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Biomarker testing is now critical for the management of all advanced solid tumors, more or less. It is now one of the first things we do whenever a patient is diagnosed with metastatic cancer, whether it be lung cancer, colon cancer, or pancreas cancer. The first thing we want to [do] is understand the biomarkers.”

John H. Strickler, MD, professor of medicine, Division of Medical Oncology, co-leader, Precision Cancer Medicine and Investigational Therapeutics Program, Duke Cancer Institute, discusses the role of biomarker testing in the management of advanced solid tumors, including metastatic pancreatic cancer. He shared these insights during Pancreatic Cancer Awareness Month, which occurs in November each year

Biomarker testing has become a cornerstone of the management of pancreatic cancer and other solid tumors, Strickler begins, noting that molecular testing should be among the first steps taken upon diagnosis. The goal is to identify actionable genetic alterations that can help guide treatment decisions, and these testing methods include tissue biopsy, liquid biopsy for circulating tumor DNA testing, and single-gene assays.

However, single-gene testing is less common due to inefficiency, especially for tumors associated with multiple actionable targets, Strickler adds. Instead, next-generation sequencing (NGS) or comprehensive genomic profiling (CGP) is the preferred approach, enabling simultaneous analysis of numerous genetic alterations in a single assay. This testing is intended to identify both somatic mutations found in tumors and germline mutations found in patients.

mutations occur in approximately 90% of patients, biomarker testing plays a pivotal role in identifying patients who may be eligible for emerging targeted therapies being investigated in clinical trials, Strickler explains. The integration of CGP and NGS into routine clinical practice has streamlined the process of identifying actionable mutations, enhancing the precision of therapeutic strategies. These advancements also highlight the importance of tumor genomic profiling in expanding treatment options and tailoring therapy to individual patients, Stricker concludes.

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John H. Strickler, MD, discusses the role of biomarker testing in metastatic pancreatic cancer.

Dr Strickler on the Role of Biomarker Testing in Pancreatic Cancer

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In pancreatic cancer, [approximately] 80% to 90% of patients will have a mutation somewhere in 

 [These mutations are common enough] that it makes a lot of sense to chase down [these targeted therapies]. It's something where probably most patients, if not all patients, are going to have something that we can offer them if we can understand the status of their mutation."

Brandon G. Smaglo, MD, FACP, associate professor, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, discusses how advances in understanding the biology of 

mutations have helped catalyze the further development of novel RAS-targeted therapies for pancreatic cancer. Smaglo expanded upon these developments during Pancreatic Cancer Awareness Month, which occurs in November each year.

 can be found in the vast majority of patients with pancreatic cancer, making this a logical target in this malignancy. The role of RAS mutations in pancreatic cancer and other solid tumors has long been understood, but 

 mutations were historically considered "undruggable" targets, Smaglo explains. However, the prevalence and oncogenic role of 

 alterations in driving tumor progression and resistance have ensured that research efforts to develop RAS inhibitors have remained a priority, Smaglo explains.

Recent advances in molecular biology and drug development have enabled the identification of compounds capable of selectively targeting 

 mutations, which could eventually lead to additional treatment options, he says. Although work attempting to develop safe and efficacious RAS inhibitors has persisted, developments with novel agents in recent years have started to shift the needle, Smaglo says.

Data emerging from early-stage clinical trials evaluating these inhibitors has been encouraging, and the development of these agents could open the door for targeted therapies to play a larger role in the pancreatic cancer treatment paradigm, which has largely been a chemotherapy-only space, Smaglo concludes.

Brandon G. Smaglo, MD, FACP, discusses the ongoing research with RAS-targeted therapies for pancreatic cancer.

Dr Smaglo on the Evolution of RAS-Targeted Therapies for Pancreatic Cancer

The improved understanding of the biology of 

 mutations has helped drive the development of novel RAS-targeted therapies for the treatment of pancreatic cancer, according to Brandon G. Smaglo, MD, FACP, who added that integrating more of these treatments into the paradigm and into earlier settings remains a key focus.

