Developing Story: The Camizestrant Vote — When Your Blood Test Knows Before Your Scan Does

The ODAC Vote on Camizestrant & SERENA-6: A Patient Advocate Panel Weighs In

When the FDA's Oncologic Drugs Advisory Committee voted 6-3 against recommending approval of camizestrant in the SERENA-6 trial setting, the MBC community had questions and opinions. Host Victoria gathered six of the most informed patient advocates in the metastatic breast cancer space for an unfiltered, expert conversation about what the vote really means.

In this episode:

• What SERENA-6 was actually testing and why the trial design drew criticism
• Why the ODAC vote was about when to switch therapy, not whether camizestrant is a good drug
• The debate over progression-free survival vs. overall survival as endpoints
• Molecular progression vs. radiologic progression and whether we're ready to act on ctDNA alone
• The "burn through treatments" concern: what early switching means for long-term options
• Insurance coverage gaps for liquid biopsy testing and the two-tier care system
• Why patient advocates need a seat at the table before trials are designed and not after
• What's next for camizestrant and the broader SERENA program

Featuring: Janice Cowden, Jill Tirabassi, Ellen Landsberger, Abigail Johnston, Kelly Shanahan, and Lynda Weatherby

The ODAC vote isn't the end of the road for camizestrant , but it raises important questions about how we define progression, design trials, and include patient voices in the process. This conversation is a must-listen for anyone navigating treatment decisions in hormone receptor-positive MBC.

Thanks for listening. If you enjoyed the episode, subscribe and leave a review — it really helps. Follow us on social media @livefromstage4 and visit our website at www.livefromstage4.org for show notes and links.

 Your support helps us continue to share important stories and advocate for those living with metastatic breast cancer.

Until next time, take care and keep pushing for progress.

