As the oncology community waits with bated breath for a possible FDA approval of GRAIL’s Galleri test, NCI Director Anthony Letai has a lot to say about multi-cancer detection tests—particularly Galleri.
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Letai spoke at a National Comprehensive Cancer Network policy summit on screening and prevention last week on Oct. 6.
“It’s very important when we consider screening studies that we don’t, in our minds, project the ideal screening test that we have in mind, but actually the real test that we have on hand,” Letai said at the summit. “Even though we aspire to ideal tests, projecting sub-ideal tests across a large population can cause harm—both financial and real, physical harm.”
In this episode of The Cancer Letter Podcast, Paul Goldberg, editor and publisher of The Cancer Letter, and Sara Willa Ernst, reporter, discuss Letai’s remarks. FDA approval for Galleri seems likely after an advisory committee voted in favor of the test during a Sept. 23 meeting.
“Now we’re waiting. What will FDA do when they have this recommendation from the advisory committee?” Sara said.
The FDA panel voted that the test was safe, effective, and that the benefits outweigh the risks. This recommendation did not consider questions of clinical benefit.
“FDA seems to be perfectly happy with sidestepping the question of benefit,” Paul said. “If FDA is not going to care about patient benefit in this case, who does?”
Letai’s comments about MCDs were “very consistent with what Phil Castle, the director of the [NCI] Division of Cancer Prevention, was saying—basically, who is going to ask questions of patient benefit?” Paul said.
If Galleri is approved by FDA, the test may sail down a shorter path to widespread Medicare coverage and bypass the usual need for a recommendation by the U.S. Preventative Services Task Force, which usually takes years.
“I have some concerns about this,” Letai said about the panel’s vote. “My concerns are that people overestimate the performance of this assay.”
This episode is sponsored by City of Hope. Learn more at www.cityofhope.org.
Stories mentioned in this podcast include:
- Letai: MCEDs are a “great ideal”—alas, the data don’t support widespread use
- Oncologist Rachna Shroff endows award to outlast her cancer diagnosis
- Cancer vaccine policy in limbo as CDC keeps canceling advisory meetings
- Oncology has a semantics problem: How do we define “early stage”?
- MUSC startup brings preclinical imaging into the light
This episode was transcribed using transcription services. It has been reviewed by our editorial staff, but the transcript may be imperfect.
The following is a transcript of this week’s In the Headlines, a weekly series on the Cancer Letter Podcast:
Jacquelyn Cobb: And I’m your host, Jacquelyn Cobb, managing editor of The Cancer Letter. We’ll be bringing you the latest stories, groundbreaking research, and critical conversations shaping oncology.
Paul Goldberg: So let’s get going.
Sara Willa Ernst: Hi, Paul.
Paul Goldberg: Hi, Sara. How are you?
Sara Willa Ernst: I’m doing good. I think it’s been a while since I’ve been on the pod or the two of us have been on the pod together. I’m filling in for Jacquelyn Cobb this week, and I thought of a silly little joke that I don’t know if I’ve said on the podcast before, but Paul has these nicknames for us and he goes, “Jacquelyn Cobb on the job.” And the one that I thought of recently is “Jacquelyn Cobb on the pod.”
Paul Goldberg: Yes, that’s very nice. Well, I think since you’ve opened that Pandora’s Box, we should probably say what the nicknames are.
Sara Willa Ernst: Yeah, the other ones are. Yeah.
Paul Goldberg: Yeah. Yours is, “Sara Willa is a killer.” You see, that’s a good one.
Sara Willa Ernst: Yeah, that’s a really hard one for me. Those are big shoes for me to fill.
Paul Goldberg: Well, and then there’s, well also, there is “Claire Porter, the reporter,” and “Jacquelyn Cobb is on the job.” And I don’t have one, but you’re welcome to come up with something insulting.
Sara Willa Ernst: Well, I think you’re like Beyonce, you’re like Cher, it’s just Paul. That’s it, Paul. Like one name and that’s all. And we know who we’re talking about.
Paul Goldberg: A one name person.
Sara Willa Ernst: Yeah.
Paul Goldberg: Yeah. No, I think it would be kind of nice to have some kind of a nasty something…
Sara Willa Ernst: Yeah. So we’ll ask our audience for submissions.
Paul Goldberg: Oh, please. Name this guy.
Sara Willa Ernst: Name this guy.
Paul Goldberg: Name this podcaster. Yeah, that would be good. I think I’ve got some names, but…
Sara Willa Ernst: Right. Other people have to name you. You can’t name yourself.
Paul Goldberg: Right. Yeah.
What did we have this week? I forgot.
Sara Willa Ernst: Yeah. So I think we had a second Letai cover in a row, and this one had to do with the NCCN summit in which he spoke. But we also had a bunch of other great stories that I’ll go through really quickly and then we can dig into the Letai story more.
