Promising new treatments for pancreatic cancer and ALS

[MUSIC PLAYING] IRA FLATOW: Hi, this is Ira Flatow, and you’re listening to Science Friday. Pancreatic cancer is among the most deadly forms of cancer and can be difficult to catch early. But there is some good news. A new drug called daraxonrasib, which just finished its clinical trials, had some really promising results. And while it’s not a cure, some oncologists are calling it a game changer, not just for pancreatic cancer, but potentially, for other forms of cancer too.

Dr. Zev Wainberg led a clinical trial for the drug and is the co-director of UCLA Health’s GI Oncology Program. He joins us from Los Angeles. Welcome to Science Friday.

ZEV WAINBERG: Thank you, Ira. Happy to be here.

IRA FLATOW: Nice to have you. First, tell us what this drug did. Just how effective was it for patients with pancreatic cancer.

ZEV WAINBERG: So this is a big moment for us because this is a drug that targets the dominant oncogene in cancer, but especially dominant in pancreatic cancer, and that’s called KRAS. And this trial has gone through several studies over the last, I’d say, four or five years in a fairly accelerated timeline, initially showing that even in advanced, very advanced pancreatic cancer, for which the usual treatments are very short lived, this drug was producing response rates. It shrinking tumors. It was making people live longer than we ever could have expected.

And when we saw that, the company and the investigators quickly moved to accelerate a randomized phase III trial in the same patient population, advanced pancreatic cancer patients who had already gone through some chemo and randomized them, half got a different chemotherapy regimen than they might have received before, which was the standard of care versus this pill. And it fundamentally showed a dramatic improvement in both the ability to shrink tumors, both the ability to have cancer be controlled for a prolonged period of time, and it doubled the survival of that group of patients compared to chemotherapy alone.

IRA FLATOW: So in the oncology world, the world of cancer, just how big a deal is this drug?

ZEV WAINBERG: Well, I think every cancer, has its moment, so to speak. We saw that with targeted therapy in breast cancer about 30 years ago. We saw that with immunotherapy across the board in melanoma and lung cancers about 10 or 15 years ago. We’ve never had a moment quite like this.

I’ve done a lot of studies, Ira, on pancreatic cancer, and most of them have failed. And if they didn’t fail, they showed very marginal benefits. So in my opinion, it is a breakthrough moment in the history of pancreatic cancer.

IRA FLATOW: What is it about this drug that might make it useful for treating other types of cancer?

ZEV WAINBERG: So this oncogene, which is called KRAS, is the dominant oncogene across all cancers, which means that it’s mutated and altered in up to 25% of all cancers. That’s led by pancreatic cancer in which it’s dominated in 90% of cases. I think pancreatic cancer is one of these cancers that we all recognize. We don’t know a lot. We don’t understand why do people get it? Why does it grow so quickly?

What we know, though, is that this oncogene, KRAS, is the driving engine behind a lot of the growth of these pancreatic cancers. So people have been interested in blocking this and figuring out drugs to block this gene for about 50 to 60 years. It’s gone through a huge, I would say, series of mainly downs, not ups in trying to find drugs that effectively block this gene.

And so this is one of the first, but probably not the only drug that is hitting that threshold of successfully blocking that gene at the source and effectively decreasing the cascade of signaling that runs through KRAS.

IRA FLATOW: Has it shown effectiveness in other types of cancers yet?

ZEV WAINBERG: So it’s being studied actively in lung cancer and in colon cancer, mainly, in combinations in colorectal cancer, which colorectal cancer also has. KRAS mutated about 40% of the time; lung cancer, about 25%, 30% of the time. We can say somewhat convincingly that it doesn’t work in the same manner. And by that I mean probably not as good as a single agent in some of these cancers as it has been in pancreatic cancer.

And one of the hypotheses behind that is that the KRAS oncogene, while extraordinarily common across a lot of cancers, may just be a more important driving engine in certain cancers rather than others.

IRA FLATOW: Let’s talk about patients, because we know, because of our audience, they’re going to hear about this and want to when they can get it. So give us an idea of how soon patients might receive this new drug.

