Metastatic Pancreatic Cancer x Dr. Michael Pishvaian 2026 UPDATE Part 2

[Music] Welcome back everyone, this is Sam. And this is Karine and we are two octups. This week's episode we're going to be discussing metastatic pancreatic cancer with a very special gas, Dr. Michael Pishvane. And so he went over all local pancreatic cancer questions for us last week. And so this week we're going to be tackling metastatic and let's dive right into it. So to start us off, Dr. Pishvane, what is the treatment if there is local recurrence after surgery in the pancreas or the surgical bed? Thanks, and thanks for welcoming me back by the way. So unfortunately about 30% of patients with pancreatic cancer do experience local recurrence in the surgical bed. So this is definitely a common finding. And the treatment really depends upon what the patient symptoms are at the time of treatment. When a patient's cancer has recurred locally, unfortunately that does mean that they have an advanced disease that has become incurable. If they're symptomatic from their local recurrence, which is actually not uncommon, symptomatic of pain and sometimes GI issues, then radiation therapy can be helpful as palliation for those symptoms. If they're not symptomatic, which definitely can occur as well, then it really becomes a question of when do you want to start treatment for their advanced disease? We don't necessarily need to start treatment right away. But if we do decide to start treatment for their advanced disease, you're essentially treating them in the same way that you would treat a patient with metastatic disease. You typically would chemotherapy or other targeted therapies, as I'm sure we'll talk about. Definitely. And so you did mention in our localized episode, the importance of germline testing for all patients, as well as the importance of somatic testing. But tell us what are the first line systemic treatment options for metastatic pancreatic cancer? So our current systemic options are pretty well established, but I will say this field is changing hopefully fairly rapidly in the coming months or years. So the standard of care that therapies that we have are founded in chemotherapy, it started with gem cytobine, which was a standard for a long time through about 2011. And I hated using gem cytobine because it really didn't do much even though it was FDA approved. But really the new era of treatment of pancreatic cancer started in 2011 with a demonstration that full fear knocks, five to few oxal platen and arunasicin, significantly improved survival and response rates for patients with metastatic pancreatic cancer. The other regimen that came out a couple of years later was gem cytobine nab-pacotaxle. Many of your listeners will notice gem cytobine a brachsine, but the generic name is nab-pacotaxle. That one similarly has been shown to improve response rates in overall survival. And then the newest kit on the block is called Nally-Refox, which is very, very similar to full fear knocks. Full fear knocks is five to few oxal platen and arunasicin. Nally-Refox is five to few oxal platen and nanoliposoma arunasicin are nally-ree. So those two regimens, both full fear knocks and nally-Refox are appropriate triplet regimens. And Nally-Refox, a big study for Nally-Refox came out just a couple of years ago that also proved that it has a place as frontline therapy. And before we move on, can you explain a little bit of the difference between nanoliposoma arunatican and just plain old arunatican? Yeah, I'll try. I mean, the honestly, the biological biochemical difference is essentially that the nanoliposoma arunatican are these tiny little nanoliposomes that contain a huge number of arunatican molecules within the nanoliposome. And the underlying premise is that the nanoliposomes are more effectively delivered to the cancer cells directly. There's some pre-clinical signs that the cancer cells are more receptive to essentially ingest those nanoliposomes and the hope would be that by doing so, there'd be reduced toxicity because it's less systemic, toxic spread. But also, greater efficacy is this larger concentration of the actual arunatican gets into the cancer cells. That's the theory. I don't know that that's necessarily borne out, but it is a reasonable regimen to use in addition to full-fair knocks. The biggest challenge with nanolipoxone and where the company has gotten the biggest criticism is that unfortunately, nanolipox is something like a thousand times more expensive or a hundred times more expensive than full-fair knocks. And we don't really know that one is better than the other. But I will, you know, all three of these regimens definitely demonstrate an improved response rate over the old standard of care of gymsighted bean. Gymsighted bean by itself had about a seven to ten percent response rate, whereas these all three of these agents now typically across different phase three trials have a response rate of about 35 to 40 percent. But more importantly, most patients, probably 80 percent of patients have some degree