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Pancreatic Cancer: Emerging Agents and Combinations

Panelists: John L. Marshall, MD, Georgetown University; George Kim, MD, 21st Century Oncology; Kabir Mody, MD, Mayo Clinic Cancer Center; Eileen M. O
Published: Thursday, Sep 13, 2018



Transcript: 

John L. Marshall, MD: We are at ASCO. It’s all about new things and new progress. We talked about some of the high-level data that are going forward there. Eileen, talk a little bit about where the new medicines are, what’s on the next wave; some IL-10—what do we do with that?

Eileen M. O’Reilly, MD: Just to emphasize the point of immunotherapy: It’s not that we think there isn’t a role here. I think we just have to learn where it fits and, again, select the patients. A couple of very interesting strategies are combining immune agents and studying them prospectively in clinical trials—combining immune agents with chemotherapy. So, an example of that is the pegylated IL-10, which has shown some interesting data with FOLFOX in a phase I setting, showing safety and a potential signal, and that’s been translated into a randomized phase III comparing FOLFOX, plus FOLFOX plus pegylated IL-10 in previously treated pancreatic cancer. That’s accruing well, and we’ll look forward to seeing data early this year, and there’s some nice immune data that support the notion that this could be meaningful.

John L. Marshall, MD: There are a lot of clinical trials going on in this space—frontline, second-line—and a lot of new medicines being brought up. Of course, that’s been the tradition, and we’ve had a lot of failures, so fingers crossed there.

John L. Marshall, MD: Tanios, some other studies that you’re looking out for?

Tanios S. Bekaii-Saab, MD: A couple of interesting studies that are ongoing in the first-line space include CanStem111P, essentially a study looking at an agent called napabucasin (BBI-608), which is a stem cell, or stemness, inhibitor that at least in preclinical study has shown to resensitize tumor cells by holding off the stem-like cells to the effects of chemotherapy and certainly enhance the kill from chemotherapy. But in the phase Ib2 study, about 66 patients essentially showed a response rate of 55%, and a couple of CRs; quite meaningful with a PFS note of 7 months—actually, survival in a select patient population close to a year now, a little bit more than a year. So meaningful, although, again, a small study, but that led essentially to the phase III study with gemcitabine/nab-paclitaxel plus/minus napabucasin—about 1100 plus patients. But it also has some stopping roles along the way; accruing very well. The other study is with nab-paclitaxel and gemcitabine, and an agent called PEGPH20, which targets human hyaluronidase—stromal targeting.

John L. Marshall, MD: I thought that study was negative with FOLFIRINOX.

Tanios S. Bekaii-Saab, MD: Yes, so there were 2 studies. There was a phase II randomized study that was recently published in the Journal of Clinical Oncology with gemcitabine/nab-paclitaxel plus/minus PEGPH20. The study initially didn’t reach its endpoints and, with more exploratory secondary points, was somewhat positive, although the survival didn’t seem too much affected by the addition of PEGPH20.
Then Ramesh Ramanathan presented his data at this past ASCO GI with FOLFIRINOX plus/minus PEGPH20. You had to really look at those curves multiple times to make sure that you’re seeing right, and they were flipped. The PEGPH20 plus FOLFIRINOX had a survival of 7 months. I haven’t seen that in quite a while.

John L. Marshall, MD: Anybody have any idea why? A theory?

Eileen M. O’Reilly, MD: I think there was discussion about the cytotoxic backbone; less systemic therapy was delivered. It wasn’t a biomarker-selected population, so we have to learn.

John L. Marshall, MD: Seven months.

Eileen M. O’Reilly, MD: I know. That’s a concern.

Tanios S. Bekaii-Saab, MD: Seven months is detrimental, I think I would argue. But I think that goes back to the argument that you have to be careful about how you handle the microenvironment. Because it’s both a friend and a foe, and you want to make sure that it doesn’t end up killing anyone.

John L. Marshall, MD: We have the gemcitabine/nab-paclitaxel study open at our site. So I saw those curves, and we thought to ourselves, and we discussed as a team: Should we maintain that trial, based on your logic? And we did. In the end, we decided to maintain that. I have a patient on the experimental arm right now. Well, it’s blinded, so I don’t know.

Eileen M. O’Reilly, MD: Plus, the Data and Safety Monitoring Board did their job and were very thorough and considering.

