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Impact of MM-398 on Sequencing Decisions in Pancreatic Cancer

Insights From:Thomas A. Abrams, MD, Harvard Medical School; Johanna Bendell, MD, Sarah Cannon Research Institute; George P. Kim, MD, 21st Century Oncology; Caio Rocha Lima, MD, Gibbs Cancer Center and Research Institute; Philip A. Philip, MD, PhD, FRCP, Wayne State University
Published: Tuesday, Mar 15, 2016


Transcript:

Johanna Bendell, MD:
Tom, let’s say you have a patient. Let’s say you’re at a place where there’s no clinical trials, and that’s a very sad place to be, but there’s no clinical trials available to you. Does the approval of MM-398 make you think more like what Caio was talking about, when we’re thinking about sequencing? Does that change what you would do in the first-line? Would you do things differently? How would you do that?

Thomas A. Abrams MD: I think that it can’t help but color the way you think about treatment, knowing that you have an approved regimen in the second-line that closely models drugs that you might think about in the first-line. So, if you have a patient that you really have clinical equipoise on whether you’re going to give them FOLFIRINOX or gemcitabine/nab-paclitaxel, based on the fact that there’s an approved effective regimen in the second-line, I think that does steer you closer to gemcitabine/nab-paclitaxel and away from FOLFIRINOX.

I don’t think you can do that for every patient. Some patients who you feel that they really would benefit from a regimen such as FOLFIRINOX, where you might get a really explosive response and maybe downstage them, or something to that degree, I think is still on the table for them. But I think that this will ultimately impact the use of gemcitabine and nab-paclitaxel in a positive way. Based on that, I think I’ll be using more of gemcitabine/nab-paclitaxel in the first-line, knowing that there’s going to be an accepted doublet in the second-line.

Johanna Bendell, MD: Yeah. Philip, what do you think? Where’s your treatment continuum now? Now, we’re talking. It used to be colon cancer, now it’s pancreas cancer.

Philip A. Philip, MD, PhD, FRCP: I agree with Tom. Again, I’m a believer in more moving to the tolerable doublets and moving along. One thing I have to make a comment on is FOLFOX. We use a lot of FOLFOX second-line, and also it’s used in the community, FOLFOX with XELOX. But, if you look at the data with FOLFOX, really it’s not consistent. In fact, the OFF study, which was the initial trial which we interpreted as FOLFOX, was positive. But if you look at it, the curves are really very close. And then the Canadians presented a study in 2014 at ASCO where they showed, in fact, FOLFOX itself was worse than 5-FU leucovorin in the control arm. And, we had also experienced in SWOG, we had a study in the second-line, and I can tell you that the performance of FOLFOX wasn’t really that good.

So, we have a study which shows benefit, although, again, it’s a modest benefit. So, we have to think of that as being, for the time being, the best evidence we have and to use that, and the best sequence will be to use gemcitabine/nab-paclitaxel in the frontline and then move on to a regimen, such as the one using NAPOLI-1 study, which makes sense. And also, you’re removing that risk of exacerbation of neuropathy, because you’re not going to use a drug that will affect that. So I think it’s a nice way of sequencing which makes sense, based on evidence. The key thing is based on evidence. And, in fact, in the NAPOLI-1 trial, there were some patients who had received irinotecan in the frontline as a combination with gemcitabine. Look at the breakdown of the prior therapies.

Johanna Bendell, MD: So would you ever then use FOLFOX third-line?

Philip A. Philip, MD, PhD, FRCP: That opens up the discussion of, what’s the philosophy of using second-, third-line treatments? I sit with academic oncologists, GI oncologists, from Dana Farber, MD Anderson, Sarah Cannon. I always hear about, in advisory boards, when people say more than 70% of my patients go on a second-line. Well, wait a second, 70% of patients who come to MD Anderson or my institution get second-line. That’s not the real world. If you look at the clinical trials, even like MPACT, even in those trials, which were patients who went on first-line clinical trials—so, they’re different than the average patient—50% is the maximum you see going on second-line treatment. If you go to the real world, community patients, it will be less than 20%, 30% that can go on second-line treatments. It tells you something. The majority of those patients are very still compromised by the disease. But, the fact is that in the second-line treatment and third-line, probably, the chance of cytoreduction and getting a good response in those patients and a good PFS is really very small. So what becomes important? Quality of life. So, do I want to use FOLFOX in the third-line? Yeah, I can use it maybe in an outpatient who’s doing very well because of biology, but it will not be my recommendation.

George P. Kim, MD: I want to brighten things up a little bit. First- and second-line in the community can be high, it can be 60%, 70%, and I think maybe they’re switching regimens a little early. But in the clinical trials it’s typically 40% to 50%. But you can get more people going for second-line.

Philip A. Philip, MD, PhD, FRCP: Well, I meant the patients who are able to take combination treatment. Sometimes people give first-line, second-line, and then third-line they give the patient capecitabine single agent, just to say, I’m treating the patient. Now, that’s placebo for me.

George P. Kim, MD: Yeah, I agree with you. We don’t even know if the drug is going to work.

Philip A. Philip, MD, PhD, FRCP: I hope you don’t do that. You’re in the community.

Johanna Bendell, MD: Wow.

George P. Kim, MD: But the other thing about the placement of Onivyde is the lack of neuropathy and the lack of thrombocytopenia, which you see with the FOLFIRINOX and the nab-paclitaxel/gemcitabine regimen. So, you kind of have a period of rest for the patient in the settings of neuropathy. So, that’s good.

Johanna Bendell, MD: So does it influence you now? Are you using more gemcitabine/nab because you’ve got the MM-398?

