Listen to Nilofer Azad, MD, FASCO, and Zev A. Wainberg, MD, as they discuss novel RAS-targeted therapies for pancreatic cancer, including optimal KRAS mutation testing, emerging multiselective RAS inhibitors, and combination strategies.
In this podcast episode, Nilofer Azad, MD, FASCO, and Zev A. Wainberg, MD, discuss novel RAS-targeted therapies for pancreatic cancer, including the following:
Presenters:
Nilofer Azad, MD, FASCO
Professor of Oncology
Associate Director of Clinical Research
Sidney Kimmel Cancer Center at Johns Hopkins University
Co-Leader, Developmental Therapeutics Clinical Trials Group
Baltimore, Maryland
Zev A. Wainberg, MD
Professor of Medicine and Surgery
Co-Director, GI Oncology Program
UCLA School of Medicine
Los Angeles, California
Content based on an online CME program supported by an educational grant from Revolution Medicines, Inc.
Link to full program:
https://bit.ly/4avdRZK
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This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.
Experts Discuss Novel RAS-Targeted Therapy for Pancreatic Cancer
Introductions
Dr. Azad: Hello. My name is Nilo Azad. I am a Medical Oncologist at Johns Hopkins, the Sidney Kimmel Cancer Center here in Baltimore, Maryland. I have really been focused for my career on early-phase drug development of new agents, and in particular in the realm of GI cancers and pancreatic cancer.
I am here with my friend and colleague, Dr. Wainberg. I will let him introduce himself as well.
Dr. Wainberg: Hi. Zev Wainberg, GI Oncology at UCLA. I also do a lot of drug development and GI cancers. It is a pleasure to be here and chat with you today about RAS-targeted therapies.
Brief Overview of Therapeutic Needs in PDAC
Dr. Azad: Dr. Wainberg, you and I have been playing in this space together for some time, and it is such an exciting time when it comes to new drugs for patients with pancreatic cancer. There are so many different kinds of drugs that we could talk about today. I am very excited about the RAS-targeted therapies that we are going to talk about.
I was just curious what you think of overall when you think of what we need for our patients with pancreatic cancer?
Dr. Wainberg: Thanks, Nilo. No shortage of unmet needs here, as we know, for pancreatic cancer. Most of our effort and attention has been on the RAS-targeted space. However, we should keep in mind there is a whole bunch of other provocative targets that are being explored in pancreatic cancer.
It is really, in many respects, at least as long as I have been doing this, the most exciting time for new drugs in pancreatic cancer, and this centers back to the topic we are here to discuss today, it really all centers around RAS inhibition. That has been the huge growth in the last three to five years, in which the chemistry has really taken off here and has led to a whole number of effective agents that have entered the clinic.
I do not know what your thoughts are on that, but this is, for me, the most exciting time.
Why Target RAS Signaling in PDAC?
Dr. Azad: Yes, I completely agree. I even have had a slide in a lot of my talks lately where that is the last slide that I put up is, that there has never been a more exciting time to be in drug development for our cancers. Your point is so valid that not only is there an unmet need in patients with advanced cancer, where, of course, survival has still been dismal with our standard therapies, but we really could improve on every level of treatment for every pancreatic cancer patient.
We need to do better when it comes to adjuvant therapy. We need to do better when it comes to locally advanced treatments. So many of the drugs that you just mentioned are going to be deployed in those settings too, which is very exciting.
The other piece. A lot of these other biomarker-based therapies that are being developed. That just really speaks to how important it is to send a new pancreatic cancer patient that shows up in clinic for mutational testing and for sequencing, because for many years, we were demoralized because there were not really many actionable mutations. Now we are in a completely different world. So I really hope that people are treating pancreatic cancer now, the way we have been doing for colon cancer for years, where it is standard of care at the moment, somebody walks in the door that you are sending them for sequencing.
Dr. Wainberg: Yes, I completely agree. The era of, Oh, there is no value to getting a sequencing in pancreatic cancer is long gone. There are really many opportunities for, particularly RAS, obviously, and we will spend much of our time talking about that, but other targets as well.
In this day and age when more core biopsies are being done and when even ctDNA can give pretty good information, particularly on the dominant oncogenic mutations in this disease, it is really critical to get the information. I even think we are headed to a phase not too long from now where we will be getting it in adjuvant patients as well, not necessarily waiting to advance disease. I do not know what do you think about that?
