Research Aims to Expand RAS Inhibitor Options in Pancreatic Cancer

Brandon G. Smaglo, MD, FACP

The improved understanding of the biology of RAS 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 OncLive® 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.

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

Smaglo: We've known about the role that RAS 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 RAS 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 KRAS. 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 RAS [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 RAS [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 RAS status goes; therefore, it's not going to be sufficient to just target one specific RAS mutation. We have to be able to target RAS [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 KRAS 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 KRAS 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 KRAS G12C mutations. However, [KRAS G12C mutations] are not very common in pancreatic cancer; approximately 2% to 3% of KRAS 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 KRAS, we might find KRAS G12D,for example, as the mutation that a person's tumor has. [However], other KRAS 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 KRAS mutations at the same time. Although we've gotten very granular around what the specific mutation is, if we use broader targeting of a KRAS 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 BRCA 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.

Given the heterogeneity of RAS 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 KRAS 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 KRAS 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.