Meet The Professors: Pancreatic Cancer Edition, 2016 - Video 4Second-line treatment of mPAC after first-line nab paclitaxel/gemcitabine
23:34 minutes.
TRANSCRIPTION:
DR SCHWARTZ: So this is a 74-year-old woman in previous good health who had a prior history of biliary pancreatitis, who actually underwent a surveillance colonoscopy and that evening developed abdominal pain, called her gastroenterologist, who said, “You better go to the emergency room.” They were concerned it was procedure related. Underwent a CT scan of the abdomen and, to everyone’s shock, had evidence of abdominal carcinomatosis with a large right ovarian mass, omental caking, ascites and either a pseudocyst of the pancreas or a pancreatic tail mass. DR LOVE: So what was the thinking in terms of what was going on and the diagnosis? DR SCHWARTZ: We got markers back very quickly at our hospital. And both the CA125 and CA 19-9 were elevated. We did a paracentesis and it demonstrated adenocarcinoma, favor pancreatic. And we also, because of this question of two malignancies, the patient underwent an EUS. And that pseudocyst did turn out to be a pancreatic body cancer. DR LOVE: So Tony, any thoughts about the presentation here? And I guess the other issue was the question of ovarian cancer? DR BEKAII-SAAB: Yes. That’s not an atypical presentation for tail of the pancreas, cancer involving tail of the pancreas, as these mostly drop freely into the abdomen, and they usually present with peritoneal carcinomatosis. And for females often would present with involvement of the ovaries, so unfortunately that is a common presentation of tail of the pancreas cancer. DR LOVE: So this also brings up the issue, obviously, of first-line therapy in metastatic disease. What was her premorbid condition, performance status, comorbidities? DR SCHWARTZ: So no comorbidities, good performance status even in the hospital. I mean, she came in because she was told to come in based on the CAT scan. So very fit. DR LOVE: So again, getting back to Tony, what would you be thinking about a 74-year-old otherwise healthy lady, Margaret? DR TEMPERO: Could I just ask a question? Mike, what was that episode of pancreatitis that she had? When did that occur? DR SCHWARTZ: More than 10 years prior. DR TEMPERO: More than 10 years. Did she have a prior CT scan at any point? DR SCHWARTZ: Not that we had available to us. DR TEMPERO: Because you wonder. It makes you wonder if there wasn’t something going on at that time, right? DR SCHWARTZ: Yes. DR LOVE: Have you seen cases where you saw something and then the patient was still alive 10 years later? DR TEMPERO: You can go back sometimes and see, really — you don’t know for sure that those are related. But you can go back years prior to diagnosis and identify things that may have been an early signal. DR LOVE: So Tony, what would you be thinking about in terms of treatment at this point? DR BEKAII-SAAB: So the treatment options for a patient who’s 74, relatively healthy, are really 2 options available to us, either a triplet regimen, FOLFIRINOX, or a doublet, gemcitabine and nab paclitaxel. My tendency has been to shy away from the triplet regimens and more think about a sequential approach and go with doublets, as they have less toxicity. And I think in terms of outcome, they end up predicting about the same outcome. So my preference for this patient would be just standard gemcitabine and nab paclitaxel as the first option. DR TEMPERO: We tend to use a bit more of FOLFIRINOX, actually. And it gets down to a discussion with the patient, considering what risks they’re willing to take, what the comorbidities are. So you end up making a decision together about what you’re going to do. DR LOVE: Could I just ask, and maybe start with Phil, when you use FOLFIRINOX, assuming you do, how do you modify it based on the original FOLFIRINOX? I’m curious how it plays out in your practice. DR BROOKS: I tend not to modify it if I’m starting it myself. And I have a pretty significant discussion. “Do you want a more toxic regimen for a little benefit? Do you want a secondary or third?” But I will say that I often have patients come back from major oncology centers and coming back with a suggestion for a modified regimen. And there are different modifications that I’ve heard. And then I do ask the question, once you’ve modified it, do we have data? And is it then superior to a doublet? Now that I’ve seen these recommendations, I’m beginning to say, “Okay. If the major cancer centers are doing that, maybe” — so I’ll often start out with the modifications. And if they tolerate it well, I’ll try to increase, but… DR LOVE: Mike, what do you do? DR