John L. Marshall, MD: Well, this will be a very interesting readout on whether that’s positive.

George P. Kim, MD: That’s a great point about the safety. They’re more than halfway through their 570-patient trial. There have not been any real concerns about lack of efficacy with the backbone of nab-paclitaxel/gemcitabine. So yes, I agree with Tanios. That was very concerning, that 7-month. But I think a lot of it can be attributed to the FOLFIRINOX and the management and the need for low-molecular-weight heparin while giving treatment—all those other issues. I think it’s still an important trial.
The phase II that was presented—they’re small numbers—but let’s see what this does. The PFS was 9 months, so the survival should be even longer, so let’s see what happens.

Tanios S. Bekaii-Saab, MD: Although we don’t clearly understand whether hyaluronan is prognostic or not, so we have to be careful about interpreting, once you start going down the line of less and less.

John L. Marshall, MD: But it’s worth continuing the trial, you’d say?

Tanios S. Bekaii-Saab, MD: I think, as Eileen said, you can’t argue with a DSMB (Data and Safety Monitoring Board) that’s essentially looking at the data in an unblinded fashion and making decisions about safety and efficacy. So, what we could only guess right now is that at least there’s no significant detriment that is observed with a combination of the 2 drugs plus the PEGPH20, similar to what was seen here. I mean 7-month, literally cutting the survival by half, you can’t miss that. You’re not going to miss that even earlier on in the study.

John L. Marshall, MD: Ninety percent to 95% of our patients with pancreatic cancer have a RAS mutation thought to be undruggable. And one of the most pleasant things I experienced during this meeting is looking at drugs that might just target RAS. We have a dedicated taskforce, the NCI and a public/private partnership looking at this. So, they’re starting to see this bubble up. You see this as maybe a way forward?

Eileen M. O’Reilly, MD: I do. I think there’s real optimism that this nut can be cracked in pancreatic cancer, and obviously it’ll be a major step when it happens. You know there are some SHIP (SH2-containing inositol 5-phosphatase) inhibitors now in the clinic for the cysteine residues that look promising for patients with lung cancer. It’s a small subset of people with that mutation in pancreatic cancer. But nonetheless, I’m optimistic that we can ultimately address this problem.

Transcript Edited for Clarity 

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Transcript: 

John L. Marshall, MD: We are at ASCO. It’s all about new things and new progress. We talked about some of the high-level data that are going forward there. Eileen, talk a little bit about where the new medicines are, what’s on the next wave; some IL-10—what do we do with that?

Eileen M. O’Reilly, MD: Just to emphasize the point of immunotherapy: It’s not that we think there isn’t a role here. I think we just have to learn where it fits and, again, select the patients. A couple of very interesting strategies are combining immune agents and studying them prospectively in clinical trials—combining immune agents with chemotherapy. So, an example of that is the pegylated IL-10, which has shown some interesting data with FOLFOX in a phase I setting, showing safety and a potential signal, and that’s been translated into a randomized phase III comparing FOLFOX, plus FOLFOX plus pegylated IL-10 in previously treated pancreatic cancer. That’s accruing well, and we’ll look forward to seeing data early this year, and there’s some nice immune data that support the notion that this could be meaningful.

John L. Marshall, MD: There are a lot of clinical trials going on in this space—frontline, second-line—and a lot of new medicines being brought up. Of course, that’s been the tradition, and we’ve had a lot of failures, so fingers crossed there.

John L. Marshall, MD: Tanios, some other studies that you’re looking out for?

Tanios S. Bekaii-Saab, MD: A couple of interesting studies that are ongoing in the first-line space include CanStem111P, essentially a study looking at an agent called napabucasin (BBI-608), which is a stem cell, or stemness, inhibitor that at least in preclinical study has shown to resensitize tumor cells by holding off the stem-like cells to the effects of chemotherapy and certainly enhance the kill from chemotherapy. But in the phase Ib2 study, about 66 patients essentially showed a response rate of 55%, and a couple of CRs; quite meaningful with a PFS note of 7 months—actually, survival in a select patient population close to a year now, a little bit more than a year. So meaningful, although, again, a small study, but that led essentially to the phase III study with gemcitabine/nab-paclitaxel plus/minus napabucasin—about 1100 plus patients. But it also has some stopping roles along the way; accruing very well. The other study is with nab-paclitaxel and gemcitabine, and an agent called PEGPH20, which targets human hyaluronidase—stromal targeting.