George P. Kim, MD: I will be, yeah, absolutely. I think it’s a very thoughtful sequence. Again, I agree with what Dr. Philip said in regards to oxaliplatin. The data is just kind of soft right now. That’s going to be challenging to use.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

Johanna Bendell, MD:
Tom, let’s say you have a patient. Let’s say you’re at a place where there’s no clinical trials, and that’s a very sad place to be, but there’s no clinical trials available to you. Does the approval of MM-398 make you think more like what Caio was talking about, when we’re thinking about sequencing? Does that change what you would do in the first-line? Would you do things differently? How would you do that?

Thomas A. Abrams MD: I think that it can’t help but color the way you think about treatment, knowing that you have an approved regimen in the second-line that closely models drugs that you might think about in the first-line. So, if you have a patient that you really have clinical equipoise on whether you’re going to give them FOLFIRINOX or gemcitabine/nab-paclitaxel, based on the fact that there’s an approved effective regimen in the second-line, I think that does steer you closer to gemcitabine/nab-paclitaxel and away from FOLFIRINOX.

I don’t think you can do that for every patient. Some patients who you feel that they really would benefit from a regimen such as FOLFIRINOX, where you might get a really explosive response and maybe downstage them, or something to that degree, I think is still on the table for them. But I think that this will ultimately impact the use of gemcitabine and nab-paclitaxel in a positive way. Based on that, I think I’ll be using more of gemcitabine/nab-paclitaxel in the first-line, knowing that there’s going to be an accepted doublet in the second-line.

Johanna Bendell, MD: Yeah. Philip, what do you think? Where’s your treatment continuum now? Now, we’re talking. It used to be colon cancer, now it’s pancreas cancer.

Philip A. Philip, MD, PhD, FRCP: I agree with Tom. Again, I’m a believer in more moving to the tolerable doublets and moving along. One thing I have to make a comment on is FOLFOX. We use a lot of FOLFOX second-line, and also it’s used in the community, FOLFOX with XELOX. But, if you look at the data with FOLFOX, really it’s not consistent. In fact, the OFF study, which was the initial trial which we interpreted as FOLFOX, was positive. But if you look at it, the curves are really very close. And then the Canadians presented a study in 2014 at ASCO where they showed, in fact, FOLFOX itself was worse than 5-FU leucovorin in the control arm. And, we had also experienced in SWOG, we had a study in the second-line, and I can tell you that the performance of FOLFOX wasn’t really that good.

So, we have a study which shows benefit, although, again, it’s a modest benefit. So, we have to think of that as being, for the time being, the best evidence we have and to use that, and the best sequence will be to use gemcitabine/nab-paclitaxel in the frontline and then move on to a regimen, such as the one using NAPOLI-1 study, which makes sense. And also, you’re removing that risk of exacerbation of neuropathy, because you’re not going to use a drug that will affect that. So I think it’s a nice way of sequencing which makes sense, based on evidence. The key thing is based on evidence. And, in fact, in the NAPOLI-1 trial, there were some patients who had received irinotecan in the frontline as a combination with gemcitabine. Look at the breakdown of the prior therapies.

Johanna Bendell, MD: So would you ever then use FOLFOX third-line?

Philip A. Philip, MD, PhD, FRCP: That opens up the discussion of, what’s the philosophy of using second-, third-line treatments? I sit with academic oncologists, GI oncologists, from Dana Farber, MD Anderson, Sarah Cannon. I always hear about, in advisory boards, when people say more than 70% of my patients go on a second-line. Well, wait a second, 70% of patients who come to MD Anderson or my institution get second-line. That’s not the real world. If you look at the clinical trials, even like MPACT, even in those trials, which were patients who went on first-line clinical trials—so, they’re different than the average patient—50% is the maximum you see going on second-line treatment. If you go to the real world, community patients, it will be less than 20%, 30% that can go on second-line treatments. It tells you something. The majority of those patients are very still compromised by the disease. But, the fact is that in the second-line treatment and third-line, probably, the chance of cytoreduction and getting a good response in those patients and a good PFS is really very small. So what becomes important? Quality of life. So, do I want to use FOLFOX in the third-line? Yeah, I can use it maybe in an outpatient who’s doing very well because of biology, but it will not be my recommendation.

George P. Kim, MD: I want to brighten things up a little bit. First- and second-line in the community can be high, it can be 60%, 70%, and I think maybe they’re switching regimens a little early. But in the clinical trials it’s typically 40% to 50%. But you can get more people going for second-line.

Philip A. Philip, MD, PhD, FRCP: Well, I meant the patients who are able to take combination treatment. Sometimes people give first-line, second-line, and then third-line they give the patient capecitabine single agent, just to say, I’m treating the patient. Now, that’s placebo for me.

George P. Kim, MD: Yeah, I agree with you. We don’t even know if the drug is going to work.

Philip A. Philip, MD, PhD, FRCP: I hope you don’t do that. You’re in the community.

Johanna Bendell, MD: Wow.

George P. Kim, MD: But the other thing about the placement of Onivyde is the lack of neuropathy and the lack of thrombocytopenia, which you see with the FOLFIRINOX and the nab-paclitaxel/gemcitabine regimen. So, you kind of have a period of rest for the patient in the settings of neuropathy. So, that’s good.

Johanna Bendell, MD: So does it influence you now? Are you using more gemcitabine/nab because you’ve got the MM-398?

George P. Kim, MD: I will be, yeah, absolutely. I think it’s a very thoughtful sequence. Again, I agree with what Dr. Philip said in regards to oxaliplatin. The data is just kind of soft right now. That’s going to be challenging to use.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Oncology Briefings™: Integrating Novel Targeted Treatment Strategies to Advance Pancreatic Cancer CareNov 30, 20181.0
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