SCHWARTZ: So I’m currently using the modified, which — DR LOVE: How do you modify it? DR SCHWARTZ: So we don’t give the 5-FU bolus. And we lower the irinotecan a little bit. DR GLYNN: So I try to really carefully preselect who’s going to get FOLFIRINOX and then try not to modify it. And then I might modify things depending on performance status, and if somebody’s got underlying liver disease, I might use FOLFOX as opposed to FOLFIRINOX. DR LOVE: Margaret, any strong feelings one way or the other about modification? DR TEMPERO: The only thing that is pretty universal — not entirely universal, but close to universal — is dropping the bolus, because that does seem to add a lot to the toxicity. There’s some very strong retrospective data from Memorial Sloan Kettering with across-the-board dose reduction. And their outcomes look as good or better than what was published. So it doesn’t make me nervous at all if somebody’s talking about modifying the regimen. Will there ever be a bake-off with the modified regimen versus the other? No. But there may be additional data about toxicity coming from other sorts of trials in which FOLFIRINOX is the control arm of the trial. DR BROOKS: So is your baseline just to take away the bolus? DR TEMPERO: It kind of depends on the patient. I have patients that I think perhaps at the outset I should dose reduce. And it’s an art form to decide when you do that. DR LOVE: Let’s hear a little bit about what actually happened with this patient. As you talked about the options, how did that strike her? And did she have any family with her? DR SCHWARTZ: Yes. So she had a very devoted husband who would go to the ends of the world to find the best treatment for her. And we can talk about it a little bit. And they wanted aggressive approach, so we did modified FOLFIRINOX. She had 7 cycles. There was evidence of response based on CA 19-9, her feeling better, but when we repeated the scan she had multiple sites of disease that were all responding except for the right ovarian mass. DR LOVE: So you were thinking maybe she might have had 2 primaries? DR SCHWARTZ: I still felt she had 1 primary, but it was a mixed response. DR LOVE: So what did you do, or what did she do at that point? DR SCHWARTZ: She did obtain some opinions. DR LOVE: That was the thing that fascinated me, because she then went to see Margaret. DR SCHWARTZ: And I don’t want to speak for you, but I remember your logic very clearly. DR LOVE: Maybe you can talk about what your response was when you evaluated her, Margaret. DR TEMPERO: When you see an ovarian, a drop met, these are sometimes considered to be a sanctuary site from chemotherapy. So the fact that that might be the site that’s growing did — DR LOVE: I’ve never heard that. You mean like a blood-brain barrier type thing? DR TEMPERO: Kind of a sanctuary. DR LOVE: Really? DR TEMPERO: Yes. DR LOVE: Wow! How did this woman look to you, incidentally? DR TEMPERO: She looked great. DR LOVE: After the FOLFIRINOX she still looked good? DR TEMPERO: Absolutely. DR LOVE: Motivated? DR TEMPERO: Absolutely. I could have had lunch with her at the country club the day I saw her. DR LOVE: So what was your thinking and what did you — DR TEMPERO: So I was really interested in what might be going on with the ovarian mass. And we suggested that that be taken out, actually, to find out. And also, if it was a sanctuary site, that would be the means of controlling it. DR LOVE: So did she have that done? DR SCHWARTZ: Yes. She underwent the surgery. DR LOVE: At your place? DR SCHWARTZ: At our place. She came back. She was out of the hospital in 2 days, feeling well again. DR LOVE: Laparoscopic? DR SCHWARTZ: Yes. Robotic laparoscopic surgery. DR LOVE: What did the pathology show? DR SCHWARTZ: Pathology was consistent with pancreatic primary. DR LOVE: Hmm. Fascinating. So what was the next step with this lady? DR SCHWARTZ: So we decided, since she had been responding elsewhere, to continue the FOLFIRINOX. DR LOVE: No neuropathy at that point? DR SCHWARTZ: No. And on her next set of scans had evidence of disease progression but still with great performance status. DR LOVE: And now we start getting into the interesting question of second-line therapy. So Tony, what would you be thinking at this point? And how would your thinking have changed — you originally said you might have given gem/nab to a patient like that — if she had gotten gem/nab? So how would you think it through now, first of all? DR BEKAII-SAAB: This is one of the limiting factors with FOLFIRINOX: What do you do second line? And there’s really not much data except retrospective data with gemcitabine-based regimens. Perhaps gemcitabine/nab