Dr. Azad: Yes, I absolutely agree. In fact, some of the drugs that we are talking about that there is a large phase III trial for RAS signaling agents that is being deployed in the adjuvant setting. We are going to start seeing more and more of that with some of the more mutation allele-specific drugs that we are going to be talking about today as well.
Dr. Wainberg: If we are thinking about targeting RAS, obviously, we have had G12C inhibitors. The chemists really have led the way here, and they first synthesized molecules that were very effective, particularly in the G12C, which chemically at least was an easier target.
Both adagrasib and sotorasib are, at the very least, NCCN-designated for pancreatic cancer in the, albeit, rare, perhaps less than 1% or 1% of pancreatic cancer. That was really the springboard, right? Because we saw great results in our colleagues with lung cancer and great results with these chemicals in colorectal cancer, particularly when combined with EGFR inhibitors.
We were little envious of the efficacy of these agents. We were so hoping that we would have something extending beyond G12C, and we are in that era now.
I do not know what your thoughts are? When that all emerged, I was like, gosh, I hope we are headed there.
Dr. Azad: Yes, I feel very much the same way. I have been on some advisory committees where I sit with lung cancer doctors and they bring lung cancer and GI doctors together. I remember how it used to be when I started my career where lung cancer was in the place we are in now. But where lung cancer was the disease that people were most afraid of, and there were less therapies.
Now the lung cancer doctors have so many options. The KRAS G12C inhibitors, of course, really deployed first in lung cancer. They were seeing such beautiful responses. For us, it was just that 1% sliver. That is why it is so important that now we have these multi-RAS inhibitors and we have RAS inhibitors for other mutations, because it is really important for us to recognize that there is no tumor that has more RAS mutations, that is more RAS-driven than pancreatic cancer.
In fact, we are the archetypical tumor that is RAS-driven, right? 90% of patients with pancreatic cancer have some RAS mutation. Turned out that G12C was only 1% or 2%.
When we think of the other RAS mutations, we are really covering 90% of our patients. Even in the other 10%, we still think that RAS signaling is upregulated. So targeting RAS signaling in pancreatic cancer makes the most sense. The data that we are starting to see from these RAS inhibitors is really helping us convert our cancer into some of these other tumor types that have had success before us.
You briefly mentioned a few different ways that we can check for RAS mutations. What is your testing algorithm? How do you test for both KRAS and other mutations in pancreatic cancer?
Testing for KRAS Mutations in PDAC: When and How
Dr. Wainberg: I prefer tissue testing if it is an option. We usually send to any of the external vendors that cover both DNA and RNA. That is an important point. There is so many commercial vendors out right now and personally getting full NGS testing, which covers things like MTAP and a full complement of sequencing is important.
Also, in addition, we do germline testing, of course. In the patients that have no tissue available, someone with an absolute fine-needle aspirate, which has no associated core biopsy tissue, we are using circulating ctDNA assays to look because it is sufficient for the most part for the dominant KRAS alleles. That is how we are thinking about it.
Dr. Azad: Yes, we do things very similarly. Lately, we have been actually often co-ordering tissue and blood testing. That might be a little bit specific for where I work, right, because we have so many clinical trials that are in that first-line setting. So the sooner we have that KRAS mutation back and with ctDNA, you can get that testing back in under two weeks, versus a brand new tumor tissue testing. Especially sometimes we do not have enough tissue in that, so then you even have a delay past that. But we definitely prefer tissue-based testing if possible as well.
Dr. Wainberg: Yes, it is still better, albeit the quality of these ctDNA assays, particularly if you are looking for KRAS G12D, KRAS G12V, we will talk about the specific isoforms, but those are the most dominant ones. It is pretty sensitive for those assays.
Importantly, and this is what we will talk about in a minute is, the eligibility for the majority of these clinical trials now will accept liquid-based assay. That has been a huge growth in pancreatic cancer because it acknowledges the reality that sometimes you just do not have tissue or the tissue is insufficient.
For things like G12D, G12V, again, G12C, the dominant KRAS isoforms, ctDNA is often very sensitive and very specific. That was a huge decision that the dominant KRAS inhibitor studies made, particularly for this disease.