We had a story about an oncologist named Rachna Shroff, who actually really sadly we found out this week that she passed away over the weekend. She wanted to create a legacy that went beyond her own work and her own cancer diagnosis. And so she created an endowment. This endowment, they had a goal of 1.35 million and they were able to achieve that and actually go beyond that goal. So that’s a really great story and also a really sad story in this particular moment.
We had three other stories, one story that I wrote about cancer vaccine policy that also related to the NCCN summit and some of the comments that were made during the discussions.
We have a perspective from Raja Flores. This is the third, I think, guest editorial that he’s written for us. And this one has to do with some of the semantics that are kind of thrown around in oncology, specifically the term, “early-stage.” What does that mean and is there a clear definition for it? So that’s something that he investigates.
And then lastly, we have a sponsored article from MUSC Health University Medical Center. It’s a sponsored article and it’s about a new imaging technology that they have called SphynxVision. So yeah, check out all those articles in this most recent issue. But yeah.
Paul Goldberg: I suggest that we talk about Raja Flores’ story because it’s kind of a fun piece, that kind of happened. He and I talked a couple of months ago when he wanted to write a piece about the early-stage promotion by Merck of Keytruda for early-stage lung cancer.
Sara Willa Ernst: Right.
Paul Goldberg: He’s a lung cancer surgeon at Mount Sinai. I said, “Yeah, this is really interesting because what is ‘early-stage?’” And he has to talk to… It’s one thing to put something in a commercial. It’s another thing when a patient comes in and needs to know and should know. And the question then it becomes something… It creates work for him. And thank God it does. And it’s all very, very interesting because it shows you how oncology really is structured right now. And then he wrote two more pieces about what is the meaning of early-stage.
And then after he wrote that and submitted it, the Pope ended up having an early-stage something or other diagnosis. We don’t even know if it’s malignant, we know nothing. But it’s an interesting question of what does that mean? So I asked him actually to keep an eye on this because… But it’s very interesting how one story written by somebody who has been asked a lot of questions and wanted to anticipate some of them and go through them, think journalistically about them and scientifically, which in this case is the same thing.
Sara Willa Ernst: Yeah.
Paul Goldberg: And then he just wrote three stories in the series, which I think should really be read and it’s not just lung cancer. So it’s a very interesting piece.
I don’t think he’s done. He thinks he’s done, but as soon as we hear more about the Pope, there could be an interesting story right there about early-stage.
Sara Willa Ernst: And you were saying it’s not just about lung cancer. I think what kind of struck me in his latest story was this chart that he came up with looking across all of these different cancer types, breast cancer, colorectal, melanoma, esophageal, and how the definition and how the phrase “early-stage” is used is just really all over the map. And this is a story in which he had thought through these questions deeply, but also had done a lot of research and put them all in one place for people to better understand it.
Paul Goldberg: Well, also what’s really cool is that functionally, some of the stage 3’s are treatable, very treatable. So it’s worth discussing with neoadjuvant, with immunotherapy, and it’s worth discussing further about what is the meaning of staging that has been used. So it’s a great story, great story, which really cuts across the diagnoses, as you said.
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Paul Goldberg: So I guess we should go back to story one.
Sara Willa Ernst: Sure.
Paul Goldberg: Just go back.
Sara Willa Ernst: Right. Yeah. So story one, basically Anthony Letai, the NCI director, attended this NCCN Summit on cancer screening and prevention last week. And he gave some of his thoughts on multi-cancer early detection tests, which have been big in the news because of a recent FDA advisory committee in which they basically voted to approve it. So now we’re kind of waiting. We’re in this moment where what will FDA do once they have this recommendation from the advisory committee? And that’s kind of the context in which Letai spoke.
Do you want to give a sense as to what he said?
Paul Goldberg: Yeah. Well, he basically repeated some of the stuff, but in much greater detail, some of the things that he said to me in the Q&A a week earlier. And really it’s very consistent with what Phil Castle was saying, the director of the Division of Cancer Prevention, which is who is going to ask questions of patient benefit here?
And he went through the data for Galleri. That’s the first MCD that’s likely to be approved. And on what basis is it being approved? I think actually we should probably take a look at the indication. You have that in front of you, yeah?
Sara Willa Ernst: I have it right here in front of me. Should I read some of it?
Paul Goldberg: Amazing. Sarah Willa is a killer.
Sara Willa Ernst: “The Galleri test is a qualitative, next-generation sequencing (NGS)-based in vitro diagnostic test intended to detect cancer-specific methylation patterns in cell-free DNA isolated from peripheral whole blood.
Galleri is intended for screening for the early detection of multiple types of cancer, in adults aged 50 years or older. The test is also intended for the prediction of Cancer Signal Origin in individuals with a Cancer Signal Detected test result.