paclitaxel based on a couple of tiny retrospective studies. I mean, a good performance status patient who’s not been exposed to taxanes or to gemcitabine and has done well with the very aggressive regimen, I probably would move to gemcitabine and nab paclitaxel, although again with the caveat that there’s very little data to support that. DR LOVE: She had BRCA testing? DR SCHWARTZ: Yes. She’s Ashkenazi, and we did BRCA testing and it was normal, no mutation. And it also was done on the ovarian mass for somatic, not germline, obviously, and she had no evidence of — DR LOVE: What kind of assay was done? DR SCHWARTZ: It was a Foundation assay. DR LOVE: Huh. Interesting. We’ll talk about that later. But Margaret, getting back to this issue of second-line therapy in a patient who starts out with FOLFIRINOX, I don't know. Were you involved in the second-line decision? DR TEMPERO: I didn’t see her, but we certainly communicated back and forth. And what we always look for in second line if you’ve got a patient who’s got a really great performance status is a clinical trial, because a lot of new drugs are being tested in the second-line setting. For those patients who’ve benefited from therapy, you’ve turned the clock back. The disease has started to progress. They’re still better off than they were when they presented. So they’re great candidates for clinical trials. And clinical trials accrue like gangbusters in that setting. DR LOVE: So what clinical trial, for example, could she have entered now or at that point that you have? DR TEMPERO: So, for instance, right now we’re part of a big Stand Up to Cancer effort in immunotherapy. DR LOVE: And what kind of immunotherapy? DR TEMPERO: We have vaccines. We have checkpoint inhibitors. We have macrophage activators. DR LOVE: Was she eligible for anything like that at that point? DR TEMPERO: We could not get her on a trial, because she didn’t meet the eligibility criteria. She had a little bit of ascites, and that was one of the exclusion criteria. DR LOVE: So what were you thinking, or what did you suggest or think about in terms of second-line therapy here? DR TEMPERO: When we start out with a fluorinated pyrimidine regimen and you need to switch gears, you go to a gemcitabine-based regimen. And the obvious choice was gemcitabine and nab paclitaxel. DR LOVE: Could I just ask, again starting to get into this concept of sequencing, in that flow, FOLFIRINOX, nab, gem, I don't know how often you get to third-line therapy, but it sounds like this patient certainly is a very hardy patient. What would you be thinking third line? DR BEKAII-SAAB: That becomes even a bigger challenge. Of course there’s no data on much, actually, in third line, so clinical trial. And I have to be frank. Sometimes I actually would consider for these patients mitomycin C when everything else runs out, mitomycin C and plus-minus 5-FU. The key with mitomycin C is really to limit exposure. We’ve had this data published a while ago, that we tend to give 7 mg/m2 every 6 weeks and limit it to 35 mg, under 40 mg/m2 cumulative. And for some patients, actually, you do see a response. Now, again, the likelihood of this patient going to third line — I mean, she may have gone to third line — is about 15% to 20%, which is pretty much the third line — patients who receive third line about 19% to 20% of all patients who are diagnosed with metastatic pancreatic cancer, so 80% chance she’ll never make it to third line. DR LOVE: So again, Margaret, in that algorithm, FOLFIRINOX, nab, gem, for you what would be next outside a trial setting? DR TEMPERO: There’s no standard option. And often those patients, we will try to get them on a clinical trial. We’ll send them to our early drug development group. Often it’s a Phase IB study, something like that. But that’s pretty — DR LOVE: If they aren’t eligible for a study and the patient’s in good condition, do you ever say to the patient, “Let’s just do supportive care for a while”? DR TEMPERO: Absolutely. DR LOVE: So we want to go through the flow also in terms of the other issue of the patient starts with nab/gem. But 1 other question about sequencing, and I’m curious — I’m sorry. DR GLYNN: So somebody who’s motivated, good performance status, we were talking about before, is this somebody you might consider gene profiling for? DR LOVE: You read my mind. Literally, that was the next thing I was going to ask you all about, which is, no matter who’s sitting at these tables, you talk about the patient who’s gone through conventional therapy. Do we do multigene next-gen sequencing assay or even a serum assay? I know Phil’s had experience with that. I just want to