of disease control and actually improvement in their symptoms. And prior to 2011, when I started faculty in 2007 and prior to 2011, I would use gymsighted bean kind of holding my nose and using it because all you really did was you would watch patients decline more slowly with gymsighted bean compared to doing nothing at least with nanolipox, gymnab, pack of acyl, and nanolipox. You actually do see patients genuinely turn around and actually I would say more often than not. I see patients symptoms, their cancer related symptoms improved significantly, less pain, less fatigue, better digestion, better overall quality of life. And they often, many of them actually return back to their normal quality of life even while they're actively on chemotherapy. How long that lasts is the unknown question for each individual patient, but they do definitely rescue some of their life back by starting these treatments. Great. And then I have one more question on frontline chemo regimens for metastatic pancreatic. How are you picking between full fear knocks, now ear-afox and gemobraccs? Sure. This is an often discussed question. There was a lot of back and forth between, for the, in the 2000 teen between full fear knocks and Gemnab pack of acyl because looking at the two big studies, the response rates and the survival for full fear knocks appeared to be greater than for Gemnab pack of acyl. But through the 2000 teens, it really became, it was appreciated that the population and patients being treated was slightly different. And long story short, there's probably not a whole lot of difference between Gemnab pack of acyl on full fear knocks. Maybe the full fear knocks and the nail ear-afox have a slightly improved response rate, a slightly improved survival benefit. But there is definitely justification for which patients might use Gemnab pack of attacks instead. And in fact, there were a couple of big studies, a randomized phase two study called the Paso-1 trial that showed really no difference between Gemnab pack of acyl on full fear knocks in a, in sort of a North American population. And then, and the big one was the Japanese J-Coast study that showed in a Japanese population that Gemnab pack of acyl actually didn't much better than full fear knocks in their trial. And actually, Gemnab pack is the frontline standard of care in Japan. So I think taking it all together, it really has to be a patient by patient decision. And the factors that I take into consideration in treating patients, first thing definitely is patient performance status because nail ear-afox and full fear knocks, of course, as three drug regimens are definitely harder to tolerate than the two drug regimen of Gemnab pack of tachylo. Gemnab pack of tachylo, we tend to reserve for our older patients, older meaning the 85 or older, so pretty old. And then, sometimes there are just patient preference differences, both nail ear-afox and full fear knocks require the use of a five if you pump that they go home with for two days. And sometimes that does kind of, you know, startle patients and they really don't like that idea. And so we choose Gemnab pack instead. But also just pure quality of life. I've had patients that have chosen Gemnab pack first because it tends to be extremely well tolerated and they want that. They don't want to necessarily be beat down by whatever side effects the full fear knocks other nail ear-afox might cause. But we do know, and I'll just say this is the last point, but we do know from some phase two studies and some retrospective looks, the patients that do best with advanced metastatic cancer are those that get experienced to essentially all of these drugs, or at least five if you some form of erinatine, oxaloplatin, but also Gemnab pack of tachylo. So only about 50% of patients will go on to get any second-line therapy at all. So it's important that if we're going to choose one regimen or the other, that we be ready to switch at the appropriate time and we not miss the opportunity for a patient to receive second-line therapy and thus get exposed to all of the agents in our armamentarium. Great. And I think you alluded to this a little bit, but after first line chemotherapy-based systemic therapies, what are those subsequent systemic line therapies? Sure. The only true level one evidence phase three study was the Napoli I study, which was the randomized study of five of uniliery versus five of you alone in the second-line setting, four patients who had received Gemnab study-based frontline therapy. And that was a positive study. And that was really the area where I use the niliery most often is second-line after Gem-based first-line therapy. And so the standard sequence for patients who receive Gemnab pack first will typically be five of uniliery second-line. And then there is some justification for using five of unoxalplatin or fulfox in the third line only because the patient has not yet been exposed to oxalpline. And if they are able to survive to receive third-line therapy. For patients who receive fulfiernox or