“This is a time to be excited for the future [regarding] what we're going to be able to offer our patients [with pancreatic cancer]. Hopefully, we get to a point where patients and providers are able to see this diagnosis as something [other than] a death sentence; [rather, it could be a disease that] is manageable, treatable, and controllable without [unacceptable] toxicity from the therapy,” Smaglo said in an interview with 

® during Pancreatic Cancer Awareness Month, which occurs in November each year.

In the interview, Smaglo detailed ongoing research with RAS inhibitors in pancreatic cancer, explained how the development of these agents has evolved, and highlighted additional work underway in the pancreatic cancer space.

Smaglo is an associate professor in the Department of Gastrointestinal Medical Oncology of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

: Why is ongoing research regarding RAS inhibition imperative for the management of pancreatic cancer?

 alterations and mutations play in pancreatic cancer and other cancer types for a long time. For so long, [RAS was considered] the undruggable target. With that being said, because 

alterations are such a common target, people have never shied away from finding solutions [to develop targeted therapies]. In pancreatic cancer, somewhere between 80% to 90% of patients will have a mutation somewhere in 

. It's something where most patients, if not all patients, could have [a targeted treatment] that we could offer them if we can understand the status of their mutation [and continue to develop these therapies].

[RAS inhibition] is an area that has never been out of mind. However, particularly in the last couple years, we've seen some exciting trials [with novel agents] that are able to meaningfully target and inhibit RAS. [This research] is opening up a lot of new hope for us in a disease that, frankly, has [generally been] a chemotherapy-only disease.

Considering the success of targeted therapies for different targets in other tumor types, what has been the biggest challenge in developing RAS inhibitors?

[There are] a number of things [to consider], and part of that was just finding a drug that would work. Targeting a 

 [alteration] is part of a pathway, and being able to shut that down to a meaningful degree is not something that we were able to accomplish [in the past]. Certainly, part of the challenge has been [developing] a drug that would get to the pathway. Once [the drug] gets there, it needs to do something meaningful to enough of the 

[alteration] that it has a cancer-wide effect.

One of the things that we are starting to understand is that there is probably enough heterogeneity across an individual's cancer as far as their 

status goes; therefore, it's not going to be sufficient to just target one specific 

[alterations] as an entity. It's been a challenge in terms of finding a drug that worked well enough, was deliverable, and checked all the boxes that we need for a good therapy, [and these] have been barriers up until more recently with these inhibitors.

For novel RAS inhibitors under development, what differentiates them from prior agents? How has this class of drugs evolved?

One of the more significant distinctions we've been able to make is that we're understanding that not every 

mutation is the same. A lot of the discussions that we're having with our patients right now get back to the basics of biochemistry. What mutation is there? Where in that protein structure is the amino acid that is causing this problem? What did it mutate into? [Understanding which specific 

 mutation is present] is important to [determine] which drugs we're going to use.

Initially, a lot of the work was done to target those [different] mutations specifically. The biggest success story around this so far has been targeting 

 G12C mutations] are not very common in pancreatic cancer; approximately 2% to 3% of 

 mutations will be G12C. For those 2% to 3% of patients, that's great news since we have a potentially effective therapy for a bad disease.

With that being said, we probably are limiting ourselves if we're targeting only 1 residue mutation. Getting back to that heterogeneity of 

G12D,for example, as the mutation that a person's tumor has. [However], other 

mutations could be there and could be playing a role [in driving the cancer], and that may evolve over time. One of the things that we're learning is that we might see greater success when we can inhibit multiple forms of 

mutations at the same time. Although we've gotten very granular around what the specific mutation is, if we use broader targeting of a 

 mutation with a pan-RAS inhibitor, we don’t need to zero in on that very specific residue mutation where we might be under-treating the tumor and not [targeting] those other mutations that might be expressed in that patient's cancer.

Within the RAS inhibitor space, what is current research focusing on? 

Most of the studies are looking at [novel agents] in later-line therapy. For a patient with metastatic pancreatic cancer, that would probably be third-line therapy. Patients get chemotherapy with a fluorouracil[-based] combination and a gemcitabine[-based] combination in some sequence [in the first 2 lines].

