How KRAS-Targeted Therapy May Advance Toward Cancer Prevention

In part 2 of an interview with CancerNetwork®, Frank McCormick, PhD, FRS, DSc (Hon), discussed his long-term vision for treating precancerous, KRAS-driven lesions before they progress to cancer, the feasibility of moving RAS inhibitors into earlier lines of therapy, what oncology teams should understand about KRAS biology, the differences between KRAS allele subtypes, and his outlook for the field over the next 5 to 10 years. In part 1, McCormick discussed the technical hurdles that made KRAS resistant to drug development, the National Cancer Institute (NCI)’s RAS Initiative, the phase 3 RASolute-302 (NCT06625320) data, resistance mechanisms, and the emerging combination treatment landscape.

McCormick is a professor in the Helen Diller Family Comprehensive Cancer Center and holds the David A. Wood Distinguished Professorship of Tumor Biology and Cancer Research at the University of California, San Francisco (UCSF). He has researched KRAS for 40 years and helped lead the NCI RAS Initiative. He was recently named the inaugural recipient of the Stephenson Global Prize from the Stephenson Global Pancreatic Cancer Research Institute.

CancerNetwork: Are there any specific trials with KRAS-targeting agents that you’re watching currently?

McCormick: The studies I’m really interested in are studies in which patients with very early stage non-tumor types of pancreas lesions are being treated. These are lesions called pancreatic intraepithelial neoplasia [PanINs], which are local, pre-malignant growths. If they can be targeted with some of these drugs, hopefully they’ll prevent progression to a later stage of disease, when patients have a lower chance of benefiting from therapy. My long-term goal, which I’m trying to pursue with support I received from the Stephenson Global Prize—which I was delighted to receive—enables me to do research into the possibility of preemptively treating people, giving people drugs against KRAS that will prevent the initiation of pancreatic cancer, lung cancer, or colorectal cancer caused by KRAS.

My dream or vision is that, in the future, a person around age 70 might take a pill every month or so, and that will prevent the growth of any tumors caused by KRAS. They would never actually initiate, and never actually succumb to, KRAS-driven cancers in the first place. That’s now technically possible, if the drugs are safe and well tolerated. A preemptive strategy is going to be the best way of eliminating pancreatic cancer in the long term.

How exactly would a pill like that work to help prevent people at elevated risk of disease from developing cancer?

It’s been well studied for pancreatic cancer that there’s about a 20-year window between initiating mutations in a particular precursor cell and the actual clinical manifestation of pancreatic cancer. During that time period, the individual has early stages of pancreatic cancer, but has no symptoms. In this case, we’d intervene with a drug that targets the cause of that particular pre-malignant disease, which is KRAS, and kill those cells before they have a chance to progress and become more genetically complicated and more difficult to treat.

Even a young, healthy person has, somewhere inside them, some pre-malignant cells that likely have KRAS mutations. If they took these drugs, those cells could theoretically be eliminated, and they’d either delay or prevent getting tumors caused by KRAS. To get there, we need drugs that are completely clean and free of symptoms or adverse effects [AEs], and that have been established to be safe and effective at killing early-stage KRAS lesions. Those things are now possible, and we can imagine how that will play out. That is the future of pancreatic cancer research: preventive strategies that stop initiation in the first place.

It hadn’t been possible previously because cancer drugs are typically toxic, as everybody understands, so no one is going to take these drugs if they don’t have some urgent need. But this new generation of drugs should be safe and well tolerated enough that prevention is now on the table.

The initial RASolute-302 reporting was in the previously treated setting. What is the feasibility of moving RAS inhibitors into earlier lines of treatment?

I don’t see any barrier to doing that. I’m not sure exactly what the logistical steps will be to get there, but there’s no other good alternative. That will eventually happen, but quite honestly, I can’t tell you the specific steps we’ll have to go through to get to that point. I’m sure it will happen eventually, either with daraxonrasib or other-generation KRAS inhibitors. It will get there eventually; I just don’t know when.

For oncology teams who will be prescribing these drugs, what is the most important thing they could understand about the KRAS biology underlying the treatment they’ll be using?

It’s important to know that in pancreatic cancer specifically, KRAS is the driver of the disease; that’s well established. It causes the disease, so it’s the right target, and there’s no question about that. Oncologists need to appreciate that, and there’s a ton of evidence from model systems showing that eliminating KRAS will benefit the patient. Some of the drugs, such as daraxonrasib, have AEs that need to be managed, but future generations of KRAS drugs will have fewer AEs and fewer issues to deal with.

The situation in other cancers, like colorectal cancer, is not as clear. KRAS is probably not the primary driver there; it’s important, but there are other genetic lesions in colorectal cancer that make the whole situation more complicated, and those tumors are more polyclonal and more difficult in many ways to deal with. In lung cancer, KRAS is one of several different drivers, and tumors can probably switch from one to the next. The situation in pancreatic cancer is simpler: it’s KRAS. Hitting that hard with a drug that’s well tolerated and clean will definitely have patient benefit.

The other indications are more nuanced and complicated, and oncologists are going to have to read the literature very carefully; it’s going to be a complicated landscape for them to navigate. There are also different mutations in KRAS, some of which respond to the drugs better than others, which is another nuance that will play out over time. It’s not just one form of KRAS; there are several flavors of it, and the drugs that have been developed hit those different flavors differentially. Oncologists may have to choose a particular drug for a particular flavor of KRAS.

What’s the difference in developing drugs for these different KRAS ‘flavors’?

The most common ones in pancreatic cancer are G12D and G12V, and those particular proteins have the property of engaging the MAPK pathway, but also the PI3K pathway, which is the second pathway those particular RAS proteins are very good at activating. Drugs that hit the PI3K pathway are likely to be effective for those particular alleles. But other RAS variants, like G12R, the third most common in pancreatic cancer, do not activate the PI3K pathway, so combinations of drugs that include a PI3K inhibitor are probably less likely to work for G12R than for G12D or G12V. Also, the arginine mutation, G12R, is quite different from [G12V] and especially [G12C], so a lot of drugs don’t attack the G12R allele as efficiently as they do the others. Also, since you asked, G12D is a slightly bigger protein than G12V, and slightly floppier, so drugs can fit into D better than V. There’s been much more success in targeting G12D and G12V, so there will be pan-KRAS drugs, there will be G12D-selective drugs, and there will be G12V- and G12R-selective drugs coming along as well. Each needs to be tailored to the individual patient’s tumor.

Looking 5 to 10 years toward the future, where do you see the RAS-targeted field headed?

In that time frame, there will be several different KRAS drugs targeting each of the alleles I mentioned, developed in parallel for lung, colorectal, and pancreatic cancer, and other indications where KRAS occurs at lower frequency. Oncologists will have to choose between a variety of different options that fit a particular patient best, based on theory and on empirical analysis of clinical data. The whole field will move earlier, so there will be more emphasis on early detection and early intervention to improve outcomes. Hopefully, the pairing of targeted therapy with immune therapies will mature enough that it becomes normal, as it is in lung cancer, also in pancreatic cancer, so patients at that point can expect the possibility of being cured, if those combinations are well tolerated and effective.

Over that decade-long time frame, we will find a way of developing drugs that can be used in a preventive setting, and then [that] mission will be accomplished, because we can just prevent the whole disease altogether, and that’s what we all want to do. That’s going to happen in that time frame also.