niliery fox frontline, while there's technically no phase three trial to demonstrate this. Most of us use Jim said to be in that type of tax in the second line setting very comfortably. And then jumping to maintenance therapy, could you talk to us about the polo trial and if this is used? Well, before I jump to guess absolutely, but before I jump to polo, I will definitely sort of extoll the benefits of maintenance therapy. I'm a big fan of maintenance therapy, at least for a full fear and off space therapy, because I think it does has definitely proven its place. And we extrapolate a lot from like colorectal cancer, where it's an absolute standard. But even in pancreatic cancer, there have been randomized trials that have shown that if you take a patient, start them on full fear and ox. And in the trials that were done, it was three months. I typically go four months just because we scan every two months. But after three to four months of therapy, if you back off, there's three drug therapy and move on to just single agent five of you, or most of us will use instead of single agent IV five of you, we use oral keep cytobine, which is completely equivalent, that the patients can definitely benefit long term. They can have a much better quality of life during that maintenance period of just single agent chemotherapy. And there's no compromise to their overall survival. So my absolute standard is to go on to full fear and ox for about four months, and then move on to maintenance keep cytobine. And again, how long they stay on the maintenance keep cytobine really depends on how their tumor behaves and how long the disease is controlled. But I've had patients that have been able to manage maintenance keep cytobine sometimes for many months and even years to be honest. And that does get back to us, just go back to a question you had earlier about what is the front line therapy of choice? Because I know that I will move on to the maintenance keep cytobine ultimately. There are definitely times also when I will kind of convince the patient to go on full fear and ox just because I know that after four months they'll be able to get a break from the pump and go on to the maintenance keep cytobine assuming their disease is controlled. So that factors in as well. So I think maintenance therapy is a rich place to be able to allow patients to get a good quality of life beyond and be on an effective therapy though at a lower dose, lower intensity and yet still allows them to have a quality of life. And in that space or sort of with that paradigm, we also have now biomarker targeted therapies being used in the maintenance setting. The one that's proven thus far is for the germline bracket one and bracket two mutated patients or patients with germline bracket one or bracket two mutations that got at least 16 weeks of platinum based therapy. They were in the polo trial they were randomized to either receive single Asian olapprib or nothing placebo. And in that trial, the primary endpoint was progression free survival, not overall survival. And that trial was definitely proven to be beneficial for the patients that received a laparit. So for the germline bracket one bracket two and actually for the even for the somatic mutated bracket one bracket two palby two patients, I will routinely put them on maintenance olapprib, which again tends to be well tolerated. Their quality of life tends to be pretty good. And there's proven at least progression free survival benefit. There are criticisms to the polo trial because it did not prove the benefit did not prove an overall survival benefit. But two things that I'll say in response to that. First of all, the trial wasn't designed to look at overall survival. It was underpowered for that. So it wouldn't have been able to. There was a lot of crossover on to a laparit for patients who were on placebo. So that confounded the results. And quite frankly, it's our paradigm in other diseases like ovarian cancer to put patients on a laparit because of the progression free survival benefit that has been proven. So I think it's still valuable to use it in that situation. And one last thing I'll say about maintenance therapy because there is some value to this. And because now we have other targeted therapies being actively studied. And I know we're going to talk about, but there are some very interesting study designs, particularly one that is looking specifically at the use of a robust inhibitor, not as frontline or second line therapy, but specifically as maintenance therapy. And I think that there's a lot of promise for that paradigm in big gratitude. Yeah, kind of gain control of chemo and then ride, you know, a good long wave with targeting. Now let's jump into it. So can you talk about the molecular driving systemic treatments for metastatic pancreatic cancer and we'll start with K-RASG12C? Yeah. So I'll start by saying that, you know, for years I was getting lectures on the idea, trying to convince the community that we had to make sure that we're doing molecular testing on all