As we're seeing how exciting these [later-line trial] results are, what a lot of us are eager to see is if we can move the RAS inhibition up [to earlier lines of] treatment. Should we be giving [these agents] in the second or first line? Should we be giving them in addition to chemotherapy, or maybe as maintenance therapy?

For example, 1 of our standard frontline treatments for patients is FOLFIRINOX [folinic acid, fluorouracil, irinotecan hydrochloride, oxaliplatin] or NALIRIFOX [irinotecan liposome (Onivyde), oxaliplatin, 5-fluorouracil, and leucovorin]. Those are both toxic [regimens], and the understanding is that patients are going to receive these chemotherapies for, at most, 4 to 6 months before moving on to maintenance.

Currently, maintenance would probably be [the continuation of] a single-agent chemotherapy; a PARP inhibitor [could be used as maintenance] if patients have a 

 germline mutation, but that's not too frequent. Maybe [the maintenance] space is where we can have great outcomes for patients. If you put them on a KRAS inhibitor after we've gotten good control with chemotherapy, you could potentially extend their time on frontline therapy. [Many of my colleagues and I] are excited to see where this goes. If we see that a drug is efficacious, how can we use it faster? How can we incorporate it into [the treatment paradigm alongside] our other therapies in a meaningful way?

Unfortunately, patients who go for surgery and get adjuvant chemotherapy still have a very high chance of recurrence. Statistically, that's approximately in the 70% range. Some institutions will do a little bit better than that, but nobody is guaranteed a cure [after surgery and adjuvant therapy], so we need better options [for those patients]. Being able to explore KRAS inhibition in addition to chemotherapy or instead of chemotherapy in the adjuvant setting is intriguing and an important next step as we better understand this disease space.

 alterations and the presence of other alterations in pancreatic cancer, what is the importance of molecular testing to identify the specific genetic components of a patient’s disease?

It's important for anybody with pancreatic cancer to [undergo] next-generation sequencing early after their diagnosis. Certainly, we are immediately gravitating toward where the 

 result is on that report. However, this is still [primarily] a chemotherapy-only disease, and [these test results help us determine] what we can to offer those patients as far as clinical trial therapy goes. We don't have multiple lines of therapy for most patients. If they do only receive chemotherapy, it would only be 2 [lines of therapy]. Thinking about that up-front is key.

Right now, most of us are immediately steering our eyes toward the 

status in those reports. Knowing that status early on is important because [clinical] trials are evolving so quickly. For example, we may not be looking at a second-line trial for a patient [at diagnosis], but it wouldn't surprise me if 6 to 8 months from now, when we do need a second-line trial for them, suddenly there might be an option with KRAS [inhibition].

The point is that it's never too early to know that [genetic] information for a patient, even if it is only to start thinking about [what their clinical trial options might be in subsequent lines of therapy] because these trials are competitive. This is a common finding, so it's not like we can always just enroll patients to a slot next week. We need to have some forethought into how we're going to work a trial into their entire cancer treatment journey.

What are the challenges in diagnosing pancreatic cancer before it reaches an advanced stage?

One of the challenges is that this is not a cancer that calls attention to itself when it’s localized. For most patients, there are no symptoms of a cancer that is contained to the pancreas. Even [patients who may have] classical, painless jaundice probably have pancreatic cancer that is advanced enough locally where surgery might not be possible or might not be possible unless we get a good cancer response [to treatment] due to the cancer and blood vessel involvement.

Finding a way forward where we can catch pancreatic cancer at an earlier stage is going to be important. A lot of promise is coming out of the work being done with circulating tumor DNA, which would apply across the cancer spectrum. Basically, patients would go to their primary care doctor, get a cancer screening blood test, and then, depending on what that shows, have additional workup. This could hopefully [help us identify] cancers like pancreatic cancer and others that might not be [easily] caught at an early stage. Having a better sense of how to identify these rare cancers is going to be important.