ask you all, would you typically do that? And is it helpful? DR GLYNN: I haven’t done it, but it’s certainly one of the reasons I came to Miami, to find out about it. DR SCHWARTZ: So we did it on this patient just because we had the tissue. DR LOVE: You did it! Really? Huh. So what did it show? DR SCHWARTZ: Really nothing actionable. She did have what you would expect, a KRAS and p53 mutations, but nothing — a couple of — DR LOVE: Phil, again, do you typically try to do some type of multigene assay in your pancreatic patients who are still in good shape and running out of options? DR BROOKS: Yes. I mean, if it’s a motivated patient, I realize it might be a 1% chance, but I will do either an assay on their tumor or I send for liquid biopsies now. DR LOVE: Margaret, I’m sure you get emails all the time from people who say, “Should I do this? Is it just going to create more problems and not really help?” How do you answer that, and what do you do yourself? DR TEMPERO: We happen to have a program that’s focused on that. So for us, it’s sort of de rigueur — that’s something you should do. How often does it help? Phil’s right. It’s very low. But for those few patients, that small percent of patients in which you find some information, that’s helpful. So I think at this point we need to learn. And so I’d just as soon see patients get this done. It doesn’t usually help with your first choice of therapy, obviously, because you can’t get the turnaround quick enough. DR LOVE: But, I mean, do you see responses to anything that comes up? Other tumors you hear a little bit. Have you ever had a patient who had an actionable mutation that you didn’t suspect, pancreatic cancer, that benefited? DR TEMPERO: So aside from mutation, the other thing you’re looking for is a mismatch repair. DR LOVE: Mismatch repair? What’s the incidence in pancreatic cancer? DR TEMPERO: It’s low. It’s about 1%. But those patients seem to be responding, like other patients with mismatch repair, to pembro. DR LOVE: So checkpoint inhibitors. But were there pancreatic patients in that original New England Journal paper? DR TEMPERO: Not in the original one, but there’s a subsequent expanding series right now. DR LOVE: So, I mean, if you had to guess what number of patients with pancreatic cancer and MSI have gotten - a checkpoint inhibitor? DR TEMPERO: I would say — you mean how many patients have been treated total? Less than 20. DR LOVE: Less than 20. And a bunch of responses have been seen? DR TEMPERO: Not a bunch, but some. DR LOVE: But some. Prolonged? DR TEMPERO: Yes. DR LOVE: Mismatch repair. Hmm. Yes. DR BEKAII-SAAB: Yes. So I can actually tell you about a patient I’ve had who had MSI high in the setting of Lynch syndrome. Treated her first for colon cancer a while, and then she presented with pancreas, bona fide primary pancreas cancer, metastatic. She was placed on a clinical trial with a PD-L1 inhibitor, actually. And she ended up with a complete response. DR LOVE: Wow! DR BEKAII-SAAB: And I must say, I’ve never seen a complete response in pancreas cancer just with 1 — I mean, 1 immunotherapy or a biologic. But she had a complete and durable response. She actually had to go off the PD-L1 inhibitor because of toxicities. DR LOVE: What kind of toxicity? DR BEKAII-SAAB: She had some significant neurotoxicity, actually. DR LOVE: Neurotoxicity. DR BEKAII-SAAB: Yes, demyelination, apparently related to the PD-L1 inhibitor. She really had some significant neurotoxicity DR LOVE: An MS kind of thing? I’ve never heard of that. DR BEKAII-SAAB: Similar. DR LOVE: I’ve heard of neurologic things, but I’m not sure I’ve heard about — DR BEKAII-SAAB: It was pretty significant. And likely related. DR LOVE: That’s really wild. Huh. DR BEKAII-SAAB: And she’s a year out, remains in complete CR. So you do see those patients. It’s only 1%, but again, it’s worth it. And I know Margaret alluded and Mike alluded to the BRCA mutations. I mean, you don’t have to have germline mutations of BRCA or PALB2. In fact, if you look at some parts of the literature, it suggests that about maybe a little bit less than 10% of the patients will have some abnormality, somatic, with BRCA2 or PALB2. And if you look at the studies, mostly outside pancreas that looked at the response to those patients with somatic mutations versus germline, they tend to do similarly good. So you don’t have to have a germline. But somatic mutations can elicit a good response to platinums, perhaps to PARP inhibitors. DR LOVE: That was the thing I was going to ask you, because this comes up now in breast cancer also. Have you, or would you attempt to use — I mean, we have an approved PARP inhibitor