John L. Marshall, MD: I thought that study was negative with FOLFIRINOX.

Tanios S. Bekaii-Saab, MD: Yes, so there were 2 studies. There was a phase II randomized study that was recently published in the Journal of Clinical Oncology with gemcitabine/nab-paclitaxel plus/minus PEGPH20. The study initially didn’t reach its endpoints and, with more exploratory secondary points, was somewhat positive, although the survival didn’t seem too much affected by the addition of PEGPH20.
Then Ramesh Ramanathan presented his data at this past ASCO GI with FOLFIRINOX plus/minus PEGPH20. You had to really look at those curves multiple times to make sure that you’re seeing right, and they were flipped. The PEGPH20 plus FOLFIRINOX had a survival of 7 months. I haven’t seen that in quite a while.

John L. Marshall, MD: Anybody have any idea why? A theory?

Eileen M. O’Reilly, MD: I think there was discussion about the cytotoxic backbone; less systemic therapy was delivered. It wasn’t a biomarker-selected population, so we have to learn.

John L. Marshall, MD: Seven months.

Eileen M. O’Reilly, MD: I know. That’s a concern.

Tanios S. Bekaii-Saab, MD: Seven months is detrimental, I think I would argue. But I think that goes back to the argument that you have to be careful about how you handle the microenvironment. Because it’s both a friend and a foe, and you want to make sure that it doesn’t end up killing anyone.

John L. Marshall, MD: We have the gemcitabine/nab-paclitaxel study open at our site. So I saw those curves, and we thought to ourselves, and we discussed as a team: Should we maintain that trial, based on your logic? And we did. In the end, we decided to maintain that. I have a patient on the experimental arm right now. Well, it’s blinded, so I don’t know.

Eileen M. O’Reilly, MD: Plus, the Data and Safety Monitoring Board did their job and were very thorough and considering.

John L. Marshall, MD: Well, this will be a very interesting readout on whether that’s positive.

George P. Kim, MD: That’s a great point about the safety. They’re more than halfway through their 570-patient trial. There have not been any real concerns about lack of efficacy with the backbone of nab-paclitaxel/gemcitabine. So yes, I agree with Tanios. That was very concerning, that 7-month. But I think a lot of it can be attributed to the FOLFIRINOX and the management and the need for low-molecular-weight heparin while giving treatment—all those other issues. I think it’s still an important trial.
The phase II that was presented—they’re small numbers—but let’s see what this does. The PFS was 9 months, so the survival should be even longer, so let’s see what happens.

Tanios S. Bekaii-Saab, MD: Although we don’t clearly understand whether hyaluronan is prognostic or not, so we have to be careful about interpreting, once you start going down the line of less and less.

John L. Marshall, MD: But it’s worth continuing the trial, you’d say?

Tanios S. Bekaii-Saab, MD: I think, as Eileen said, you can’t argue with a DSMB (Data and Safety Monitoring Board) that’s essentially looking at the data in an unblinded fashion and making decisions about safety and efficacy. So, what we could only guess right now is that at least there’s no significant detriment that is observed with a combination of the 2 drugs plus the PEGPH20, similar to what was seen here. I mean 7-month, literally cutting the survival by half, you can’t miss that. You’re not going to miss that even earlier on in the study.

John L. Marshall, MD: Ninety percent to 95% of our patients with pancreatic cancer have a RAS mutation thought to be undruggable. And one of the most pleasant things I experienced during this meeting is looking at drugs that might just target RAS. We have a dedicated taskforce, the NCI and a public/private partnership looking at this. So, they’re starting to see this bubble up. You see this as maybe a way forward?

Eileen M. O’Reilly, MD: I do. I think there’s real optimism that this nut can be cracked in pancreatic cancer, and obviously it’ll be a major step when it happens. You know there are some SHIP (SH2-containing inositol 5-phosphatase) inhibitors now in the clinic for the cysteine residues that look promising for patients with lung cancer. It’s a small subset of people with that mutation in pancreatic cancer. But nonetheless, I’m optimistic that we can ultimately address this problem.

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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