we’re hitting the cancer cells simultaneously. And that is a nice theme to have, right? A tumor is very complex. But if we can hit it with 3 drugs that have a very similar mechanism, that’s very interesting.

Transcript Edited for Clarity

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Transcript:

Johanna Bendell, MD:
Now tell me, Caio, George keeps talking about the hyaluronidase data. He keeps calling it “PEGPH20.” What is he talking about?

Caio Max S. Rocha Lima, MD: He’s talking about using a brick to break concrete and trying to get chemotherapy to the tumor bed—I think that’s a good mimic. Hyaluronidase is an enzyme that breaks down hyaluronic acid, and it’s a component of the stroma in pancreatic cancer. The component is the concrete. And in preclinical animal models, in a combination with gemcitabine—that’s the first preclinical model done. It improves outcomes with the addition of the hyaluronidase to gemcitabine. This was a segue way into a phase I trial that showed promising results. This led to a randomized phase II trial, but the results are not as exciting as was felt in the beginning. But then, when they stratified the population based upon the immunohistochemistry expression of hyaluronic acid—2 plus or 3 plus—then there was really a widening of the survival, favoring the experimental arm with the addition of the PEGPH20 hyaluronidase to gemcitabine and nab-paclitaxel. And the randomized phase III trial is ongoing, and it is word-of-mouth that things are going in the right direction.

Johanna Bendell, MD: So, this is gemcitabine/nab-paclitaxel plus or minus the hyaluronidase.

Caio Max S. Rocha Lima, MD: One more issue here, and I think this is very important, is about quality control and watching the trial that the patients are going through. I remember being part of the randomized phase II trial when we got a call that the accrual was suspended. The Safety Monitoring Committee called it off because there was an excess of thromboembolic events. It’s already a phenomenon that is very prevalent in pancreatic cancer, but patients that are receiving the study drug had the higher incidence of thromboembolic events.

Initially, they used a low dose of low molecular weight heparin and enoxaparin at a fixed dose of 40 mg, and there was some improvement. There was a high incidence in the study arm and they actually had to go up 1 mg/kg per dose in order to really diminish the risk of thromboembolic events. So, if this agent makes it to our shelf, it’s going to be with a tag of enoxaparin. And this is interesting because there has been a trial done in the past with a low molecular weight heparin that did not improve survival. But it did decrease the incidence of thromboembolic events. That actually may impact that phenomenon in pancreatic cancer, in addition to improving outcomes.

John Marshall, MD: I’ve kind of always looked for an excuse to give it. I hate doing it to patients because it’s not fun, but this might give us our excuse.

Johanna Bendell, MD: For once, I can even get somebody to provide it, right?

John Marshall, MD: Yes.

George Kim, MD: They’re already doing their insulin injections and now you’re going to throw this in. But in the trials that were done with heparin-like compounds, unfortunately, the endpoints were clot, not survival. So, we’ll have to see what impact this really has; it will be interesting. But it’s what we said earlier: if this trial is positive, then it’s going to set the table for sequencing for us. It can simplify things, and hopefully, it’s a 9-month progression-free survival. So, that should translate into maybe a 15- or 14-month overall survival. That’s a whopper. That’s really good.

Eileen O’Reilly, MD: The other exciting thing, if this holds off, is that this is for a biomarker-selected population, right? And it may be the first truly validated biomarker that we have in this disease. So, we’ll see. I think, again, there’s an optimism that this may hold up. It’s exciting.

George Kim, MD: Optimism in pancreatic cancer?

Caio Max S. Rocha Lima, MD: Is there any other cancer where a stromal-targeted therapy is approved?

George Kim, MD: There are some breast subtypes that are stromal-associated.

Caio Max S. Rocha Lima, MD: I understand, but is there a target agent to the stroma? I think this is going to be the first.

Eileen O’Reilly, MD: Well, there are hedgehog inhibitors in basal cell carcinomas and medulloblastomas.

George Kim, MD: But it does simplify things. We’re hitting the stroma and we’re hitting the cancer cells simultaneously. And that is a nice theme to have, right? A tumor is very complex. But if we can hit it with 3 drugs that have a very similar mechanism, that’s very interesting.

Transcript Edited for Clarity
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Online CME Activities
TitleExpiration DateCME Credits
Oncology Briefings™: Integrating Novel Targeted Treatment Strategies to Advance Pancreatic Cancer CareNov 30, 20181.0
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