Unfortunately, if you look at how survival outcomes go, patients who have a cancer diagnosed at an earlier stage in the pancreas don't do as well as [patients with] other cancer types. For example, a patient with early-stage prostate or breast cancer has an approximate 90% chance of being cured, whereas [the cure rate for] pancreatic cancer at that same stage might be 30% to 40%. It's clear that finding pancreatic cancer early and having an operation is not enough. These are still immune-cold cancers, and they're not well controlled by the body. Therefore, having better adjuvant therapies is going to be key to [improve] outcomes. It's great if we can do surgery, but we need to know more about the biology [of these patients].

Outside of the RAS pathway, what other potential therapeutic approaches currently being investigated could provide additional treatment options for this patient population?

The holy grail is going to be how to use the immune system and some type of immunotherapy against pancreatic cancer. There have been a lot of trials that have [looked at ways] to modify the cancer environment in a way where it becomes recognized by the immune system to make immune checkpoint inhibitors useful. Those [approaches] are interesting. We haven’t cracked the code there, but there has certainly been some encouraging work.

The other thing that will bring us forward is being able to modify the immune system itself. Earlier phase studies have looked at cellular therapies, such as CAR T-cell therapies or otherwise, and even some vaccine studies. Weaponizing the immune system against pancreatic cancer is something that has a lot of potential and interest. Again, it's not going to be a simple matter of just tossing [an immune checkpoint inhibitor] into the mix; rather, we need to find a good way to modify, alter, or stimulate the immune system to go fight that cancer for us.

In honor of Pancreatic Cancer Awareness Month, what would be your message for colleagues about the ongoing research in this space?

It's a message of optimism. It's been a long time since we've had anything in this particular disease space that's been so exciting with what we're seeing now with RAS inhibitors and other therapies. This is probably a disease type where a lot of folks can get discouraged. I certainly understand that based on my own clinic and how things can go sometimes. However, we’re going to get there.

I'm happy for what we've seen in other cancer communities in the last decade or so. Look at melanoma with immunotherapy, for example. We're [may be] on the verge of having our breakthrough moment where we could start to see some good long-term outcomes.

Articles

Brandon G. Smaglo, MD, FACP, discusses ongoing research with novel RAS inhibitors in pancreatic cancer.

Research Aims to Expand RAS Inhibitor Options in Pancreatic Cancer

 mutations have emerged as a primary target in the development of pancreatic cancer therapies, and the scope of RAS inhibitors has grown increasingly complex, despite persistent challenges with targeting this gene, according to Tanios S. Bekaii-Saab, MD.

“I’ve always been optimistic that we would [reach treatment advances] at some point, but what I’m seeing today makes me excited.” Bekaii-Saab said in an interview with 

. “It’s going to make such a difference in patients’ lives. We’re on track.”

In the interview, Bekaii-Saab discussed the evolving role of RAS-targeted therapies for patients with pancreatic cancer, where future research in the field may be headed, and clinical practice reminders for his colleagues in observance of Pancreatic Cancer Awareness Month, which takes place in November each year.

Bekaii-Saab is the David F. and Margaret T. Grohne Professor of Novel Therapeutics for Cancer Research, chair and consultant in the Division of Hematology and Medical Oncology at Mayo Clinic, and co-leader of Advanced Clinical and Translational Science at Mayo Clinic Cancer Center in Phoenix, Arizona.

 mutations among patients with pancreatic cancer?

: Pancreatic cancer is predominantly driven by 

 mutations. Depending on what report you look at, including [Mayo Clinic] internal data, [the prevalence of 

 mutations] hovers between 85% and 95% of patients; it is probably approximately 90% to 93% of patients, so it’s a dominant [mutation]. Overall, 

 is the most mutated gene in human cancer, but in pancreatic cancer, almost every patient, minus 7% to 10%, will have a 

 is a driver mutation for many cancers. Among oncogene drivers, 

 is identifiably mutated in many cancers. In my world of gastrointestinal [GI] cancers, [

 is] primarily [mutated in] colorectal cancer [CRC] and pancreatic cancer, but [these mutations are] also present in other cancers.