pancreatic cancer patients because 17 to 25% of all pancreatic tumors harbor a so-called actionable alteration. Right. That line of discussion became irrelevant because now we actually have RASG inhibitors. And so essentially 100% of pancreatic cancers will have some targetable actionable alteration because 90 to 95% of them will harbor a RASG mutation. And that's one thing that's important to emphasize because there have been surveys that have done, been done of the community and understandably the community may not be as familiar with pancreatic cancer and the survey asks people what is the mutation rate of RASG and pancreatic cancer and the most common answer was only about 25%. But we really need to emphasize the folks that know 90 to 95% of pancreatic cancer is harbor RAS mutations and coupled with the other alterations that we're going to talk about. It's essentially 100% of patients that are going to have some kind of targetable alteration. And the RASG, targeting RASG has really truly been transformational, revolutionary, whatever term you want to use. And I definitely, definitely do think that in the coming years, all of our therapy for pancreatic cancer will go through RASG targeted therapies in one direction or the other. Whether it's frontline, maintenance, second line, adjuvant, but I think all patients with pancreatic cancer will ultimately should ultimately be exposed to some form of RASG inhibitor. So this wave started with the K-RASG 12C inhibitors. The G12C mutation is specifically one that forms a pocket in the RAS enzyme that is actually more drugable, more targetable within the drug. And so in the early, late 2000, in early 2020s, the data started to come out with a dagressive and saturistive and most recently a drug called Cliclearosib. And then there's a lily drug that I don't remember the name of, but several drugs that have shown clear benefit to K-RASG 12C inhibitors for second line and beyond pancreatic cancer patients. And that response rate was in the range of about 30 to 40%. Just to put that in context, we were talking earlier about chemotherapy, Gempside-Vinab, Pactotexel, and five-fifuone aloeary have response rates of only about 7% with a progression freeze survival of four months and an overall survival of six months. And those numbers are remarkably reproducible with chemotherapy. So that really sort of serves as the foundation. So with a dagressive, for example, in the second line and beyond setting for pancreatic cancer, the response rate was, I believe, 35% with a median progression freeze survival of seven months and an overall survival of 9 to 10 months. So really, that is definitely an appropriate regimen to use for patients if you happen to find a K-RASG 12C mutation. Unfortunately, only 1% of pancreatic cancers are K-RASG 12C mutated, but you do see it once while if you go looking for it. Well, it's exciting that we've made waves as far as precision oncology and pancreatic cancer with K-RASG 12C, as you mentioned. And although they're found at a small percentage, it's at least evolving towards that direction, but what about other targeted therapies and pancreatic cancer? Yeah. And certainly we need to talk about the other RAS mutations, which comprise the vast majority of these patients. So 90 to 95% of all pancreatic cancer's harbor or resputation, most of those 40% are K-RASG 12D, but then there's a G12V and G12R that are the next most common alterations. So they definitely exist in other percentages. And the wave of the targeting RAS overall has started with the pan-RASS inhibitor, Dirac R-R-C 6236, and we're all very much hoping for FDA approval of this drug, hoping for the sake of our patients for FDA approval of this drug, because in the second line and beyond setting, this drug has shown really, really great promise. This is just from a phase one B study, so we don't have yet the randomized data comparing it to chemotherapy, at least as of the time this recording. But in the second line setting is in the phase one B study, the response rate to Dirac R-R-C with 36% for all K-RASG 12D mutations, and progression free survival of about nine months in an overall survival of 14 and a half months, which is just absolutely remarkable for a second line and beyond pancreatic cancer population. The definitive phase three trial Dirac R-R-C was a study in the second line setting of Dirac R-R-C versus chemotherapy, and that's powered for overall survival. And we're literally waiting with baited breath for the results of that study to come out any day now. And then there are allele-specific RASG inhibitors as well. The G-12D inhibitors are the most common. There's a one from RevMed called Zodon RASG. There's one from Insight. There's several that are up actively in study. And the allele-specific inhibitors also are showing about a 30% response rate with disease control rates upwards of 80 to 90%. So these are generally very, very effective and really are going to probably drive our therapeutic choices in the near future. One of the things that will ultimately drive