How to Treat Pancreatic Cancer – Treatment Algorithm with Dr. Shubham Pant

Hello and welcome back to the oncology brothers podcast. I'm Rahul Gossane here with my brother and co-host, Rohe Gossane. In her first half of the year for treatment algorithm series, we're covering breast cancer, lung cancer, g-o-malignancies and GI malignancies. Today, we're focusing on pancreatic cancer. You know, unfortunately, this still remains one of the most challenging malignancies we see because majority of our patients show up with metastatic disease. To guide us through the crunstand of care and some of the nuances we all struggle with in our clinic, we're joined by Dr. Shubham Pant, a GI medical oncologist at MD Anderson Cancer Center. Shubham, thank you so much for joining us. Thank you for having me. Shubham, welcome sir. There's quite a bit to cover, so let's jump right in. Well, as Rahul stated, this is a devastating disease that we see, mostly in metastatic setting. However, if we do catch it early, do you check for NGS or germline testing, and does that tie in your decision-making process at all? I'm going to go first with resectable. So they're resectable and resectable, let's say, in that I think germline should be tested, and it's important because we know there's a good response of platinum agents, right? So you would think, if you were to choose, you would choose full pharynx, or right now, with a platinum agent as a new adjuvant therapy for these patients because of the higher chance for response. Now, it's interesting when you really look at the data in localized disease, there was a phase two trial from Swag, which compared Gemma Braxane to full pharynx, and it kind of, they kind of look the same. Now, it was a phase two trial in a way, so we don't know honestly in the new adjuvant setting, which one is better, even for resectable disease. Interestingly, at MD Anderson, it's split 50/50 across the US, for resectable disease, we actually give new adjuvant therapy to patients with pancreatic cancer. And the reason is we think it's a systemic disease at the onset, that means even if you have resectable disease, you could have some cells which have already metastasized, and then it also tells us a few other things. 30% of the patients who get resected and get full pharynx, they relapse within these first six months. So again, maybe those patients, you're going to expose them to this big surgery, big quality of life change, maybe, you know, if those metastases were shown up early, that surgery probably would not have benefited them, essentially. So we actually give new adjuvant therapy to majority for resectable patients. And we normally for the fit patients start with the pharynx, but if the C and 99 goes up, tumor doesn't look that, then we pivot to Gemma Braxine. And we've actually seen patients sometimes get a better response with Gemma faculty taxil than with full pharynx. It's still unclear which approach is better. Absolutely. And again, just to bring home a few points here, reason why we're talking about Gemma like testing, roughly what, about 57% of pancreatic cancer ends up having that germline mutation of Braka one, Braka two or Pavitu, again, will come to the parpinopitres as maintenance. But even here, this is across all disease sites, when something is Braka one or Braka two positive, we do believe that there's more platinum response here. So I'm coming back to the story of new adjuvant. How many cycles are you giving everything up front? If that's C and 99's going up, yes, you're switching. But what if the patient's not tolerating that treatment? Off to surgery and then you're making up for leftover in adjuvant settings? Yes, that's what we do. So we actually, honestly, it depends, like the beauty is in the eyes of the beholder. So I love my surgeons, but they all can have differing opinions on this. So some surgeons prefer two months, and then to take them to surgeries. We, let's say if there's some other reasons, we go to six months for the patient. The other interesting thing that we actually do at Anderson is we have a pre-hab program. Like the rehab, we pre-hab these patients. So remember, wipple surgery is not a small surgery. So we try to get them, like, you know, they're, they're, they get some coaching on, doing some exercising, if their obese to maybe lose weight a little bit, to try to make the post-surgical time a little bit better, right? The post-surgical recovery a little bit better, because post-op is very important in this disease. So there are different aspects which can play into it. But to answer your original question, it's honestly, it's, you know, it's a cop out. When we say that, it's truly that way. Because again, it's patient dependent, surgeon dependent, you know, on their performance status, how they're doing. But we normally do, I would say on an average, we about do four months of new adjuvant therapy, if I had to guess, but we do try to finish it off at the, at the, in the back end, essentially. I just want to add that this is a very morbid surgery, even those young patients who look very fit up front, especially after surgery, giving that post-op therapy or adjuvant therapy is quite a bit. And at least for our cases here at Rosalapark, we do go for neo-adjuvant, even for resectable cases. Rala is wondering, what is it at Rochester, like for resectable cases? - Yeah, I