Episode 52: A New Trial in Pancreatic Cancer

Dr. Deva Mahalingam shares on Healthcare Unfiltered EXPRESS a new paper published in Nature Medicine on a regimen showing significant promise in pancreatic cancer. You want to listen to this podcast and check out the paper. https://www.nature.com/articles/s41591-026-04327-4

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Transcript

SPEAKER_01 0:01

Welcome to the Healthcare Unfiltered Express, where I conduct short video interviews packed with relevant and timely information that you cannot miss. So sit back and enjoy the show. Well, very excited to host Dr. Deva Mahalingham on Healthcare Unfiltered Express. Deva, welcome to the show. It's your first time on the Healthcare Unfiltered series. Thank you for coming.

SPEAKER_00 0:25

Hi, Chari. Yeah, thanks for inviting me. I was I was I was pleasantly surprised to get your email last week and uh after we published our results. And so I'm happy to come here and talk to you about my study and also the the growing interest around pancreatic uh cancer given some of the new drugs that are coming. And I think there's a lot of excitement. I think we needed this excitement given a decade of uh you know of quietness of chemotherapy and negative results. So I think finally patients are now gonna get some options in this space, you know.

SPEAKER_01 0:57

So well, absolutely. Congratulations. And uh, you know, we uh we are uh uh you know a pedigree of northwestern right now.

SPEAKER_00 1:05

You know, you're you're at northwestern right now, right? Yes, I'm I'm currently uh I'm a GI medical oncologist and I kind of oversee the developmental therapeutics program and also the AD of clinical research at Northwestern. Yes.

SPEAKER_01 1:17

Congrats on everything you're doing. So let's let's delve deep into this. First of all, congratulations on the paper. Came in the nature nature medicine, I believe. Yeah, um, this is uh not an easy feat. It's uh one of the most amazing journals out there. So congrats. Take us through uh the paper and uh uh what the premise is and why this trial was conducted.

SPEAKER_00 1:39

So I I think to to kind of uh talk about the paper that was published uh recently, I think we need to go back to where it all started. You know, so this um I have to credit the scientists that worked on this this new pathway. You know, I mean no one has heard of it. You know, many of us in the oncology space, we are used to certain targeted treatments, and then suddenly out of nowhere, someone hears about a target known as GSK3 beta. And and and GSK3 beta, at least in its initial infantile days 15 years ago, were kind of people were trying to look at it in kind of neurodegenerate conditions and stuff like that. Uh, but certainly in the labs, when experiments were going on, uh we found that there was certainly an anti-cancer property, it's just based on some of the mechanistic actions that were going on at the time. So this is an academic collaboration uh between Northwestern, uh, the Mayo Clinic was involved with some of the preclinical work as well as UIC, all working to try and figure out what would be the developmental pathway for this compound. There have been one or two pharma drugs that have come out, you know, in so we were not the first two patients. There have been a GSK3 inhibitor in the past, but the properties of the drug made it kind of hard. The pharmacokinetic properties were poor, so never really kind of took off in the cancer space. And then this drug came along, uh, it was known as 9 ING41 before it was named L.R. Glucip. And some of the preclinical activities that were done at the time uh would suggest that certainly oncology would be a space, and some of the work that was going on in the lab was focusing on colorectal cancers, breast cancers, including pancreatic cancers. And uh, and based on some of the initial preclinical data, we did some kind of animal studies in vivo work, and finally this drug was spun off uh out of Northwestern into a small biotech known as Actuate. And I was fortunate enough to come to Northwestern around the time and they were ready to start early human trials. My colleagues and I across the country were involved in a lot of this kind of early phase one trial development, looking at how this drug was work working. And we published this paper in uh clinical cancer research a few years back where we did a wide variety of tumors, solid tumors, and you know, we were startled by some of the single agent activity. We saw a melanoma patient who had a complete response, we saw cutaneous T cell lymphoma who had a partial response just with single agent. And we always kind of can work across tumors uh because yeah, we don't normally so like with any kind of phase one trials, we we did it across a variety of tumors, but we were kind of seeing benefits across a variety of tumors. Uh, but the the development path was always on pancreatic cancer, just based on some of the mechanistic work that we were doing already. And so I think uh, you know, but you know, so whether this drug has got the potential to be applicable across a variety of tumors, that work is ongoing, and some of my colleagues are doing that in other tumor types. So this is a new class. I think the excitement around it and got into nature was because of its new class of agents that obviously was positive in a very tough cancer, right? So I think that and in, you know, the mechanistic actions of how it works is still needed to be teased out, you know, because we we kind of explored a variety of pathways that it kind of works on. And then uh, you know, and then when the we ran some of the early trials in pancreatic cancer, we did a single-arm trial that we published in Asthmo Open last year. We we saw, like, although the responses were not much better than historical controls and the PFS was only modestly better, patients were living longer, patients were on the trial longer. Some patients had kind of dropped the chemo and was just taking the drug alone as a maintenance strategy just to have a chemo break, as we do in pancreatic uh treatments. And some patients were living a year and a half later. We just don't know, we didn't know why. They were just kind of hanging around with us and doing well. Uh, none of these patients, none of the patients on any of the LRA trials were on a K RAS inhibitor. So people always ask me that hey, maybe it was the when they progressed, they won KRAS inhibitors. No, no one, no one on the nature publication trials uh went on to get K-RAS inhibitors.