Dr. Azad: Agreed. Absolutely.
Emerging Therapeutics
Dr. Wainberg: Maybe we will talk a little bit about some of the specific therapeutics that are obviously very exciting. We have learned to classify drugs quickly into allele-specific or pan-RAS and then another way of thinking about it is RAS on, RAS off.
I wonder if you could just give us a quick overview, Nilo, as to some high level explanations.
Dr. Azad: Sure. When we have both native KRAS and mutated KRAS that protein cycles between being on and off. When it is on, of course, the RAS signaling circuit is on. When you have a mutation in KRAS, we now have a KRAS protein that is constitutively active. It is just much more on than it is off compared to a wild-type RAS protein.
Many of the drugs that are being developed are being developed and they will only bind and inhibit KRAS when it is in that on-conformation. There are other drugs that will bind RAS in either conformation, and in fact, some drugs that will only bind it in the off-conformation.
These all just speak to how active these drugs might be. That is one part, how toxic they might be and how long their durability may be. A lot of this is theoretical. It makes sense that if you can bind RAS in both the on and off setting, that perhaps that that drug would be more active and stay active longer. But that is theoretical. It is very possible that even when a drug binds, because the cycling to the on-conformation is so common that that is all you need.
These are things that are going to come out over the next few years as we start comparing some of these different drugs to one another.
For today's situation and what we are doing with patients, that piece is less important because we do not have data about it. What is more important is to make sure that if you have a pancreatic cancer patient, you are doing everything that you can to get them access to a KRAS inhibitor.
That maybe, god willing, sometime soon, might even be standard of care. It is already standard of care for patients with KRAS G12C mutations, where they can get adagrasib or sotorasib in the second-line as standard of care therapy. But very soon we may have other agents that are improved and available for patients.
When you think about all of these different drugs, this is a great time to just start talking a little bit about the early data that is coming out from some of these drugs. Why are we so excited? What are we seeing with these drugs?
Dr. Wainberg: So almost every meeting, we see new data, which is really exciting. And we are expecting to see new data, which makes it even more exciting because we are going in and saying, “Gosh, we cannot wait to see what this KRAS inhibitor shows or that one.”
The leader in the field insofar as drug development is going is daraxonrasib, which is a pan-RAS on/off inhibitor. It has a unique binding. It is a tricomplex inhibitor, which takes advantage of some chemistry in which it has a very small binding pocket and essentially binds to ubiquitin component and then fits in nicely into the pan-RAS and into all RAS, which includes wild-type and mutant RAS.
It has been the drug that has had multiple meetings now been presented with single-agent activity in the order of 30% to 35% as a single agent in refractory pancreatic cancer. So if we think about that, that is at least one line of therapy. Sometimes, often patients with two lines of prior therapy, we are looking at a response rate of about 30% to 35%, ballpark.
Beyond that, some of the very exciting data that has been presented at a few meetings, albeit not yet quite published, is a median PFS approaching eight to nine months in the second-line setting, which is showing you not just response, which is not the main important variable for drug approval usually, but also durability and sustainability.
That median PFS really struck a lot of people as quite impressive. That led quickly, as you know, to a randomized phase III trial, which has completed enrollment. Actually expectations are, at some point in 2026, we are going to see that result of randomizing about 500 or so patients to either standard of care chemotherapy, which was investigator's choice versus daraxonrasib.
We are all really excited to see that result. That has got a lot of people very excited. Beyond that, of course, daraxonrasib has moved into frontline studies, has moved into adjuvant studies. So moving it earlier as quickly as possible is where that drug is going.
Dr. Azad: Yes. I will add in that just a little bit of context that when you mentioned that eight to nine-month median PFS seen and, of course, that is not a large study. That is the initial study, but it still was a good number of pancreatic cancer patients. That compares favorably to what was seen with FOLFIRINOX in the first-line.
FOLFIRINOX in the first-line did not even make seven months progression-free survival. That is why we are so excited to see what we have seen in the second-line with daraxonrasib. This year there is a launch of the first-line study that is randomized. There is also the launch of the first-line allele-specific inhibitor.
I am going to ask you right now, like when you think about the pan-RAS or multi-RAS inhibitors like daraxonrasib, and you compare those to drugs that are more allele-specific, which, for example, the G12D mutation, which is present in a 40% of pancreatic cancer, so still a lot of patients. What has been the difference between those two? I know we are not supposed to do cross-trial comparison, but they are reporting both and they are both exciting. What do you think about allele-specific versus multi-RAS?