think a lot of times, these are the longest discussions on tumor board. And we go back to what we've been doing always, saying, all right, let's give three to six months for adjuvant chemotherapy, your sweet spot ends up being four months. And then we make up for all this in the back end. Actually, before we get carried away, here in resectable, we have potential three options. Full furion ox, Gem napacto taxone, this neo-adjuvant, we also have data for Gem capesite to being, one thing to bring up here is for five FU and capesite to being, there is this updated FDA label, two check for DPDYD mutations. So that's one thing that we all should be doing regardless. Okay, now on to board and line resectable. Here are things that are a little controversial as well on what to do again. Should we rely on full furion ox? What about liposomal urnotecan-based regimen here? Should it be Gem napacto taxone? How many cycles are good enough? From here for board and line resectable disease, how do you approach this and what data do we have? - Yeah, so the data again, it's fairly, for lack of better word, kind of messy, a lot of data out there. But normally what we do is we don't have a data of it in our ladyfawks. That's more for the metastatic. So for the neo-adjuvant, for the board line resectable, again, they do need neo-adjuvant therapy. Otherwise, outcomes are very poor. If they get taken to surgery, the surgeries are not good, they are urban resections. So they need neo-adjuvant therapy. And again, honestly, it's 20, 26, we should have a better answer, but we don't know how to pick the front. If they're fit, then we go with fit young, then we go with the triplet regimen. If not, so they go with the doublet. But honestly, we track the CA199s in the ones who are, the majority do have a CA199 level that we can track. And we track the CA199. And if the CA199 is going up, our group has published this again and again, that if you have a CA199 going up in the cofacility, they do very poorly. But if you bring down the CA199, that actually correlates to long-term, better survivor prognostically, it's better essentially. So we try to pivot. So let's say, again, patient is getting full pharynx, but they don't show a response to us either on the scan or their tumor marker is going up, tells us this disease is really not under control. Then we pivot to gem that pachytaxyl in that setting. Again, it depends a lot on patient factors, but that's what we normally do for our patients. - Shibum, how do you tie in in these multidisciplinary approach, chemotherapy or the role of SBRT? - Yeah, so again, SBRT or the longer course chemo radiation, we kind of look to our radiation oncologists for that because again, aware the tumor lies, you know, how can they give it safely? But for borderline resectable, I would say for a majority, unless there's like a dramatic, dramatic response, we do tend to give them chemo radiation. Either it's a long course, you know, six weeks chemo-arty or the SBRT, it's very individual, mostly dependent upon our radiation oncologist for that. But I would say in majority, borderline resectable, they do tend to get the chemo-arty basically. - Apparently multidisciplinary is the key here. I do want to take a pause here because all we're talking about is a curative approach. But even when we're talking about cure here, we often miss on supportive care aspect of it. That is, if a patient is presenting in with weight loss, de-attery or low-albumin, which is rather correctable with pancreatic enzymes, there was a study rather to show that out of all the patients who actually need pancreatic enzyme replacement, only less than 40% patients actually received it. - Yeah, 100%. You're speaking to the choir, I'm so glad. I see a lot of patients who come to me, because again, our referral practice is, you know, a lot of second opinions, which come into MD Anderson, you know, the folks who are especially who are not local. But yes, I see them that they're like suffering. They're like losing weight. They're just, and I'm telling you some of my patients who've been more appreciative have been whom, you know, I've just said, hey, you know, try a pancreatic enzyme, right? I mean, make them meet with the nutrition and they're like, wow, that changed my life around. Because really, they start feeling better, better digestion, they start gaining weight. It's truly in the ones whom it works. It's truly like you just see this light switch on and off, essentially. It's a very pancreatic answer as a complex disease. It's a very multidisciplinary care. So you need the medical oncologist, radiation oncologist, surgical oncologist, nutrition. We also have pre-hab and then you have the supportive care folks, right? They manage, all that. So it's actually, it takes a village, honestly, to take care of your pancreatic, that's a patient. Couldn't agree more, sir. And even to tie in, if a person has an albumant of 2.8, no matter how much you dose a justful pharynx, if they are not gaining weight because of just pancreatic enzyme replacement, this therapy is not going to work. Shobam, could you just talk a bit more on Borkrayon or pancreatic enzyme replacement? And how do you go about managing this? Yeah, it's very dependent on what their needs are, right? So let's say start basic, even once we're not maybe the 12,000 or 24,000 units, two to three