the decision as to whether to use a pan-rast inhibitor versus an allele-specific inhibitor. Well, specific inhibitor will be side effect profile because there are differences in the side effects of these different drugs. Deraxanrasib, for example, the pan-ras inhibitor carries with it about a 91% rate of the developing a rash, about a 50% rate of developing diarrhea, and sometimes these adverse events can be fairly significant. Fortunately, the drug is so effective that the patients generally have been sort of suffering through the side effects to get the benefits of the drugs. The drug discontinuation rate was actually really quite low, but the rash and the diarrhea and other side effects can be fairly significant. Interestingly, the G12D inhibitors don't tend to cause the rash and the diarrhea, but they do still have a fairly high rate of nausea. So all of these things need to be sort of figured out as these new drugs are developed. To get to your question, know about other targeted therapies, and this gets back to the pre-rass era, about 17 to 25% of all pancreatic cancers are bornon-rass, molecular alterations that are targetable. Most of those fall into what we call the DME damage response and repair pathway or DDR pathway. Most people know this mostly through the BRCA1, BRCA2, or POP2 alterations, which as we talked about a few minutes ago, can be targeted with carbon inhibitors like elaprib, but there actually are a number of other DDR inhibitors that are being developed as a trial right now of a very promising ETR inhibitor, for example. And there seems to be some degree of synthetic lethality when an ETR inhibitor is used in combination with chemo and an ATM deficient tumor. So we're really getting to the point that we can refine the patient population that best responds to these therapies. Everything else falls into the roughly 1 to 2% category. And I always emphasize the importance of testing. In fact, actually just yesterday, the NCCN guidelines for pancreatic cancer was modified to suggest that 100% of pancreatic cancer patients should be tested, and that that testing should include assessments for RNA fusions, because there's nothing clinically about a patient with an RNA fusion, an actual RNA fusion or any other alteration. So you really don't know that they have these things until you go testing them. But though roughly 1% of patients who harbor N-trec fusions, 0.2% of patients who are harbor NRG1 fusions, these rare patient populations can benefit significantly from appropriately targeted therapy. So just to sort of go through it systematically, the N-trec fusion positive patients, they can definitely benefit significantly from drugs like Lyra tractinib or N-treccinib or more recently the Repotrectinib, these all are very, very powerful agents for those population of patients. The NRG1 fusion positive pancreatic cancers can benefit from the Zeneca Tuzimab, which was FDA approved for that population about a year ago. There are very rarely patients who have ret fusion positive pancreatic cancer and self-percatin ed can be very effective in that population. There's about 2% of patients with pancreatic cancer that harbor B-Rafi 600 emutations. And for that population, these 600 target therapies like de-braphin, terrentinib or n-craftinib, banybatinib can also be very effective. And then very, very rarely you can identify patients that have F-GFR alterations, F-GFR fusions, and F-GFR inhibitors such as pemigatinib or foodibatinib can be effective. Hard to get access to because it's technically off-label, but they can be effective for that patient population as well. There's about 0.7% or 7 out of every thousand patients with pancreatic cancer that are MSI high. And so certainly immunotherapy targeting agents for those patients can be beneficial. And then the last thing I'll mention actually is going to be for patients with herchuposid pancreatic cancer because there have been some case reports of herchuparigative therapies, including with things like terrentinib and dress to can. The challenge for that population of patients, not so much with TVXT, but certainly with other herchuparigative therapies, is that herchuparigative therapies and GI cancers have mostly been ineffective in rast mutated patients. So for example, in the Mount Niro III study in colorectal cancer, it turns out that two catatoma transcusumab has no efficacy in herchuparigative amplified colorectal cancer that is also rast mutated. And given that 95% of pancreatic cancers are rast mutated, it really kind of begs the question as to whether how effective the herchuparigative therapies will be in that disease type. So we'll have to wait and see. Thank you so much for joining us again. This was so incredibly insightful learning about metastatic pancreatic cancer. And we're going to be back for the final series next week talking about supportive care and pancreatic cancer as well as future exciting trials and hearing about tumor board Tuesday. So everyone have a great week and stay tuned next week. Thanks. [BLANK_AUDIO]