SPEAKER_01 5:31

So, in that nature publication, what was the actual treatment that was received and what were the results of the treatment?

SPEAKER_00 5:38

Yeah, so obviously this uh we wanted to combine uh all of the clinical development was the single agent and then in combination with GAMA braxiin. So the patients got standard gem abraxin in combination with ELRA that was given weekly on the days of the chemo. We had this run-in where we had, because early on in the phase one trial, it was we were giving it twice a week, but we had a run-in of a twice a week versus once a week versus the chemo alone, a three-arm design. And then during the run-in, we found that the weekly regimen and the twice-weekly regimen were equivalent, you know, from an efficacy point of view. It was easier to give the patients giving the treatment once a week with the chemo. They would come in, get the LRA, the chemo, and then they would kind of go on. And the chemo can kind of you know, over time can be reduced or dose reduced based on AEs and stuff like that. And that's pretty much it. And then there was a control arm. So basically it was a two-to-one study uh with patients getting LRA versus uh uh standard GMO brackin.

SPEAKER_01 6:34

And you know LRA plus chemo versus chemo plus plus SEBO?

SPEAKER_00 6:38

No, that's chemo. So open label LRA plus Gemma Brackin chemo versus Gemma Braxin alone.

SPEAKER_01 6:44

Yeah, yeah. So okay. And what were the results?

SPEAKER_00 6:47

So the the results were uh uh basically the primary endpoint was uh uh uh kind of a one-year, 12-month overall survival rate and median overall survival. So we the power was calculated to see an improvement in the one-year overall survival rate, and we saw a near doubling of that. So 22% versus 44% in terms of the 12-month overall survival rate. And the median overall survival rate was improved by about 2.9 months. So we saw an improvement of median overall survival of 2.9 months with a hazard ratio of 0.62, so a 38% risk reduction in the death. Now, one of the challenges with the the study is that the historical gem abraxin seemed to be a little bit lower than what we are used to. And I, you know, this was a phase one, two randomized study. So a lot of the eligibility criteria was flexible. We didn't, you know, we did not restrict like what we do with registration trials where we say if someone is anorexic and is losing weight with pancreatic cancers, they have low albumin. We we didn't we didn't restrict it. Some trials do restrict that things like that. We didn't restrict on tumor burden. So a lot of these patients had, you know, we had patients with 50,000, 60,000 uh CA99. And so more than 25% of our patients had large disease burden just by CA99 graded in 8,000. So, you know, we we did not restrict that. And generally, when you think about gemraxian backbone, you you know, the comp the opposite would be polforinox, which is usually reserved for patients who are better performance status. Generally, there's this kind of you know bias in investigators to kind of put people into gem abraxian when they are a little bit on the borderline of like zero and one and two, you know. So generally, I think it was very reflective of community uh kind of practices. In fact, some of the trials were run in some of the community sites in Minneapolis, min, you know, Minnesota, and all that stuff. And uh so we saw that the uh uh very reflective of real-world uh over uh control arm data, despite that, you know, we uh we saw an improvement of uh 2.9 months or a 38% risk reduction in the death of patients on study. And the other thing to note is that we with pancreatic trials, it's not easy. You know, we have this groups of patients that within the first month they drop off for whatever reason, yeah, because they have very aggressive cancers. So we see this kind of drop-off, and we see it in other trials as well. And you'll always see this kind of early drop-off in that in the Kaplan Meyer curves, and we saw that too. But then we started seeing the separation very early on, within two months in the Kaplan Meyer curve, and then it persisted. And so this drop-off, you know, if you select your patients properly, you might kind of save some of the drop-off. And if we take patients who completed one cycle and beyond, the survival is improved. That you know, we see a four months difference, you know, like 12.5 and 8.5 difference, you know, just by even if you select the groups that maybe might not make might be, you know, not as sick starting off the trial. Uh so overall, in every angle, in every kind of subgroup analysis that we did, whether they had liver metastasis, no liver metastasis, they all benefited from the the treatment in terms of survival.

