Chapters Transcript Video KRAS-targeted therapy and the future of pancreatic cancer treatment After about 10 days when she came into my clinic, she told me haphazardly, not like as a report, Oh, I forgot to take my pain medication the other day. And she said that she had forgotten to take her pain medication several times. And this is a woman who had been on pain medications for over 1 year at that point. And a single tear rolled down my face and the hairs on my arms started to stand up. And she said, she looks at me and she says, Doctor Valerin, are you crying? And I told her, You have no idea what a big deal this is. Hi, I'm Lindsay Carrillo, director of Business Development at UCI Health. Hi, I'm Doctor Sunil Verma, Associate Chief Medical Officer for ambulatory and an otolaryngologist here at UCI Health. Welcome to Physician Huddle by UCI Health. Today we are joined by Jennifer Valorin, medical oncologist and pancreatic cancer specialist at UCI Health. Welcome. Thank you for having me. So you've had an interesting path to becoming a pancreatic cancer specialist. Tell us a little bit about your journey. Um, yeah, so when I was in college, I was actually, um, planning on doing a PhD. So I was working in a neuroscience lab, um, doing a lot of basic research on the development of the retina, and, um, I started that my junior year at UCSD and then when I, um, graduated, I ended up living with my aunt in North County, San Diego in Vista. And when I was living with her, she started to lose weight and she thought, Oh, wow, this is amazing. I've been trying to lose weight for, you know, a decade already. Um, but then she continued to lose weight. And so we got some imaging done and it turned out that she was diagnosed with pancreatic cancer. And so I lived with her from the day that she was diagnosed until the day that she passed away. And I remember, you know, at that time, because this is over 20 years ago, frantically looking on clinicaltrials.gov and there were no options for her. She, like a traditional pancreatic cancer patient, she failed standard chemotherapy. We tried all sorts of other experimental things on our own. Like mushrooms and electromagnetic, you know, treatment. And like most patients, she succumbed to her disease. And so I just remember feeling really helpless. And so at that time, I decided to instead shift what I wanted to do with my life and go into medicine and decided to become a pancreatic cancer doctor so that I could bring new therapies to pancreatic cancer patients that were really desperately needed. And so that's what I do now. Wow, that's quite a touching story. How, um, how long, like, where did you end up going to medical school? Uh, I went to George Washington University on the East Coast. And did you know then that you wanted to be in, you have an MD and a PhD, so that was part of the plan was to fulfill that void that you had, had identified previously. Yeah, so, you know, I was, I always have loved science and, and I'm kind of, I'm nerdy, and I like, you know, working with my hands. And so, um, it was really fun because throughout my entire medical journey, I was always involved in like the research curriculum and, and doing all that. So when I was at UCLA for residency, um, I also worked in the lab. And then when I went to MD. Person for my fellowship, my clinical fellowship, they had offered us a free master's degree. So the project that I was working on at the time, uh, it was in a genomics laboratory and, um, it was already a much bigger project than it was going to be for just a master's and so, um, I had already also at that time, um, been awarded a two year research. Fellowship after my clinical fellowship at MD Anderson. And so I decided that I would have a meeting with all the deans from the PhD group and convince them to allow me to transfer from the master's to the PhD program instead. And so, yeah, so I, I ended up getting my MD PhD, but I did it a little backwards and did it at the end of my training instead of in the middle. Must have been nice to have that perspective though. To know to do exactly what you wanted and to be able to align it with your clinical interests, as opposed to, I've seen at least a few people that do the MD PhD program from the outset. The PhD doesn't always align with what they end up doing clinically down the road. Yeah, you know, my, my PhD was really working on hereditary cancer syndromes, specifically hereditary pancreatic cancer. So, one of my niches here at UCI is that I actually also help co-manage the hereditary cancer clinic. And so, um, it's really dovetailed nicely into what I do in my practice and what I do in my research. And, um, the great thing about it then is that exactly how you're, you're, you know, what you're discussing is that I kind of, you know, I do exactly what, you know, the, the typical MD PhD would like to do, which is I bring things from bench to bedside and back. And so I have a couple of basic science collaborators that I work with also, um, and we, you know, publish about my patient samples and questions that we come up in clinic because I think those are what makes the best research questions are where are the gaps and the holes in practice to help patients. Let's talk a little bit about pancreatic cancer. Who gets pancreatic cancer and is the story of your aunt still the story of sort of unknown weight loss? Yeah. So, you know, um, typically, pancreatic cancer comes in people's 60s. And