Dr. Wainberg: Okay. From a toxicity perspective, we all expect and we have all seen this in the clinic by now the pan-RAS inhibitor, daraxonrasib, suffers from a rash. That is the single most common toxicity, and it can be a difficult rash to be fair. It requires management. It requires aggressive dermatology management. It also has some other toxicities, mucositis. What is spared when you look at allele specific drugs, by and large, what we are seeing there is a little GI toxicity perhaps. So there is going to be certainly a trade-off of toxicity that the allele-specific drugs probably have a little less toxicity than the pan-RAS inhibitors.
Now, speaking specifically, there are a whole bunch of G12D inhibitors. Zoldonrasib, obviously, is showing very nice safety data. There is a whole bunch of others and including some combination data. Incyte has a very active G12D inhibitor, which also has response rates somewhere in the 30% range with probably similar median PFS, which has not been reported yet, but it is approaching those numbers.
From a clinical perspective, when we look at cross-trial comparisons, it is very hard to say. From a toxicity perspective, my sense is that the allele-specific drugs, at least the D inhibitors have a little less toxicity profile.
Now I am curious to get your perspective, because I have heard both sides of this scientific argument that some people are saying it makes more sense to start with allele-specific and then move to a pan-RAS versus vice versa.
I have to say, I think we are headed in this direction very soon, where, believe it or not, we are going to be having to answer these sequencing questions. I have heard scientific arguments on both sides that seem compelling. I do not know what your thoughts are, Nilo?
Dr. Azad: Yes. The sequencing question is going to be key. I always think we have to keep the quality of life question in mind too, right? We, of course, want to do whatever is going to keep people alive the longest and have the best durability of response. In that setting, to me, it makes sense the idea that you might want to do an allele-specific inhibitor perhaps first.
Then we know that from the G12C experience that when resistance emerges, there may be some benefit to then jumping in with the multi-RAS. There is some pre-clinical data of that as well that has been reported by the companies in the last couple of years, as well as investigators that if you do allele specific, you can then rescue resistance potentially with the multi-RAS inhibitors.
Another question is should you give them together? Are you going to do better by giving them together at the beginning? There is, which one first? Then there is also, is together better? Some of that is around feasibility of drug development if a company has both and they can combine both. If they do not, it is a little bit more difficult. That is going to be an interesting and important question as well.
Always keeping quality of life in mind. In fact, daraxonrasib, zoldonrasib, they are both from the same company and there is a clinical trial plan that is going to be looking at that question that will be really interesting, whether combining with chemotherapy is better versus whether you give the agent alone and how do you do that? It is exciting times.
The one thing I do want to mention is now there are so many drugs in this space. The last time I looked this up, there were 30 drugs that were being developed in the KRAS space. The clinical data you were talking about has been really compelling. There have been some misses, though. There have been some drugs that, initially in the laboratory looked good, but then they were not able to get the high levels that they needed in patients.
I do not think they are necessarily all going to end up being the same. It is important to look at which trials a patient is being offered and make sure that we can do our best to strategize in that way.
Dr. Wainberg: Yes, I completely agree. This will take a number of years to sort out, which is, of course, exciting for patients, because it means there is more opportunities to participate in this. Usually, after the clinical experiments are done, the most effective agents hopefully will rise to the top. That is the way it works.
I will say this has been a great discussion, and I really think it is, like we said in the beginning, such an exciting time. The one thing that I have been struck by, though, is how many of these drugs now are moving quickly to the front line? What that means is the reality is that the studies are not available for a large majority of patients.
So one of our tasks is to make sure, and I am sure you have this problem, as do I, that even patients who receive chemotherapy in the beginning may still have opportunities to participate in these RAS inhibitors. When all the companies move to the front line, there is this void that is left in the field and we have to make sure that we are managing that.
Dr. Azad: So true.
Dr. Wainberg: It has been a great discussion, though, and thanks so much for taking the time. It is always fun to chat about this kind of stuff.
Dr. Azad: Absolutely. It is always good to be able to go back and forth with you about anything around this stuff. Thank you for spending some time with us and with me on this.