A test result of Cancer Signal Detected, including a predicted Cancer Signal Origin, may indicate the presence of an invasive solid tumor or hematologic malignancy and should be followed by a diagnostic work-up recommended by qualified healthcare professionals. A test result of No Cancer Signal Detected does not rule out the presence of cancer, and individuals should continue with guideline-recommended single-cancer screening tests.”
So that’s the indication.
Paul Goldberg: Yeah. Yeah. So it’s to be used in conjunction with people over 50.
Sara Willa Ernst: Right.
Paul Goldberg: So is that what’s going to happen? I somehow doubt it. I don’t think it will be. And also there’s a question of early. You see, what is…
Sara Willa Ernst: This was discussed at the FDA meeting. Yeah.
Paul Goldberg: Yeah. It’s really interesting what language do you use? Are the MCEDs with an E, which is what Galleri wants to be called? Or is it MCD, which is what the NCI nomenclature has been? Although Letai seems to like MCED more because I think it sets the goal for this early thing to be happening because some of the cancers you might be detecting are are not early-stage. They’re late stage. So the question becomes what do you do about false positives, false negatives? What do you do with utilization?
Sara Willa Ernst: Yeah.
Paul Goldberg: And he goes through this entire thing in a very systematic way here and it’s worth reading. But that begs another question, which is who is to focus on patient benefit in this case? Is it even a goal? If not, gosh.
Sara Willa Ernst: Well, when it came to the FDA meeting, the members were kind of told consistently: You are to answer these questions and provide recommendations not based off of clinical benefit.” The question is whether or not the tests can detect cancers. And I just remember I watched most of the meeting, which was nine hours, and repeatedly people were asking questions about clinical benefit and FDA had to interrupt or correct them and say: These questions are not about clinical benefit.
Paul Goldberg: Which is also interesting because one of the trials that the company had done to support one of the studies to support the application was the NHS-Galleri trial…
Sara Willa Ernst: Yeah, in the UK.
Paul Goldberg: Which followed patients in the UK National Health Service for three years and actually came up negative. They really needed to do it longer to get an answer. So FDA seems to be perfectly happy to sidestep the entire question of benefit. Now, if FDA does not care about patient benefit in this case, who does?
Sara Willa Ernst: Yeah.
Paul Goldberg: Let’s talk about U.S. Preventive Services Task Force. That’s another subject you know a great deal about that. Do you think they can handle it? The answer is I don’t think they can because they’re bypassed in terms of payment. The payment system cannot defer to them.
Sara Willa Ernst: Right.
Paul Goldberg: Does it mean that they can do it anyway? I don’t know. What do you think?
Sara Willa Ernst: Yeah. So the fiscal year 2026 bill basically said that when it comes to a multi-cancer detection test, as long as there’s FDA approval, there’s a pathway to Medicare coverage, which is massive. I mean, we’re talking about millions and millions of people that would be able to be covered. And usually…
Paul Goldberg: Well, they can pay. They don’t necessarily have to pay, but they can?
Sara Willa Ernst: They can, yeah. It creates a pathway and it creates a possibility that… a whole process that would be a lot shorter than the usual pathway, which is getting a recommendation A or B from the USPSTF.
Paul Goldberg: Which is, yeah, one can argue on that one, “Oh man, this is going to be a good one.” But yes. But what’s happening with USPSTF? Is the place going-
Sara Willa Ernst: It’s also a very awkward moment. Yeah. It’s a very awkward moment for USPSTF, which we’ve been covering throughout the months. Essentially, they haven’t been meeting at all. And Kennedy has replaced a lot of the people on the panel with specialists, which is a controversial move. People are looking at this and they think that it’s a bad move.
Paul Goldberg: Well, with some stories, you kind of have to go back to the beginning and the creation of U.S. Preventive Services Tasks Force.
Sara Willa Ernst: Oh yes. Yes.
Paul Goldberg: The idea of implementing the principles of evidence-based medicine, which is essentially flying by instruments, and that’s what the government has been doing. It was never really intended to be tied to coverage until Obamacare, until ACA, which said that you needed to have A or B recommendation that would lead to coverage under Obamacare. Well, now you basically have a board that had this structured pre-specified review that is not meeting, that has a bunch of new members, and it was not supposed to have any specialists in it. Maybe we should talk about why not have specialists.
Sara Willa Ernst: Yeah. Do you want to dig into that a little bit?
Paul Goldberg: I can certainly do that. Thank you. I thought you’d never ask.
Basically, the people who have to be on that USPSTF are kind of a jury that looks at all of the data and decides, and the people who are on it are generalists or people who understand data. And they shouldn’t be specialists because specialists live in the numerator, meaning they know what can happen. They understand the ravages of disease. The generalists here and the data experts live in the denominator. They understand what this form of screening is going to cause in a larger population. They understand it in a much different way.