so, um, but we have seen, like other cancers, that the disease is moving to younger, you know, patients as well. But usually, it's typically in patients who are overweight, um, patients who are smokers, alcoholism, chronic pancreatitis, those are some of the risk factors associated with pancreatic cancer. Um, but, uh, you know, and, and it's not uncommon for patients to come into my clinic and say that they've lost 50 pounds before they came in. And so I think the other thing that makes it a little bit confusing nowadays too is that so many people are on GLP medications, right? And so they were intentionally trying to lose weight and then they're found with this disease. And so I think that's, that's one confounding thing that's been happening more recently. And it's diagnosed with imaging or is it diagnosed on GI endoscopy? Yeah, physical exam, I don't, yeah, so, so the reason why I think that it is caught late, there's a couple of reasons for that. And one is because a lot of times aside from the weight loss, patients may not have symptoms or their symptoms may be very non-specific. So, you know, a lot of patients actually present with back pain because the pancreas is located more posterior in the abdomen. And so the pain is, they won't really describe stomach pain. They'll say that it's pain. Radiating to their back. And so how many people out there have back pain, right? So, you know, the diagnosis is can definitely be made by imaging, but then they have to undergo a procedure called the endoscopic ultrasound, where you get a biopsy of the pancreas to actually definitively diagnose, and that's during an EGD or an extended EGD transoral endoscopy, correct? Yeah. So you mentioned when you first were looking at treatments or clinical trials. For your aunt, there was nothing. So why has pancreatic cancer been so difficult to treat and why has it gone so long without a lot of movement in that area? I think that there's a few reasons. So one of the things is that, you know, for example, um, we look at something, one of the modalities that we're using to track cancers these days is something called CTDNA, circulating tumor DNA, OK? And we've shown that in stage one disease, already 40% of CTDNA is positive, meaning that this is a disease that metastasizes very early. Um, even when patients undergo surgical resection, you have about a 70% chance or so of patients to have disease recurrence. Um, it is a resistant disease because it's also considered to be an immunologically cold tumor, so there's not very much infiltration into the immune system. And um also there is this fibrosis or kind of a rind around the pancreas created by um stromal cells. So, non-pancreas cancer cells, or at least from what we understand, not pancreas cancer, but are cells actually made from your own body that then kind of There's still a debate about whether the use of these cells is to actually protect the body so that the cancer doesn't metastasize out. Um, or at the same time though, it does make it difficult to treat because you're trying to get into that fibrotic rind. The fibrotic rind does not exist previous to the cancer developing. Like in a normal pancreas, is there a fibrotic rind around it, or is it actually just smooth, like fascial tissue? Yeah, it would be smooth tissue. So there is definitely some dynamic relationship between these cells that are activated and the pancreas cancer as a. Develops. I think you said it's like trying to chip into a rock. Exactly. And that's actually what makes it tough sometimes to biopsy, you know, pancreatic lesion because you're trying to stick a needle into a rock and so frequently it'll come back as non-diagnostic and we have to try several times. I'm going back a little bit. I mean, you've said that a lot of people, some people present with low back pain. So I imagine even the imaging that's performed for low back pain, be it plain film X-ray or spine, CT or MRI, probably doesn't capture imaging of the pancreas. It is definitely not uncommon for me to have seen patients who have had several months of workup because You know, so for example, I had a woman in her 50s that presented with pancreatic cancer just about a week ago, and they had been looking for the cause of her pain for several months, several images. Um, and, and each time, you know, when you look at it, You know, in hindsight, it seems like it should have been obvious, but, but at the time, it wasn't. And, you know, the other thing I hadn't mentioned before is that in sometimes in younger patients, these can be hereditary in nature as well. And so, you know, that happens in about maybe 10 to 20% of these diseases. So younger patients can present, which may not make it, you know, as obvious. So the youngest patient that I ever treated um in my clinic, I think she was 24 when she was diagnosed. Hm Is the circulating tumor DNA used for diagnosis? Um, yes and no. So we don't use it for you, you still need tissue diagnosis. However, you know, sometimes, um, You know, there could be, we could use it for mutation profiling. Um, so typical sequencing, which is what I used to do in my laboratory, uh, takes about 4 to 6 weeks. But you can actually take blood samples from a patient and get a result in about 10 days. And there are specific what we call canonical mutations associated with pancreatic cancer. So 90% of the time, they're driven by a gene called KRAS, which is what some of these, you know, these new latest