 mutation] is an early event in the development of the disease. In pancreatic cancer—similar to lung cancer and a bit unlike CRC—it is a primary event on its own. With CRC, [

 mutations] get a little complicated because there are parallel, cross-talking pathways, [such as] EGFR.

 is a driving, mutated oncogene on its own, which opens the door for us to target it and see [treatment] effects. In colon cancer, to get the best effects, we have to target KRAS and shut down EGFR as well. In pancreatic cancer, [KRAS inhibition] seems to be a bit cleaner, but [there are] limitations of targeting 

 overall, and [we need to] overcome some of the resistance. However, at face value, [

 mutations are] a primary event [in pancreatic cancer], and they are a common event and sometimes a single event.

 gene affect patient treatment and the development of targeted therapies?

In pancreatic cancer overall, approximately 91% of patients will have a 

 G12D, [which is present in approximately] 40% of patients, followed by 

 G12V, which is in approximately one-third of patients, then 

 G12R and KRAS G12C [mutations, which are each present in approximately] 1% of patients and are the least common.

What gets complicated is trying to understand how RAS works. RAS is a membrane-bound regulatory protein; it belongs to GTPase family. That’s what switches it between an ‘off state’ and an ‘on state.’ In the off state, which is the inactive state, [RAS is] bound to GDP, and when it goes to the active state, it gains phosphorus and is bound to GTP. That’s a basic understanding. The efforts, though, to target KRAS have been unsuccessful for decades, primarily because it has a small binding pocket and a high affinity for GTP, which activates it. [KRAS also has] redundant mechanisms of post-translational processing, which make it difficult to effectively target.

 mutation] to be targeted because it was easiest to target, as a proof of principle, because its binding pocket is a bit more conducive to targeting, but also because of the way it interacts with its downstream effectors by actively cycling between GDP and GTP. To make the story short, it ended up being the most favorable [mutation] to start [targeting], despite all the challenges in all the decades trying to find this out. Starting with [targeting] 

 G12C led to [use of these agents in] the clinic, and now we’re seeing targeting of 

 G12S, and then the ‘on’ and ‘off’ pan-RAS targeted pathways. Once we could show as proof of principle that we can target 1 [

 mutation], we started going after the more common ones [individually].

 mutations within pancreatic cancer, what is the importance of biomarker testing to identify those specific alterations whenever an individual patient presents with this disease?

Many years ago, there was a discussion about whether we need to profile tumors from the pancreas, and the answer was no because all we were going to find were 

 mutations, and we couldn’t do much about them. For the longest time, that had been one of the limiting factors with pancreas cancer. The other limiting factor with pancreas cancer is the availability of tissue. Oftentimes, patients undergo endoscopic ultrasounds, they get a fine needle aspiration, [and we] get a little bit of tissue, but not enough to [conduct] profiling. [However, tissue] didn’t seem needed at the time, so we would not [biopsy] the larger lesions.

Today, it’s a completely different world, as it should be. The difficulties of the past are opportunities for the present and future. At this point, every patient with pancreatic cancer should undergo genetic or genomic profiling of their tumor. This is in addition to ensuring they undergo inherited panel testing to make sure there are no [germline] driver genes. That’s a different discussion, although it can lead to some changes in how we treat patients. However, every patient with advanced pancreas cancer should undergo genetic and genomic profiling.

One [reason for this testing is because we’re evaluating] the 

 mutation profile. We have more and more studies in the second- and first-line settings [with agents targeting] these 

 alterations. In the [National Comprehensive Cancer Network] Guidelines, there are 2 agents targeting 

 G12C [adagrasib (Krazati) and sotorasib (Lumakras)], but there are also [different recommendations patients with] microsatellite instability [MSI]–high disease or [those harboring] 

 [mutations], which have implications for the use of DNA damaging agents. [Some other] fusions are rare, but if you don’t look in every patient, you will not find them.