Well, now that’s not to say that specialists are not consulted because that’s a part of what they do. It’s just that it’s taken to generalists. So now we’re starting to see specialists being put in. So will this continue? Probably. What will this do to USPSTF, which is not meeting anyway? I don’t know. What’s the role? I mean, the bigger question is what is the role of evidence-based medicine in the U.S. government today? It’s not what it has been. It’s one of those consequences of the elections. So here we are.
Sara Willa Ernst: Yeah. And USPSTF hasn’t met for, I think, at least two, if not three meetings. And recently, these new panelists have been appointed by Kennedy. So we are definitely watching for the next meeting, what’s going to happen? Are they finally going to meet? And how is that meeting going to shake out? So keep a lookout for that future coverage.
Paul Goldberg: But I still have more to say, if you don’t mind.
Sara Willa Ernst: Sure.
Paul Goldberg: NIH used to be in the business of occasionally writing guidelines. Then it stopped after breaking its teeth on mammography. It really has no business doing that. However, NIH, and in this case NCI, is able to answer the question of patient benefit with MCDs or MCEDs or whatever the heck you want to call them. And in fact, it’s trying to do so with the Vanguard trial, which NCI is trying to put together right now. So when Letai is speaking about this, he’s speaking as the guy who is also trying to get the answers on patient benefit. Not the guidelines, but the answers.
Sara Willa Ernst: Yeah. And tell our audience what’s different about the Vanguard trial as opposed to the NHS-Galleri.
Paul Goldberg: Well, the Vanguard trial is going to look at patient benefit questions. Mortality, of course, is the best possible endpoint in this case, but is it feasible to get that answer with a technology like this, which is changing rapidly?
Sara Willa Ernst: Right.
Paul Goldberg: And it should also be noted that the… And how are these technologies different from each other? It could be very different from each other.
Sara Willa Ernst: Right.
Paul Goldberg: And we won’t know that for Galleri because Galleri is not a part of the Vanguard test.
Sara Willa Ernst: Yeah.
Paul Goldberg: So the question of benefit needs to be studied further in some way. And also what’s the value you could argue on the other hand, what’s the value of getting that answer if it takes 10 years and the technology has changed?
Sara Willa Ernst: That’s a question that is circled back to again and again, which is this kind of weighing of the benefits and the risks. And part of the arguments that I hear when it comes to the risk is the time it takes to achieve a trial that has a mortality endpoint and all of the kind of death and suffering that could happen with waiting and not knowing. So that’s kind of one side of the argument that I’ve heard time and time again.
Paul Goldberg: Yeah.
But going back again into history, I covered the beginnings of the national lung screening trial, which was started because spiral CT looked like it was pretty promising for lung cancer screening, for early-stage lung cancer screening. And this is a much simpler thing, really, you could argue, than MCEDs in terms of getting answers or MCDs.
And interestingly, I covered the I-ELCAP founder, Claudia Henschke, lobbying Congress against NLST, to put an end to NLST. And then NLST was run anyway by NCI, which is National Lung Screening Trial, which was really asking the question of patient benefit from lung screening. And guess what? It turned out to be a positive trial. So she was arguing against it. And then when the trial came up positive, she was given all sorts of credit for having come up with the answer before the NLST.
Well, it’s really important to have a prospective randomized clinical trial to be certain that what you’re doing is not doing harm because you can do some harm very easily. And with an MCED, you can really do some serious harm.
Sara Willa Ernst: Yeah.
Paul Goldberg: So it’s a good thing NCI is looking at this, I think. It’s a good thing, but because really, I don’t know if anybody else is.
Sara Willa Ernst: I mean, they’re the only ones working on a randomized control trial, a prospective one that I am aware of.
Paul Goldberg: There could be other trials. We just don’t know. So we should probably not even go there.
Sara Willa Ernst: Yeah. It’s just what we’re aware of.
Paul Goldberg: Because there could be some industry trials.
This is a story we’ll be covering for a very long time. Very long time.
Sara Willa Ernst: Yeah.
Paul Goldberg: It’s a good time to be a journalist.
Sara Willa Ernst: Thank you so much, Paul, and we’ll see you on the next episode.
Paul Goldberg: Right.
Sara Willa Ernst: Take care.
Paul Goldberg: Thanks.
Jacquelyn Cobb: Thank you for joining us on The Cancer Letter Podcast, where we explore the stories shaping the future of oncology. For more in-depth reporting and analysis, visit us at cancerletter.com. With over 200 site license subscriptions, you may already have access through your workplace. If you found this episode valuable, don’t forget to subscribe, rate, and share. Together, we’ll keep the conversation going.
Paul Goldberg: Until next time, stay informed, stay engaged, and thank you for listening.