and greatest medications are targeting are mutations in KRRAS. So if you get, you know, a tissue or blood sample, and that shows a mutation in KRAAS, then you're pretty certain that this is likely coming from a pancreas cancer. Talk to us more about KRAS, which is not a radio station. I'm now aware. Um, there was a breakthrough not too long ago by one of our sister institutions, I understand. And tell us what happened and why that was such a big deal. Yeah, so for many, many years we used to think that KRAS was undruggable. And then um there was a scientist at UCSF, Kavonhokat. Um, who found a binding pocket in the molecule that allowed us to target it. And you know, KRAS comes in various different flavors. So, you know, the most common for pancreatic cancer is G12D as in dog, but we see it G12C, for example, in lung cancer, colorectal cancer. And so we initially had Drugs that targeted G12C at the beginning. But the issue with those drugs is that they targeted KRAS in a non-activated state. And so, more recently, by a company called Revolution Medicine, we've had a drug called Daraxonraib, and that is a pan. KRRAS inhibitor, meaning it targets, you know, different moieties of KRAS, um, but, um, but does it in both on-off state. And so, you know, in pancreas cancer, where we think that the mutations cause the molecule to be continuously on, it's obviously more effective if you're targeting while it's on and causing cells to grow and divide. And then this has led to multiple drugs which you have been bringing to patients here at UCI for a few years. But tell us what is different about these drugs that has made such a big difference. And by the way, when you talk about bringing drugs, is this through a clinical trial, or these are OK, so sorry, go ahead. So this is, these are through initially they were through early phase clinical trials. Um, right now, Durax and Raib in second line, meaning after failure of chemotherapy. Therapy, um, has already, at least per press release, and we'll get the final data at ASCO this year, um, seems to have improved survival in patients over chemotherapy. Um, and so, you know, um, these drugs are, uh, very effective. They keep disease stable and pancreas cancer somewhere we think around 88, 90% of the time. Um, they cause disease shrinkage, maybe in about a third of patients. But, you know, the bottom line is, is that we haven't seen anything like this for decades. And the drugs, they can, you have to know what you're doing when you're managing medications. They definitely have different side effects than chemotherapy. But I have many patients, so for example, one of my patients who I started treating in In the beginning of 2024. So, about 2.5 years ago, she is still on the medication. She is alive, she is doing well. Um, and she has, you know, day to day, some issues, but for the most part is, is living her life the way that she wants to be living her life. So when you kind of hit a sweet spot, because there's always, you know, dose adjustments and holds and things that you have to, to, to do, um, for the most part, these patients can do really well. Um. We can talk about my patient with pain in a minute if you'd like, or I can tell you about that now. Yeah, tell us about it. Yeah. So, um, the very first patient that I treated, uh, with this medication was actually, I believe, in December of 2023. So again, over two years ago, she came to my Clinic. And this is a woman who had failed already several therapies, because on our initial protocol that we had for the medication, you could give it to patients after one or two different regimens of chemotherapy that were failed. So she had already had two different chemotherapy regimens. So she was in the 3rd line. And she was very weak. She was on a ton of pain medications. Um, and honestly, I wasn't sure how she was going to do. And after about 10 days when she came into my clinic, she told me haphazardly, not like as a report, Oh, I forgot to take my pain medication the other day. And she said that she had forgotten to take her pain medication several times. And this is a woman who had been on pain medications for over 1 year at that point. And a single tear rolled down my face and the hairs on my arms started to stand up. And she said, she looks at me and she says, Doctor Valerin, are you crying? And I told her, You have no idea what a big deal this is, because I knew that that was a shift, and it was the first time that I had ever seen a drug like that work and work so quickly. And that woman lived, I believe, for, um, she passed away just a few months ago, but she should have had only a couple of months to live at that point. And so, you know, she was able to still see milestones and see grandchildren born and and um so it was just Nothing short of a miracle. So when you have something like that in your hands, how do you exercise, you know, how, how are you judicious with using this medication and holding yourself in realistic expectations? I mean, that's such a magical moment, right? And I'm sure unfortunately it probably doesn't happen with everybody or maybe it does. So how do you balance even your own emotions with taking care of this vulnerable patient population that you, you clearly have, uh, an emotional investment in? Yeah, um, what I always tell people is that I practice cautious optimism because You know, I'm an oncologist and we always have to look at the glass half empty or half full, right? Um, and, um, so