Even if an alteration is in 1 in 100 patients, if you don’t look consistently in the 100 patients, you’re not going to find the 1. If you make it random and have your own criteria to pick 1 patient [for testing] vs another, then it’s a 1 in 1000 or 1 in 10,000 chance to find that alteration. We should be consistent with testing and do universal testing for every patient.

How might ongoing research address some of the biggest unmet needs for patients with pancreatic cancer?

We’re starting to scrape the surface and work on the tip of the iceberg, but there’s a lot hidden under the surface that we still need to work on. Although we’ve made some strides with RAS targeting, unfortunately, even with 

 G12C targeting, I’ve had patients who have responded nicely to adagrasib, which targets 

 G12C. However, both with adagrasib and sotorasib, we still see patients who quickly progress; most patients will progress at some point. Although we’re targeting an essential component of the driving force for pancreatic cancer, we’re still not moving the needle significantly to the point where we can say that now we have this disease under control for years to come.

We also continue to think about how to move [RAS inhibitors] to earlier stages of the cancer. A bit more than one-third of patients will present with earlier stages of disease, and many of these agents that we are evaluating in later stages need to start moving to the earlier stages, where we can make an even bigger difference than what chemotherapy, surgery, and radiation are doing. It’s important to start expanding our understanding and the paradigm, but the unmet need is in every direction.

How can we improve outcomes significantly for patients with these targetable mutations? We’re starting to do well, but we’re not where we need to be yet. How can we prolong the responses we’re already seeing? How can we have more patients respond to these incredible treatments?

These are incredible discoveries. When I finished my training and thought about 

, I never thought I would see [agents] targeting RAS in my lifetime. Now it’s [being targeted] in every direction. That’s fantastic. Now we need to start building on that gain and moving those [agents] to earlier stages of the disease and earlier lines of therapy.

Most of the studies [with RAS inhibitors] have [been in] later lines of therapy. That’s good because that’s where we need proof of principle. The opportunity is that if we hit biology early in the game, we get the best outcomes. One strategy is to start asking: How do we move those [agents] to earlier lines of therapy and earlier stages [of disease]? This is where we’re going to start making an even bigger difference.

However, [we also need to] understand mechanisms of resistance and see how we can improve on resistance. A lot of studies are underway; we have hints about what drives resistance. Some of them pertain to the same pathway. We see other 

 alterations or amplifications showing up. With 

 G12C, we see quite a bit of amplification; [we also see amplification of 

 and other genes], but these are all relatively targetable, so trying to understand the dynamics of targeting and rising resistance will also help us start putting all these [agents] in place.

What areas of opportunity do you see for developing therapies that could complement RAS inhibitors and chemotherapy within the advanced or metastatic pancreatic cancer setting?

 [mutations] seem to be an initiating event with, commonly, little background noise. We have to understand the timing of targeting [the on/off stages of these mutations]; each of those alterations behaves a little bit differently. 

 G12C, for example, is one we favor targeting in the ‘off’ stage. 

 G12D [we consider targeting in the ‘on’ and ‘off’ stages], and then [there are all the stages] in between. It’s an interesting dynamic.

We hear a lot about ‘on-RAS’ targeting, ‘off-RAS’ targeting, [and agents that can] do both. We have to understand what all that means. It’s a complex equation. The ‘on’ inhibitors, for example, are interesting, especially the pan-RAS agents, which also target 

 wild-type. In that sense, they increase, at least theoretically, the level of toxicity. It’s a balancing act, and we have to understand where to place those.

Additionally, data have been published regarding the mechanisms of resistance to, say, 

 G12C inhibitors, since those are in the clinic right now. We see emerging mutations in 

 G12V, and others. We also see acquired alterations with the MAPK pathway. [There are also] some gene fusions, but I’m not clear on how to make sense of them.