ZEV WAINBERG: Well, we can say that this is under review by the FDA. Our hope and expectation is that review is very quick and the drug will receive full approval. It’s hard to the timelines of that, but obviously, I think we’ve concluded this study quite successfully and shown a fairly definitive result. So that’s not always the case in oncology drugs. Here it is, in my opinions.

IRA FLATOW: What’s it been like to see these kinds of positive results for patients, as you ran the clinical trials? Because people with advanced pancreatic cancer really have very short life expectancies, don’t they?

ZEV WAINBERG: Yes. And really, in this study, we tested it in those with the worst life expectancies, quite frankly, and the patients who had already received chemotherapy. So we knew, unfortunately, that chemotherapy is going to have a very limited success in that patient population.

It was very emotional and in a challenging way. First of all, we did not know that this drug would perform as well until we saw the results. But we did know that it was doing something. And it became challenging for many of us to enroll patients in chemotherapy, which was necessary to preserve the randomized study.

And ultimately, when you see a drug, a pill, turn someone’s cancer around in pancreatic cancer, if you ask many of us five years ago, we never would have thought this would have been possible.

IRA FLATOW: If the drug gets approval from the FDA, would this then become frontline treatment for pancreatic cancer, or would patients need to try chemo first?

ZEV WAINBERG: So it’s hard to say what the FDA will do exactly. But I think our vision, this is a stepping stone. We’re doing the other studies as we speak. We’re even testing this drug and others in earlier lines of pancreatic cancer, those who had surgery and are, unfortunately, very likely to recur after surgery. But we’re testing the drug there.

We’re making efforts to test this drug and others like it before surgery. So the emphasis now is beyond this immediate second line indication, which just became public. We’re already moving three steps ahead, trying to get a better handle on the disease by using this drug and others even before it becomes advanced.

IRA FLATOW: I want to thank you for taking time to be with us, and good luck with it.

ZEV WAINBERG: Thanks, Ira. It’s been great to chat with you today.

IRA FLATOW: Dr. ZEV Wainberg is the co-director of UCLA Health’s GI Oncology Program based in Los Angeles, California. After the break, another story of a promising drug. This one is for ALS. Stay with us.

ALS is a degenerative and ultimately, deadly disease. Patients lose their ability to walk, swallow, and eventually, breathe. But now, there’s a drug for a rare genetic form of ALS, able to stop or even reverse some of these symptoms. My next guest, Pam Belluck, a health and science reporter for The New York Times in New York, reported on this development. Pam, welcome back to Science Friday.

PAM BELLUCK: Thank you so much.

IRA FLATOW: Tell us about this drug, tofersen. How does it work? Who is it for?

PAM BELLUCK: Yeah, it is for a genetically-caused version of ALS. So about 10% of ALS cases are caused by known genetic mutations. The rest of the cases, we don’t really know the cause, but about 2% of ALS cases are caused by a mutation on the SOD1 protein. And this often causes a particularly aggressive form of ALS. People decline very rapidly, and the patients that I focused on in this story, some of them had lost multiple family members over generations.

IRA FLATOW: So then we’re very hopeful about this drug. Tell us how effective it is.

PAM BELLUCK: Yeah. So it’s a sort of synthetic drug, and what it does is it binds to the mutated form of RNA on SOD1 genes. And what that does is, it stops a toxic form of SOD1 protein from being produced. And that’s the protein that causes ALS or worsens ALS, for sure, in these patients.

And it’s actually the first disease-modifying therapy that’s been approved for ALS, which is pretty huge. As you note, patients die within a few years. Typically, almost nobody stabilizes or even improves. And when this drug was approved in 2023, it was given a conditional approval called accelerated approval. Because it hadn’t actually been shown to be effective. It had been shown to reduce the protein, but they weren’t able to show that it worked better than placebo.

But as time has played out and people have been followed for several years on this drug, they have found that about 25% of the patients who have received it have either stabilized or improved, which just does not happen in ALS. And when we’re talking about improvement, we’re talking about things like their muscles have gotten stronger. They’ve been able to maybe walk better.