you, you plan for the worst, but you hope for the best. And you have to be realistic about your expectations with people. So, you know, I'm not going to tell everybody when they first walk into the room that I'm going to cure their disease. Um, you know, we have, as of today, a 13% 5 year survival. And I think that that number is going to definitely increase with these new medications. But, you know, the things that we talk about are, you know, what are the short term and long term. Goals for patients. So, you know, I might not be able to get you to 5 years, but is there a graduation that you want to see? Is there a wedding that you want to go to? Is there a trip that you want to, you know, go on? And we, we go based on those goals and trying to kind of live in the moment and live day by day with patients. So that's kind of how I manage my own expectations in my own heart and um. Yeah, you know, like I just, I tell patients, you know, I put on my boxing gloves with them because that's what we're gonna do. Is pancreatic cancer a surgical disease now? It can be, but only at this point about 20% of patients will be eligible for surgery. And as I said, even though that's the only way to cure the disease, um, but we have such a high recurrence rate. But what I do think is going to likely come down the line, my prediction is that we're going to use drugs like this, like the KRAS inhibitor, or for example, um, in locally advanced disease, which is where the cancer is still. Localized, it hasn't metastasized outside of the primary location, but it's wrapped around the blood vessels and is unable to be cut out. Um, in those cases, we're using other kind of interesting novel therapies in order to treat the disease locally to free it up from the vessels. So, for example, you lead in with a neoadjuvant treatment, maybe like a KRAS inhibitor or chemotherapy or whatever it is that you're using. And then we have these local modalities that we use with the interventional radiologists, things like TAAMP, which is like essentially where you deliver local chemotherapy at the artery level itself, or things like VTP, which is essentially like a photoactivated therapy where um we, we give a medication, same thing at an area. And we use a drug in order to activate it to um cause necrosis and cell death right around the vasculature. So, I think when we combine these novel modalities that we are also running in clinical trials here at UCI, um, that's the way that we're really going to push the limit and push the envelope to start, you know, raising that five year survival. So I love the talk about like partnering with IR and your surgical friends, but there are also some other sort of famous symptoms that come along with these drugs. We've mentioned like a skin rash that can be really tough on people. So tell us a little bit about some of the side effects and then how you're partnering with other faculty here at UCI Health to try to, you know, make headway on those as well. Yeah, you know, I mean, so that's, that's honestly is part of one of the reasons why I love being at UCI is because we are really collegial here. Um, it is not uncommon for me to pick up the phone in the middle of clinic and phone a friend and say, I'm walking into a patient's room, you looked at that imaging, you saw them a couple of weeks ago, like, what do you think? Um, in the case of these KRAS. Inhibitors. One of the main side effects that we're seeing is rash. So you may have seen the senator on or the former senator on TV with, you know, blood coming down his face. That probably happens in about maybe 10% of patients, but about 90% of patients will end up with some form of a rash. And so, um, You know, we work very closely with our dermatology colleagues in order to get them into clinic with them early. They see almost all of our KRRAS mutation patients who are on these medications, but they also see drugs of not the same class, but classes of medications that also cause similar reactions. So we have a little bit of experience already working with these drugs. And, and the, the The Bottom line is you intervene early and, um, additionally, you, if we have to, then we make dose holds and dose adjustments, you know, obviously, we have to go by the protocol, but I think it is going to be important to, when we, when we, you know, start using these drugs as a community oncology, that people are educated about what are the ways that they can manage the patients so they can stay on the medications for as long as they can. Um, that's the main side effect. We do see, of course, some diarrhea, we see some fatigue, we see sores in the mouth. Um, those are some of the common side effects as well. But the thing that I think is the most amazing about these medications, so, you know, for example, when we're giving chemotherapy, I try to give patients, you know, set expectations. OK? So what I'll say, one of our regimens, Folfirinox, it's a 3 drug regimen. And there, um, it's every 2 weeks. And so what I'll tell people is, is that the first day you spend the majority of the day in the infusion center in the chair. And then we give you a bunch of premedications that you will feel great for about 2 days later. Then you have to come back to the office and we unconnect you from a pump that we're using to give chemotherapy, and then you'll feel good maybe for another couple of days after that. And then you're going to take a nosedive, and you're going