[Furthermore, regarding] amplifications, proof-of-concept [studies have evaluated] other agents that could salvage [disease management after the development of] these types of resistance mechanisms. [One agent, which has been assessed] both in CRC and in lung cancer and is being evaluated in pancreatic cancer, is an agent called RMC-6291, which is a KRAS G12C ‘on’ inhibitor. We could potentially salvage some [off-targeted treatment] failures by moving to an on-targeted agent, especially because 

 G12C amplification is a driving force for many of these resistance mechanisms. In lung and CRC, patients have responded equally [to this agent regardless of] whether they were exposed to a prior KRAS G12C inhibitor. That’s interesting.

[Another advancement is the] development of pan-RAS inhibitors. Data with RMC-6236, which is a multi-on inhibitor, [were collected in patients with pancreatic cancer with all 

 G12C. [In patients harboring 1 of these mutations treated with 160 mg to 300 mg of RMC-6236 per day in the second-line setting (n = 42), the agent produced] a 29% objective response rate.

Is a multi-RAS inhibitor the right strategy to start with or to follow up with? We now have developments with [agents targeting] 

 G12V, etc., that are being developed to be specific to their targets. Then we have the multi-RAS inhibitors. How do you pick between the 2 if both show activity?

The answer is not simple yet, but at least what we’ve seen with the KRAS G12C ‘on’ inhibitors is that you can salvage a lot of patients who [progress on their first line of therapy]. Do we combine [targeted and multi-RAS inhibitors]? Do we sequence [these agents]? Do we add them to chemotherapy? How do we evaluate the dynamics of these mechanisms?

It’s an interesting field that’s emerging, but I think the right answer is we either combine or sequence [these agents]. Sequencing may be a good strategy, but we have to consider a partner for each of those sequencing strategies. However, we may ultimately have 2 pathways. One is, if we have a mutation or an alteration that predicts resistance early before we treat patients, then perhaps combining [these agents] makes more sense. If we have alterations that arise under pressure, which most of them do, meaning tumor exposure to, say, a KRAS G12C inhibitor, then it may make more sense to sequence [these agents]. These are aggressive tumors, so biological targeting is perhaps not enough, and we may need [the addition of] chemotherapy, at least in the induction phase. All these [treatment plans] are being evaluated. That’s good news. We have a lot of assumptions. Some proof-of-principle data have been established in some ways with sequencing, but there is more to be done.

Overall, reality is going to favor those [agents with] specific [targets], if they prove [effective]. For KRAS G12C [inhibitors], that accounts for approximately 1% [of the population], but with KRAS G12D–targeted agents, we’re seeing tons of development. [Many companies are] developing KRAS G12D inhibitors, which makes sense because that is the most common 

 mutation in pancreatic cancer. We’ll see if those [remain effective] as they move forward. They may be preferred.

What do we do with the pan-RAS inhibitors? How do we get them to turn on and off? Will the pan-RAS inhibitors ultimately replace them or [be combined] with them?

We’re seeing some sequencing studies and some combination studies with the mutation-specific and the pan-RAS inhibitors. We’re also seeing studies investigating combining those with chemotherapy, which makes the most sense in pancreatic cancer, but perhaps [they have a role] in other GI cancers. In lung cancer, they’re investigating immunotherapy and other [types of agents in combinations], depending on known entities to help with response. However, in pancreatic cancer, chemotherapy makes sense. Those tumors respond at an approximately 30% to 40% rate to chemotherapy. The thought is: if we combine them with the RAS inhibitors, we may deepen and prolong the response and even create a maintenance strategy after that.

There are a lot of possibilities. The RAS revolution has started. For pancreatic cancer, which remains one of the most devastating cancers, the RAS revolution is going to move the needle, as long as we know how to place all these pieces together. [I’m] optimistic, not just about RAS. There are a lot of other [targets] that are opportunities, but RAS is the biggest opportunity.

Since November is Pancreatic Cancer Awareness Month, what is your main message for colleagues about the state of research in the pancreatic cancer field?

