FDA Approval Marks a Sea Change in Pancreatic Cancer Treatment

For decades, progress in pancreatic cancer came slowly, a little more time, a slightly better response, another incremental step. The FDA approval of daraxonrasib, the first therapy to directly target RAS across the most common mutations in metastatic pancreatic cancer, marks a new era.

John A. Chabot, MD, Executive Director of the Pancreas Center and Chief of the Division of GI/Endocrine Surgery, explains the deep significance of this advance, Columbia’s critical contributions in bringing the science forward, and why the questions beginning now may be every bit as important as the approval itself.

You’ve spent your career watching pancreatic cancer treatment slowly advance. Does this moment feel fundamentally different?

Very much so. All of our progress in pancreatic cancer until this year was very incremental. A little step here, a little step there, making progress, but painfully slow, and each sort of event just a little bit better. This represents potentially a massive change.

And the reason for that is the new drugs are not traditional chemotherapy. They’re drugs that, if necessary, can be taken for a long time. And the response rates with just a single agent alone have been better than any prior drugs or combination of drugs.

So this first phase is sort of a sea change. And I think we’ll start to make incremental progress on top of that.

What makes targeting RAS such an important change from the way pancreatic cancer has traditionally been treated?

The really important difference is that the dominant mutation in pancreatic cancer, a mutation of a gene called KRAS, which is mutated in 87 percent of people with pancreatic cancer, has never been able to be targeted before.

And that’s the big difference. We’ve now got a target that’s almost universally present in pancreatic cancer. That is different from the sort of shotgun approach that chemotherapy takes, which is just going after dividing cells.

The trial that led to FDA approval studied patients with metastatic pancreatic cancer whose disease had already stopped responding to chemotherapy. What did those results show?

The clinical trial that convinced the FDA to approve the drug was done in patients with chemotherapy-refractory metastatic pancreatic cancer. So, worst case, right? And it doubled survival in those patients.

That’s why this is so exciting. We’ve seen sort of the revolution, and now it’s building on that revolution to start to make additional progress. It’s a really, really exciting time.

Will you explain the FDA-approval indications for daraxonrasib? Is it indicated for more than worse-case disease?

Yes, the good news is the FDA approval is much broader than the initial clinical trials that brought about the approval. In that trial, you had to have failed chemotherapy. The approval is for anyone for whom chemotherapy is not working, whether it’s because of toxicity or because the tumor is not responding.

They wrote the approval in a way that we can use it in a lot more people than the very restricted category of patients that were in the actual clinical trial. And I think they did that because the results were so dramatically good.

Once you know a drug can work in that very difficult setting, is the next question how much earlier you can use it?

Exactly. We’re involved in trials using the drug in different settings. We’re participating in a clinical trial now where the design is to give daraxonrasib for two years after traditional postoperative chemotherapy. That starts to look like breast cancer, where you get initial upfront treatment and then you stay on medication for sometimes up to five years.

For postoperative patients, that trial is going to take much longer to reach an endpoint because their lifespan expectation is obviously much longer. If you double seven months to 14 months, you don’t need your trial to go that long to confirm that success. In postoperative patients, it takes much longer to know.

But some of the preoperative questions, where we’re trying to shrink tumors to make them operable, those answers can come more quickly.

Are there preoperative trials underway already?

We don’t have any open at the moment, but we’re designing them now. Trying to figure out how we’re going to use this in the preoperative setting is very important. I wouldn’t describe it as a trial yet, but we are actively investigating how we’re going to design trials in that setting.

What could using a drug like this before surgery change?

I think, in our smaller world of surgery, expanding this to preoperative patients is going to make a lot more patients appropriate for surgical intervention.

That’s going to be patients whose tumors are involved with critical blood vessels and therefore the surgery is too risky, or patients with very limited metastatic disease that responds to the new approach.

Then we can go after the main tumor because we’ve treated the metastatic disease effectively. So in our small world, I think that’s going to be the big difference.

How much could that change the number of people who ultimately become candidates for surgery?

I think within a few years, we may double the number of patients that are appropriate for surgery.

That also seems to make the decision about surgery more complicated. If a patient with disease you traditionally never would have operated on has an extraordinary response, how do you know when it’s time to operate?

It’s actually gotten a lot more difficult.

Historically, we would never operate on people with any level of metastatic disease. In the last three or four years, with improvements in other approaches, in the immunotherapy approaches to pancreatic cancer, we’ve dipped our toe in those waters.

And I think this advance is going to bring us to a state where we’re consistently asking the question, should this patient who never would have been offered surgery in the past be offered surgery at this point?

One of the important things is timing. Do we wait a year? Do we wait two years? How much reduction in tumor burden do we need? All of those are moving targets right now that we have to redefine.

Does having a successful RAS-targeted therapy also open the door to combining it with completely different kinds of treatment?

Definitely. We’re putting together strategies to combine different approaches to try to get an asymmetric benefit. We now have all sorts of trials going on, combining daraxonrasib with other agents that act in a similar way or that are completely different, and combining it with traditional chemotherapy.

We also have the immunotherapy work going on. How do we put those approaches together with this? That’s a question we’re asking now. We try very much to do as much of this as we can through a trial mechanism so that we can be confident at the end that we actually know what we’re doing.

Some patients just don’t fit into those situations, and then we have to put our heads together and think carefully and come to a joint decision between all of the various people caring for the patient. These are never, ever decisions made by a single physician or a single provider.

Where does immunotherapy fit now that so much attention has shifted to RAS?

It has taken a bit of a backseat because daraxonrasib has sucked all the oxygen out of the room.

There are still lots of immunotherapy trials going on. And I believe firmly that ultimately it’ll be a combination of immunotherapy and drugs that act directly on the tumors that will be the combination that we use.

But right now, all the excitement is on daraxonrasib.

Columbia was involved well before this drug reached the FDA. What role did the Pancreas Center have in its development?

It’s very important for the world to know that we were deeply involved in the development of this drug. Revolution Medicines is the company that owns the drug and has developed the drug, but we did all of their preclinical animal testing here in our labs. So we were deeply involved.

You’ve compared where this could be heading to breast cancer, where patients may take medication for years. Does that change the way you think about the idea of curing pancreatic cancer?

Well, it becomes less critical. If we can keep people alive for 10 or 20 years, then perhaps we don’t take as much risk in attempting to achieve a cure.

Surgical decision making, at its core, is risk-benefit. When the only opportunity to live more than a couple of years is a curative operation in an appropriate patient, you’re willing to take a lot of risk. And more importantly, the patient is willing to take a lot of risk.

Even now, the conversations with patients who are in their 40s and 50s and facing a very, very high-risk operation are different with the opportunity to take a drug that they may be able to take for many years. Those conversations have already changed.

After years of incremental progress, how do you balance the excitement around this with what pancreatic cancer still is today?

We can’t communicate that we’ve solved this disease.

It’s still an evil disease. And all of our treatments, new and old, take a real toll on people. So we can’t communicate, “Raise the flags, we’re done, we’ve won.” I think communicating optimism and enthusiasm without telling people that this is solved is where we need to be.