to pretty much be in bed for about 3 to 5 days thereafter, and then the last few days you'll start feeling better, and then we repeat. And that's the expectation of people's lives. Whereas with these drugs, especially when we get to the point where things are, you know, better managed and we have side effects controlled, patients are doing all the things that they want to do, and it's a pill, so they're not attached to the infusion center. And that also makes quality of life important, you know, better and important. How are you pulling the data in this because it's still an uncommon or would you call it a rare cancer, pancreatic cancer. It is still relatively rare, you know, so we have about 60,000 patients that are diagnosed per year, um. But I think that it's um the thing is, is that in 2030 it's estimated to be the second cause, a leading cause of death for cancer. Now that may change given these new medications. Um, so, so it is still relatively rare, but it is a deadly disease. So you share the data. So these trials are going on at multiple sites. Absolutely, yeah. Most of the trials that we run, because we do have what's called investigator initiated trials where they are usually single institution trials, which we do. Run ourselves here and I'm running a few of those, um, but for the most part, these are also sponsored by different drug companies that have the drug themselves or also by cooperative groups where we have national groups and cohorts that we, um, you know, run these at various different institutions. And one of the things we've been trying to do at UC Irvine is that we have a relationship with, um, all the rest of the UC, so the all UC Pancreatic Cancer Consortium for which I'm the president. And um it's, you know, us, UCSF, UCLA, UCSD, UC Davis, and we work together in order to run clinical trials because as a team in the UC system, we treat about 20% of patients with pancreatic cancer in California. So, one of these trials you mentioned, UCI you in your clinic have been enrolling like a lot of people, even more than some like, you know, perhaps more nationally known centers, like, what do, what do you think is driving that? Are, are people just understanding that we have excellent resources here or We have an excellent clinical trial portfolio, you know, out of our Stern Center. Um, we have great relationships with, like I said, our collaborators and also with different companies, um, and we have an excellent clinical trial team. And so, um, we have a lot of options available. And you know, the other thing is, is that the way that I approach pancreatic cancer. It's a team sport. You know, cancer is the enemy, not each other. And so, you know, like through like the UC system, for example, I have people that I am constantly messaging, like, I have a study for this, um, send people over, or do you have something for this? I'll send my people to you. And so we've become a very well known hub in Southern California and a referral center for patients. I also have a really great relationship with my community oncologist as well, because, you know, the thing about pancreatic cancer is it's a very intensive and difficult disease to treat. Patients have a lot of morbidity, you know, especially as you can imagine, like we were discussing. with, you know, someone comes in with a 50 pound weight loss, your pancreas is so essential for, for various different body functions, you know, glucose regulation, digestion of food. And so if that's not working very well, um, it's, you know, also we have complications of blood clots and other things. So, you know, when that's, those things aren't, that system isn't working appropriately, it's just a lot to manage each. Patient. So coming to somebody like me, where, you know, the large majority of my patients that I see are pancreatic cancer, um, and we have an expertise, we have, you know, nursing staff that's used to the phone calls that we get, we have a dietitian, we actually have several dietitians that specifically focus on on pancreatic cancer. We have a psycho-oncology team who's helping with the emotion. side of pancreatic cancer and with family members. So we kind of have the whole package that we've created. And, and then, you know, on our surgical side and on the IR side, we have expertise in this disease and um doing biopsies. We have a referral for all of Orange County, um, because we have a couple of um excellent specialists who are, you know, can get, get tissue and others can't. So do you, at this point, allow yourself to hope, even just a little bit? That the percentage can move. Absolutely. I mean, like I said, you know, this is such a different era than 20 years ago when I started this. And so I am so excited for all of the new treatments that are coming down the pipeline. I'm excited to be able to provide those to patients. Um, and, um, yeah, I think we're definitely going to, to, to move the, you know, Um, to, to, you know, move the numbers up over the years and um set a new precedent for the disease. Amazing. Well, thank you both so much for being with us today. This has been Physician Huddle by UCI Health. Thank you for joining us. This was an episode of the Physician Huddle podcast by UCI Health, produced by Brett Shaheehan, Angelica Yagubi, and Victor Ting. For more episodes, information on clinical trials at UCI Health, or to refer a patient, review the show notes or visit clinical connection. UCIhealth.org. Created by