for ovarian cancer, olaparib. Would you use it? Have you used it in a somatic pancreatic cancer, a BRCA patient? DR BEKAII-SAAB: Only on study. And we do have those studies. DR LOVE: Margaret, any thoughts about BRCA? DR TEMPERO: Just to comment first that in our ICGC data set, there are probably about 24% of patients who have BRCA like. DR LOVE: In other words, they’ve got DNA damage repair problems, right? So those patients, that 24%, now we’re talking about a significant subset. Those patients are probably all going to be fairly responsive to platinum agents, maybe also to PARP inhibitors. DR LOVE: But have responses been seen in — DR TEMPERO: Responses have been seen with PARP inhibitors. DR LOVE: Really? So let’s go back through the other maybe even more common algorithm in clinical practice, the one that this patient would have gone down, most like — if she had seen you, which is nab/gem. So second-line therapy after nab/gem, Tony? DR BEKAII-SAAB: I mean, it’s straightforward. So following gemcitabine/nab paclitaxel, my second-line choice would be for 5-FU and, now, irinotecan. So now a liposomal irinotecan or MM-398. DR LOVE: And could you go through why that’s your choice and what other things you think about that you’re choosing this over? DR BEKAII-SAAB: So the other option would be FOLFOX. However, the data is a little bit more mixed with FOLFOX, 2 studies from both parts of the Atlantic. The European study suggests that FOLFOX, actually a derivative of FOLFOX, OFF, which is a weekly 5-FU regimen plus oxaliplatin, looked positive versus 5-FU in the second line following gem failure. On the other hand, the Canadian study — they’re both small studies, albeit, although they’re Phase IIIs — suggested that FOLFOX was not superior, if anything maybe a little bit inferior to 5-FU in terms of survival. But there are other factors that may explain that. So it’s a wash for oxaliplatin. On the other hand, the data with nanoliposomal irinotecan added to infusional 5-FU versus 5-FU following gemcitabine failure — albeit again, most patients did not receive nab paclitaxel in the first line with gemcitabine. But nonetheless, these were gemcitabine failures — looked positive in the second line compared to infusional 5-FU. So the default has become to go to 5-FU and nanoliposomal irinotecan. The other positive aspect of this is, you have nonoverlapping toxicities for the most. So with nab paclitaxel and oxaliplatin, you have overlapping neurotoxicity, which makes it tough even when you start with FOLFIRINOX and move to nab paclitaxel in the second line or vice versa. And you end up with patients being exposed to 2 neurotoxic agents sequentially, whereby with this sequence, you actually avoid the neurotoxic agent in the second line. DR LOVE: So I’m going to ask the 3 of you in a second what your typical second-line therapy is after nab/gem, but first, Margaret, maybe you can talk about it. DR TEMPERO: Yes. I agree pretty much with what Tony said. Also, I just want to emphasize again that we have so much work to do in this cancer that we have clinical trials in the first- and second-line setting. And that’s always going to take a higher priority in terms of what we offer the patient. DR LOVE: So Phil, what do you usually do in the second line in this situation? Have you used nal-IRI? DR BROOKS: I have not used nal-IRI. In general, I’d say most of the time I’ve come down to either using — when I look at patients and stratify them, I tend to use FOLFIRINOX and then often modified — so again, getting down to less toxicity — or I’m using gemcitabine. I guess I would ask a question, though, with this new drug. Do we know that it’s better than FOLFIRI, just — DR BEKAII-SAAB: So we don’t. We don’t. And we actually just recently published our experience with FOLFIRI. It looks historically interesting, but it’s tough to say that the 2 regimens are equivalent. FOLFIRI has not been looked at in Phase III studies. It has been looked at in small Phase II studies or experiences like ours. There is a theoretical advantage with nanoliposomal irinotecan. However, unfortunately in the clinical setting, these 2 regimens have not been compared. So the question is, do you use an irinotecan-based regimen in the second line and whether a nanoliposomal or irinotecan? Right now, because the data is with nanoliposomal irinotecan — although I understand the caveats with why is it really any better than irinotecan — with patients who have very few options, albeit if you have a clinical trial, it takes precedence. But if you don’t, then I think nanoliposomal irinotecan would be the choice until we have more data suggesting otherwise. |