SPEAKER_01 9:44

A couple of more questions, Dave. One is uh this is a frontline uh therapy that you did. So uh it's probably gemraxin, like you mentioned, is more commonly used in the community. Do you feel that um I mean are you able to extrapolate if somebody's gonna get folpharinox or modified folpharinox? Do you feel the drug is um can be combined with this or you really can't tell?

SPEAKER_00 10:04

Yeah, so we did the same trial. So Colin Weeks and MGH should be presenting his study. Uh so with the the same study he did, he did it in combination with uh folforinox with the drug, and he felt you know patients were tolerating it. He also wanted to add another thing of using Losartin. So he kind of looked at it at two different angles, and he should be presenting, he's kind of shown some safety results, but I think he should be hopefully showing an efficacy results in the uh in the coming months.

SPEAKER_01 10:33

What's next for this drug? It seems it's it's promising. Um, and uh the trial is impressive, like you mentioned. I mean, this is an awful disease. What's next for the drug? What are you guys doing with this drug?

SPEAKER_00 10:44

Yeah, I think you know the the goal was always to kind of do a kind of confirmation, large phase three trials. Uh, you know, what has changed is obviously the current landscape in pancreatic cancer with the RAS inhibitors coming in, right? So we do have RAS inhibitor trials. Now, you know, the recent resolute uh study just, you know, gave a press release showing a second line study showing an improvement in survival that was impressive enough that I think it would be the standard treatment in second line. But a lot of the a lot of the trials that are ongoing right now in pancreatic cancer is trying to add RAS inhibitors to the chemotherapy, whether it's germobraxin or whether it's falforinoids, right? So, with this landscape, the question is if this changes, if we ran any trials going on right now with uh, you know, DR drug plus the chemo, even if it was positive, how will the RAS inhibitors come in? So I think everything we are thinking in the pancreatic space is like now that we have RAS inhibitors, how do we, you know, how is the trial going to change if even if you have a positive results, should the RAS inhibitors come into play in the frontline setting, uh, which is really the the reason why we've been kind of trying to figure out how to uh kind of design a registration trial, taking into account this changing landscape in the pancreatic space. It's very to me, it's an exciting time to be because patients are going to be given greater options, which they really never had. Uh, and but I I still believe that regardless of what drugs that they're going to get, you know, that is there uh a way to partner some of these drugs together? So we are doing some preclinical work right now, uh, where we would we're starting to see Rust resistant tumors developing. We've got those models in the laboratories and whether LRA, and we do know that it does it, at least in mechanistically, it does partner with some of the partnering proteins in the Rust RAF pathway. So we're actually doing that experiment right now, and I think that will kind of decide how we would kind of design our frontline or second line trials in pancreatic cancer.

SPEAKER_01 12:42

Deva, congratulations. This is uh it's a great paper, uh, caught our attention uh with a tough disease and uh well-conducted trial. And um congrats to you and to your uh to your co-authors.

SPEAKER_00 12:54

Any last thoughts before I let you go? I you know, I I think I I cannot, I'm glad, you know, I want to thank all of my co-authors, all of the sites, you know, this obviously any clinical trial, like you know, obviously you you present the data, but uh I know having been co-authors on many, many trials in the past, that it takes a village, everyone puts in a lot of work, and this goes to the even the clinical research teams that put in so much work that they go unnoticed, you know, they do a lot of the heavy lifting in most academic institutions. And I think everyone, you know, everyone involved with it was happy that it was a positive trial. And I think it's nice to have that wins after so many negatives in pancreatic cancer. And really, I think it's an interesting space, uh, interesting target for other many of my other colleagues to look at in other tumor types to see whether there's a pathway for something else maybe we are missing uh that might be applicable in other tumors uh that they they are treating themselves. And for the patients, at least it gives them an opportunity to look at options for pancreatic cancer that has been so limit limiting, and the growing landscape of drugs that are coming certainly gives some patients hopes as well. So thank you, and I look forward to having you again. Thanks, Jody. Thank you.

SPEAKER_01 14:02

Thank you for listening to this edition of Healthcare Unfiltered Express. Until next time, take care.