with meals, one with snacks, and then we kind of escalate it, right? So we can go on the higher dosage pills if it's not working. But what's changed is, again, in the literature, and mostly we're lucky at MD Anderson to have nutritionists who work with us, great nutritionists. So what I've seen them change a little bit about their guidelines also, is now we tell them to simulate like the enzymes would be during food. So take the first, while you take the first bite, and they take the next one. one, but what happens lots of times is you always have to follow up with the patients to say, hey, are you really doing this? You should always ask them, hey, are you taking it like we prescribed? And some say yes, but some say, oh, you know what, I take it sometimes and I forget, but you're right, because coming back to your original point, Rohit, if your album in pre-album was low, you're going to do very poorly after the surgery, right? Even the surgeons are not going to take a patient in for surgery who is nutritionally so deficient that they will have a very tough time with recovery. Supportive care has to be tied in because again, this is devastating disease, but quality of life does affect with all the supportive care management. All right, moving along to metastatic disease space, where unfortunately we do see majority of these patients. Because of the fact that there are no screening modality, the choice is full pharynx or naliri fox or gem-side-of-be-nap-packlet-haxle or single-agent chemo for our frail patients. Shrubim, how are you deciding amongst full pharynx versus naliri fox because that's what we at least resort to for our young patients or a fit patient? Yeah, I think both are good options for our patients as the folks know full pharynx was compared to gem-side-of-be-n single-agent. The trial was run in France, showed improvement in survival, similar naliri fox with a global phase three trial, or compared to gem-nap-packlet-haxle and showed an improvement in overall survival about two months benefit with the naliri fox. I think one of the main side effects, as we know and why the patients get off is because of oxal platenine neurotoxicity. I feel like if somebody is set up for that, if they're diabetes, hence of neuropathy, and you know those ones I think about, you know, naliri fox in a way, but I think both are good options in these patients. Even somebody who doesn't have neuropathy doesn't mean you don't need to get them full pharynx. You can always give them naliri fox. It's just that it's a little different. I do think one of the positive is naliri foxes you can really, and I'm learning more as we go along, essentially I'm kind of changing my practice. If you maybe have a higher burden of disease, maybe naliri, you could keep the oxal platen going on for longer maybe. If I think I won't take that oxal platenine out for longer, not stop it after six months, maybe I would choose the naliri fox. Because remember the interesting naliri fox was, even you see the A.E. chart, the percentage chance of neuropathy was double in gem-apraxane, gem-nap-actyl-versus-naliri fox, which was you're like, what? So I think if I look at that, I look at like how much oxalia I'm on a poishan everything, and the good thing was again it was such a big difference like 85 milligram per meter, so it was a 60 milligram per meter square. So, you know, kind of making my decisions based on that, but this data to give both. You know, there's not enough. For the slightly like ecaug again, one to two is gem-nap-actyl-apraxane. Now coming to the frail patients, honestly, I really have a conversation with them about, like what are we achieving? Are we improving your quality? Because again, I don't think we should give chemo blindly. I mean, they should be a reason to give chemo. You should improve the patient's quality of quantity of life. You should be doing something, impacting something. So I have a hard to hard conversation with the patients about, you know, it's your personal choice. And some folks say, Dr. Panth, yes, I want to do the single-agengem side of being or something, or you know, I'm good at home. But honestly, I'll tell you, I haven't had many patients who've taken me up on the offer of single-agengem side of being. The ones who are frail, you know, just are doing poorly. Well, again, because the data is so bleak there, right? And coming back here in this metastatic settings, we talked about supportive care heavily early on. This is important here as well. Deceitment here is with palliative intent. And again, that's why we're balancing these side effects and the efficacy, be it from full fur and ox, be it from nileary fox, gemnap pathletaxle. And again, when we're talking about gemnap pathletaxle, we have enough data to say every other week works. So that is what a lot of us are doing in our practice. Coming back to full fur and ox and the nileary fox here for a second, full fur and ox ends up being one of the toughest regimen we've talked about neuropathy, fatigue, diarrhea. Can you touch a little what to expect from nileary fox? And am I compromising any efficacy by using this? So I'll take the second question first. You're not compromising any efficacy by doing. We know that for sure. We've got a global phase utral to tell us that essentially. The main side effect of a nileary fox is the diarrhea. You can get the