I’m seeing a re-energized field of research in pancreatic cancer. We hit a wall at some point, because [we were only] asking: Can we add [certain agents]? Can we change chemotherapy? Can we look at 3 drugs vs 2 drugs? We got only more confused because, at first, we thought 3 drugs was better, then we showed that 2 drugs is probably at least as good, and some Japanese studies showed that it may be even better [for patients to receive] gemcitabine plus nab-paclitaxel [Abraxane] vs FOLFIRINOX [leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin]. Then we had NALIRIFOX [liposomal irinotecan, 5 fluorouracil, and oxaliplatin] data from the phase 3 NAPOLI 3 trial [NCT04083235] that show superiority to gemcitabine plus nab-paclitaxel. Now it gets even more confusing, and with all this confusion, the average survival has moved only a tidbit, but not much, for patients.

However, we’re seeing all these alterations now that we can go after, separate from MSI high, which is [seen in approximately] 0.5% of patients. Those patients do incredibly well with pembrolizumab [Keytruda] and other immuno-oncology–based agents, but [they represent only] 0.5% [of the pancreatic cancer population]. I have patients who technically were cured of their stage IV pancreatic cancer because of the presence of MSI high. It’s not common, but when you see it, it’s satisfying for the patient, and the responses are amazing. Even after 6 to 9 months of treatment, we see maximum responses. I’ve had patients drop [treatment] early, unable to continue through the whole treatment because of toxicities, and yet, 10 years later, I see them thriving and alive.

I hope we can find more ways to go after other targets, but we have 

 G12C–targeted agents, and we’ve seen adagrasib and sotorasib make it into the guidelines. I work mostly with adagrasib, and I have patients [who have achieved] significant and durable responses [with this agent]. [It has not been] enough, though. I want to see better. Now we have emerging strategies with the ‘on’ KRAS [inhibitors] that could salvage patients, such as the pan-RAS inhibitors, combinations, etc. We’re also seeing an emergence of KRAS G12D and KRAS G12V [inhibition] in addition to the pan-RAS inhibitors that are being evaluated extensively in pancreatic cancer alone, in combination with other RAS inhibitors, or with chemotherapy. I am excited about how energized the field is.

Other agents are targeting RAS. One specific agent from Immuneering, a MEK inhibitor, is showing promising early responses [in combination] with FOLFIRINOX. It’s too early to tell, but it seems that it’s on track with good, early responses. We’ll see what the rest of the study looks like. That’s all in that RAS world.

 fusions are those we primarily find, for example, in 

 wild-type group of patients, which is approximately 7% of patients, is target rich. This is where we see 

 mutations. Data with trametinib [Mekinist] and dabrafenib [Tafinlar] have shown interesting responses. I’ve had some patients with these [

] mutations who have had exquisite responses. Others have not.

We’ve scratched the surface for too long hoping to find a target, but now we have multiple targets, and we’re finding every way to go after these targets. 

 mutations are becoming prime targets, but also in 

 wild-type disease, several targets are being evaluated with a lot of promising results. The question is: How do we take those promising results and make them more interesting and durable? In the history of all other cancers, improvement starts with showing proof of principle, understanding why it works, understanding why it doesn’t work, and coming up with a strategy to enhance responses to make them more durable and make them more likely to affect outcomes. The research has to be bidirectional to earlier lines and later lines. I’m optimistic about the future of pancreatic cancer.

Revolution Medicines presents updated data from RMC-6236 monotherapy study in patients with advanced pancreatic ductal adenocarcinoma. News release. Revolution Medicines. October 23, 2024. Accessed November 4, 2024. https://ir.revmed.com/news-releases/news-release-details/revolution-medicines-presents-updated-data-rmc-6236-monotherapy 

Tanios S. Bekaii-Saab, MD, discusses the evolving role of RAS-targeted therapies in pancreatic cancer and where future research in the field may be headed.

Pancreatic Cancer Awareness Month: Updates in Ongoing Research in RAS Inhibition | Supplements and Featured Publications

Dr Strickler on the Role of Biomarker Testing in Pancreatic Cancer

Dr Smaglo on the Evolution of RAS-Targeted Therapies for Pancreatic Cancer

Research Aims to Expand RAS Inhibitor Options in Pancreatic Cancer

Continued Development of RAS Inhibitors Leads the Charge in Pancreatic Cancer Research