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

Tanios S. Bekaii-Saab, MD

RAS 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 OncLive^®. “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 leader of the Gastrointestinal Cancer Program at the Mayo Clinic Comprehensive Cancer Center, as well as the medical director of the Cancer Clinical Research Office and the vice chair and section chief for Medical Oncology in the Department of Internal Medicine at the Mayo Clinic in Phoenix, Arizona.

OncLive: How prevalent are RAS mutations among patients with pancreatic cancer?

Bekaii-Saab: Pancreatic cancer is predominantly driven by RAS mutations. Depending on what report you look at, including [Mayo Clinic] internal data, [the prevalence of RAS mutations] hovers between 85% and 95% of patients; it is probably approximately 90% to 93% of patients, so it’s a dominant [mutation]. Overall, KRAS is the most mutated gene in human cancer, but in pancreatic cancer, almost every patient, minus 7% to 10%, will have a RAS driver mutation.

RAS is a driver mutation for many cancers. Among oncogene drivers, KRAS is identifiably mutated in many cancers. In my world of gastrointestinal [GI] cancers, [KRAS is] primarily [mutated in] colorectal cancer [CRC] and pancreatic cancer, but [these mutations are] also present in other cancers.

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

In pancreatic cancer, KRAS 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 RAS overall, and [we need to] overcome some of the resistance. However, at face value, [RAS mutations are] a primary event [in pancreatic cancer], and they are a common event and sometimes a single event.

How does the heterogeneity of the RAS gene affect patient treatment and the development of targeted therapies?

In pancreatic cancer overall, approximately 91% of patients will have a KRAS G12 mutation. The most common is KRAS G12D, [which is present in approximately] 40% of patients, followed by KRAS G12V, which is in approximately one-third of patients, then KRAS 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.

KRAS G12C was the first [KRAS 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] KRAS G12C led to [use of these agents in] the clinic, and now we’re seeing targeting of KRAS G12D, KRAS G12V, KRAS G12R, and KRAS G12S, and then the ‘on’ and ‘off’ pan-RAS targeted pathways. Once we could show as proof of principle that we can target 1 [KRAS mutation], we started going after the more common ones [individually].

Given the prevalence of RAS 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 RAS and TP53 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 RAS mutations and the RAS mutation profile. We have more and more studies in the second- and first-line settings [with agents targeting] these RAS alterations. In the [National Comprehensive Cancer Network] Guidelines, there are 2 agents targeting KRAS G12C [adagrasib (Krazati) and sotorasib (Lumakras)], but there are also [different recommendations patients with] microsatellite instability [MSI]–high disease or [those harboring] BRCA2 [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 KRAS G12C targeting, I’ve had patients who have responded nicely to adagrasib, which targets KRAS 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 RAS, 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 RAS alterations or amplifications showing up. With KRAS G12C, we see quite a bit of amplification; [we also see amplification of MET 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?

In pancreatic cancer, RAS [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. KRAS G12C, for example, is one we favor targeting in the ‘off’ stage. KRAS 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 KRAS 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, KRAS G12C inhibitors, since those are in the clinic right now. We see emerging mutations in KRAS G12D, KRAS 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 KRAS 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 RAS mutations except for] KRAS G12C. [In this population, the agent had] a 20% [14+ week] objective response rate.1 [These data are] interesting but not strong enough.

Is a multi-RAS inhibitor the right strategy to start with or to follow up with? We now have developments with [agents targeting] KRAS G12D, KRAS 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 KRAS 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 RAS. We started with KRAS 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.

Then we have NRG1 fusions and RET fusions. These are rare. NRG1 fusions are those we primarily find, for example, in RAS wild-type disease. The RAS wild-type group of patients, which is approximately 7% of patients, is target rich. This is where we see NRG1 fusions and BRAF mutations. Data with trametinib [Mekinist] and dabrafenib [Tafinlar] have shown interesting responses. I’ve had some patients with these [BRAF] 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. RAS mutations are becoming prime targets, but also in RAS 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.

Reference

RMC-6236: pancreatic cancer update to support pivotal phase 3 trial. Revolution Medicines. July 15, 2024. Accessed November 4, 2024. https://ir.revmed.com/static-files/eeeb0690-0ef4-44b8-b5fe-8d11d8df3c9a