fatigue, the main side effect is the diarrhea. So when you look at full fur and ox, you know, in the neuropathy, but the diarrhea can be an issue with that question about it. So just like we educate our patients on irino tecan, I really do educate them on the lapism, lionity can make sure they're ready for that. And then we are aggressive with those adjustments if we need to. They were followed up abstracts published and everything that really doesn't decrease the efficacy of the regimen essentially with those adjustments, which you can do. And you know, it's just tolerable for the patients, but diarrhea is the main one that I worry about and I counsel the patients on. At the end of the day, balance that safety and efficacy and what we have the data from nileary specifically more data, particularly that if we are reducing that dose, we're not compromising the efficacy of it. Okay, moving on to discuss if the disease was to progress. If you used nileary fox or full fur and ox upfront in second line choices, gempsideobin napaglitexyl or if you use gempsideobin napaglitexyl upfront, in second line, we have liposolmalarionateecan. We also have targeted therapies approved here as a result, biomarker testing or NGS is extremely important here. So, show them how are you deciding your treatment approach and how does that sequencing look like on your end? I'll tell you like a side example, I fell on my clinic, it came to me from a breast clinic and was like, Dr. Pant, this is like a little easy. I was like, yeah, hopefully we want to make it more complicated for the fellow soon with all the rass agents, but honestly, which is kind of a little tragic, but you know, hopefully this will change soon is it's an easy algorithm, right? So, if you have, if you treat with gem based therapy front line, we give five or a few liposolmalarionateecan, second line or full fox, depending on what we have, rarely full fur and ox, they definitely need a dose adjustment at that time. But if you've got enough five or a few based therapy front lines, then we give gem or gem nap athlete axle, but you're right Rahul, I think you said every other week, you know, that's what we do because again, remember all the data for the weekly is in the first line setting, even that is fairly toxic in the first line setting. So, we have published our data in retrospectively on every other week in the front line setting and overall it looks very similar. It's a retrospective analysis, but it looks very similar to the weekly regimen. But the good news though is that we have a lot of clinical trials for these patients. So, you know, majority of our patients get next in sequencing upfront because what also happens is people say, oh, well, why should we do it upfront, we'll just do it when they progress. So, what happens in pancreatic cancer patients, but when they progress, you need to get them something pretty fast, okay, you can't wait for a couple of months. So, you do the biopsy, then you do the NGS, and I know at the variable times of turn around, and by that time you're looking for a clinical trial, you know, six weeks without any therapy for a pancreatic cancer patient, two months, which is a long time for a pancreatic cancer patient, progressing in front of pantherapy. So, we try to do the NGS earlier, so we have it in our hand. So, we can quickly figure out if you can find a trial for them. So, that's the utility of doing NGS earlier, because now you actually do have drugs which have activity in this disease. So, I want to come back to that change that your fellow is looking for, but before we get there, we started off with parpinopitres. I just want to touch on that story as well. Let's go back to that maintenance parpinopitres. We have two parpinopitres here. If the disease was to progress while they're on maintenance parpinopitres, do you go back on the platinum-based chemotherapy, do you now move on to second line? Is there any role of switching to another parpinopitre? Yeah, no, I don't think there's any role of switching to another parpinopitre. My longest survive is in my clinic. Our actually patient who's a Brockone Brockadoo, they prognostically do better. I actually had a patient who progressed after like, I mean, four years, we finally sent her to hospice because she got brain mats, you know, to kind of live that long with metastatic pancreatic cancer. But to answer your question, after the parpinopitre, I try to introduce them to platinum again. I try to actually do gymsis if they can take it. At that point, I think this platinum is very, very powerful in this disease also. We had actually a phase three trial of like gymsis platinum with a parpinopitre agent called Valeparib turned out to be it was not a really great parpe, but what it taught us was that the response it for two was like 70% in the front line with just gymsis. So that's what I try to do. I honestly kind of juggle chemo and this, you know, I just try to, again, this is more anecdotal honestly than any data driven, but that's what I try to do. I try to bring in a platinum again because I think they'll have exhausted the platinum in that disease. I want to try to, you know, I don't, I don't switch them. But that's purely like puns sitting in his office like anecdotally thinking about how I should do this patient, you know, parpe does have its own, we think it's benign, but it has