And crucially, for several of them, their breathing scores have improved to the point where maybe they don’t need a portable ventilator as much. And that is really extraordinary in the world of ALS.

IRA FLATOW: Yeah, it must have been incredible for them. I mean, to see their own improvements, what were their experiences like?

PAM BELLUCK: Yeah. I mean, the other thing that has just been extraordinary here is that people are alive. So many of them expected not to be alive, based on their family history, based on how they were progressing. So the main patient that I focused on in my piece, Amanda Sifford, before she started on tofersen three years ago, she was really, as her doctors told me, falling off a cliff in terms of her breathing.

She had gone from about 86% on a test of breathing function to 48%. And they really thought that she would have, maybe a matter of months or a year left to live. And three years later, she scored a 63%. So that is about the range for somebody who has chronic asthma. So of course, it’s not perfect, but it’s much more functional for her.

She’s been able to go dancing.

IRA FLATOW: No kidding.

PAM BELLUCK: Yeah, she loves to dance, and she hadn’t been able to do it for years.

IRA FLATOW: Amazing.

PAM BELLUCK: And is a woman who’s 58. One of the tragedies of ALS is that very often strikes people in the prime of their lives. And these kinds of improvements, in function, can be just really dramatic.

IRA FLATOW: We’re going to be broadcasting this, hearing you talk about it, and people are going to want to how they get this drug. Is it possible?

PAM BELLUCK: Yeah. Well, so right now, it is targeted only to roughly, 2% of patients who have the SOD1 mutation. It is possible. It is expensive. Insurance has been sort of slow to cover it. So yes, it is available.

The larger question is, if you have another kind of ALS, what does this mean for you? And at the moment, we don’t really know. There is a small clinical trial that’s going on right now for people who do not have SOD1-caused ALS.

There’s a lot of debate about whether this makes sense biologically. The theory behind it is that some percentage of people who don’t have that specific cause of their ALS also seem to have misfolding of the SOD1 protein. And so it’s possible that tofersen could help them, although scientists don’t really know whether their misfolded SOD1 protein kind of does anything. Does it really play a role in their type of disease?

So that’s really an open question. And I think people also do hope to learn a lot from just general ALS. What can we learn from this to a person approach that might help everybody?

IRA FLATOW: Are there some side effects, or limitations, that might prevent people from getting–

PAM BELLUCK: So the main harmful side effect that people have experienced is different types of spinal inflammation, which can be very painful. And sometimes it can mimic progressive symptoms of ALS. So it’s something that neurologists have to watch for.

And so now, when they administer– tofersen is administered in a monthly infusion into the spinal canal. And when they administer the infusion, they precede it with an infusion of or an injection of steroids. So there are things they can learn about how to ward that off.

IRA FLATOW: You mentioned that a lot of people who have ALS that’s caused by this rare genetic mutation have family members who have died from it. Could this drug be used to prevent the onset of ALS with people who have this gene mutation?

PAM BELLUCK: That is exactly what they are looking at now. There is a trial going on where they are monitoring people who have the mutation, but they are not symptomatic yet. And they are monitoring those people for increases in a protein that’s called neurofilament light chain, which is a protein that increases in ALS and a lot of other neurological disorders. It’s kind of nonspecific, but it is like a warning system. It tends to rise before people develop symptoms.

And so what they’re doing is, when those people’s levels of neurofilament light chain reaches a certain threshold, some of them are getting to a person and others are getting placebo, and they’re going to see if those who are getting tofersen have any delay in their expected age of onset of symptoms, or maybe even prevention, which would be remarkable.

IRA FLATOW: That’s great, Pam. Thank you for bringing us some hopeful news in these days when we can always use some.

PAM BELLUCK: Thank you so much.

IRA FLATOW: Pam Belluck, health and science reporter at The New York Times. This episode was produced by Shoshannah Buxbaum. If you like the show, please rate and review us wherever you get your podcasts. And if you have ideas of what you think we should cover, give us a call. 877-4-SCIFRI. 877, number 4, SCIFRI. Our listener line is always open.

I’m Ira Flatow. We’ll catch you next time.

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