side effects. So no combination, I stop the parpinopitre and then just continue to give them on chemo. Thanks so much for touching on the side effects. Yes, parpinopitres are not side effect for you. One has to keep in mind fatigue, nausea, and bone marrow suppression. All right. Now for that fellow of yours, RAS story. Historically, if you've not had any targetable therapy, at least in pancreatic cancer for RAS, but this is changing as we are seeing more of this story unfold, 85 to 90% of the disease harbors Keras mutation, where in pancreatic cancer is Keras G12D, G12V or G12R. We also have rare G12C here where we have targeted therapies approved in colorectal cancer or lung cancer. That is a dagressive or satorecept. Shibam, what are we learning from panrass inhibitors? What kind of response are we seeing here? C, G12C hasn't charted about 1% of pancreatic cancer patients. So actually, adegressive and sort of RAS, are in the NCC and guidelines of pancreatic cancer patients. So we did a basket trial of these of adegressive and we had a response of about 31% in very refractory pancreatic cancer patients. So if your listeners have a G12C patient, they can get access to adegrasib or SOTORASIB. I tend to use adegrasib in my practice, but SOTORASIB is there in the NCES and guidelines also. So you have that availability to you. It's not approved because of the percentage is so small. Coming to pan-race inhibitors, there are two big things. One is the pan-race inhibitors like Diracson RASIB. So that's the one that we are waiting out for the trial called RASILU3 or 2 in the second line setting. Hopefully the reader should be this year. We're all fingers crossed, deep breaths. It's positive for our patients because looked very promising in the phase one trial. And now you have the K-RAS GTWL-D as in Delta agents, which is 40% of pan-race cancer. There are already three phase three trials in the front line, which have been announced on that. One is an insight on off inhibitor, and the trial is called Dawn 303. Then you have two trials which are coming on from Revolution Medicine. They recently announced it, RASILU3 or 5 and 309. So 305 is front line with chemo, Gemma Braccin, or Fulferinox, front line. And then they have the 309, which is their pan-race inhibitor with their Zoldon RASIB, which is the K-RAS GTWL-D inhibitor, versus chemotherapy. So think about it. In pancreatic cancer, we are thinking about a novel novel going against chemotherapy. It's blowing my mind. I feel like we should-- I'm thinking-- I'm going to relabel myself as a lung cancer doctor, hopefully. Yeah. I think it's about time. I've had a couple of years to go. I'm like, look at this pie chart. Like I got this little pie chart that I can show. Now this is about Fulferinox. And now almost like-- And no carcinoma lung. Yeah, it's like-- I mean, people will call me a little bit like overtly optimistic, but I'm cautiously optimistic, honestly. But I think there is real-- I mean, I feel like I've done pancreatic cancer for a long time. I feel that this is the time when there's real hope and optimism that is not unrealistic. Very true. And again, just to put things in perspective and majority of these pan-rest trials are the one that you brought up for G12c, edigrassib, or Sotorosib, roughly about 25, 30, 35% response rate. That's not home run, but let's take a step back. This is an heavily pre-treated disease. So again, in frontline settings, hopefully, this is going to look whole-up better. And it's just so good to see some more treatment options here in this otherwise aggressive disease. Shibam, thank you so much for walking this through the current data and your treatment algorithm in pancreatic cancer with us today. For those tuning in, let's touch on few key takeaways from this discussion. Today, in our pancreatic cancer treatment algorithm discussion with Dr. Shibam Pant, we touched on early disease where surgery still remains the mainstay. In these settings, we're relying on neoadjivin or adjivin chemotherapy. And the data here is around full furnox or gem-napakletaxle in neoadjivin settings, and gem-capeside-to-beam combination in adjivin settings. For that borderline, resectable disease, chemotherapy is again being used to address those micromats, but mainly to see if it can shrink that tumor and convert this into a resectable disease. Rohe thier thoughts in metastatic settings? Rohe, we touched on where the options are full furnox, nalluri-fox, gem-side-of-be-napakletaxle, or even single-agent chemotherapy. Then also, we talked about the supportive care management here. I said this during our conversation as well, that one way or the other, one is getting exposed to five FU, nine-o-liposomolirin, a TKN gem-side-of-beam, and napakletaxle because our options are limited. We also reiterated the importance of checking DPYD mutation, especially the given FDA label update for five FU and Cape-side-of-beam. To close off, we touched on care-ass mutations, which we are seeing in about 85 to 90% of pancreatic cancer. And we might see some options here to attack this mutation. Thanks for tuning in. Make sure to check out our other discussions around conference highlights, talk, check, and challenging cases. And if you're going to be at annual Asco, we'll look forward to seeing you there in person. See you in next episode. We are The Oncology Brothers.