Transcript

SPEAKER_04 0:09

Could a cure for cancer be closer than you think? Welcome to Life from Stage 4, where MBC takes center stage as we talk to experts, share inspiring stories, break down signs, and shine the spotlight on what matters most. Because when it comes down to it, the spot for us and by us is all about us. Hi everyone, and welcome back to Life from Stage 4. MDC News for US by US. This is the news that matters to our lives, shared by the people who live it every day. I'm Victoria Goldberg. Today's episode is truly hot of the presses. We're talking about a major decision that came down just a couple of weeks ago, a decision potentially on how our care is managed in the future. On April 30th, the FDA's Oncology Drug Advisory Committee, better known as ODAC, met to vote on a new treatment strategy involving the drug channel's astronaut. If you're new to these terms, ODAC is a panel of outside experts, doctors, researchers, and patient representatives who review clinical data and vote on whether a new drug or strategy offers a clear benefit to patients. While the FDA makes the final decision, they rely heavily on ODAC's recommendation to guide them. The vote was 623 against the proposed strategy, which involved switching treatments based on a blood test rather than waiting for a scan to show tumor growth. This decision has really highlighted a divide in how we think about precision medicine. To help set the stage for our discussion, we're looking at a LinkedIn post that has been circulating widely from Dr. Adrian Lee, a professor at the University of Pittsburgh and a researcher at the UPMC Hillman Cancer Center. Dr. Lee described the vote as a step backwards, arguing that the Serena 6 trial provided strong evidence that acting early on blood test results, specifically CT DNA, can significantly delay the progression of the disease. But as with everything in the MBC world, it isn't quite that simple. While some see this as a missed opportunity to stay ahead of the cancer, others, including several members of the ODAC panel, have serious questions. They are looking for more proof that switching early actually helps patients live longer or better in the long run. And they worry about changing the gold standard of care without that data. There are valid points on both sides of this vote, and that's exactly why we've gathered here today. The bulk of this episode is a discussion among a panel of seasoned patient advocates who have spent years navigating these treatments and following the science, and they have a range of perspectives on what this vote means for us. Later in the show, Janice Cowden will be citing Dr. Lee's post as we dive into the nuances of this debate. Is the FDA being appropriately cautious or are we standing in the way of a new era of care? There are no easy answers. But this is the news for us by us. Let's get into the conversation. Actually, before we do, I want to make sure everyone listening is starting from the same place. Most breast cancers are fueled by estrogen. They are called hormone receptor positive or HR positive. Treatments like aromatase inhibitors or AIs work by blocking estrogen from reaching the tumor, essentially starving it. For many patients, this works well for years. But cancer adapts. Over time, some tumor cells develop a mutation in the gene that codes for the estrogen receptor itself, the ESR1 gene. When that happens, the estrogen receptor changes shape in a way that keeps it permanently switched on, even without estrogen. The drug that was blocking estrogen is no longer enough because the receptor no longer needs estrogen to function. This is how resistance develops. The ESR1 mutation does not appear at the beginning of the treatment. It typically emerges during treatment, often after one or two years on an aromatase inhibitor. And here is what makes it clinically significant. It can be detected in a blood test, a liquid biopsy, before anything shows up on a scan. That brings us to molecular progression versus radiographic progression. Radiographic progression is what oncologists have traditionally used to decide it's time to switch treatment. Something shows up on a scan, a new lesion, a growing tumor, you can see it, you can measure it. It's the conventional signal that the current treatment has failed. Molecular progression is different. It means a resistance mutation like ESR1 has appeared in the bloodstream, detectable through CT DNA testing, even though scans still look clean. The disease hasn't visibly progressed yet, but the biology is telling you it is heading there. The question at the center of this entire episode is should that molecular signal, a mutation on a blood test, be enough to switch treatment? Or do we wait for the scan to confirm what the blood already suspects? Serena 6 tried to answer that. And as you're about to hear, the answer is complicated. Before we go further, let's define some of the clinical trial terms you're about to hear a lot. So primary versus secondary endpoints. Every clinical trial is designed around a central question. That's the primary endpoint. It's what the trial is statistically powered to answer. And it's what regulators use to decide whether a drug gets approved. Secondary endpoints provide additional information, things like side effects, quality of life, or longer-term outcomes. But they don't drive the approval decision. In Serena 6, progression free survival was the primary endpoint. OS or overall survival was secondary. That distinction is at the heart of much of the debate that you'll hear in this episode. A surrogate endpoint is a measurement that stands in for a clinical outcome that we care about but can't measure quickly. Instead of waiting to see whether a patient lives longer, researchers measure whether their tumor stopped growing. The hope is that tumor control predicts survival. PFS is a surrogate endpoint. The FDA accepts it, but not everyone agrees it's enough. How long a patient lives without their disease getting worse? It's faster to measure than survival, which makes trials shorter and less expensive. The trade-off, it doesn't tell us whether patients actually live longer. OS, the gold standard. Did the drug help patients live longer? Full stop. TFS2. Progression free survival to a newer, more complex endpoint. After a patient's first treatment stops working and they switch to a second drug, TFS 2 measures how long that second drug holds the disease at bay. Serena 6 used it to try to capture the downstream benefit of switching early. As you hear, it raised serious questions, partly because the control arm patients could go on to any therapy after progression, making the comparison uneven. CTD or time to deterioration. CTD measures how long it takes for a patient's quality of life to meaningfully worsen, as reported by the patient themselves. It's a patient-centered endpoint that captures something PFS can't, not just whether the disease is controlled, but whether the patient actually feels better or worse on a given treatment. And then TDF or time to drug failure. It measures how long a patient stays on a drug before stopping for any reason progression, toxicity, side effects, or patient choice. Unlike PFS, which only counts disease progression. TDF captures the full picture of whether treatment is actually workable in practice. A drug might delay progression on paper, but be so toxic that patients stop taking it. TDF would catch that. PFS would not. This is the endpoint Linda references directly, and it's gaining traction as a more realistic measure of real world treatment durability. Why it matters? These endpoints aren't just academic. Which endpoint a child chooses shapes what gets approved, who gets access and what we know or don't know about how a drug actually affects patients' lives. The debate in this panel is at its core, a debate about which of these measures we should trust most. Okay, so with those definitions in hand, let's return to the panel. My goodness, we don't get that very often, do we? Before we start, I'm gonna quickly go around and just let our audience know who is here, but I don't think we need the introductions because if we do the introductions, it will take an hour. So just quickly, who is here? Ansley, I'm so excited to have all of you here. So Janice Cowden, Jill Tiribasi, Ellen Landsberger, Abigail Johnston, Kelly Shanahan, and Linda Weatherby. And there is a reason why we're all here today at a very short notice. We got this ODAC vote on Friday, and here we are on Monday talking about it. So, what is it we're talking about? So we're here to unpack the FDA advisory vote, not really about chamasestrand, which is another oral third. This is more about switching to therapy early based on liquid biopsy identification of ESR1 mutation rather than waiting for a scan to confirm that there is a progression. So let's talk about it. This Serena 6 trial. Is that meant to be a paradigm shift or was it premature?

SPEAKER_05 12:12

What do you think? Well, I think in terms of switching based on emergence of mutations, it's emerging. I think it is going to be a paradigm shift. And I don't think that we have come up with the tools with how to assess this. There were flaws in the Serena 6 trial. The FDA pointed out some of them that I've been saying for a long time, dude, where's the crossover?

SPEAKER_04 12:50

Kelly just said something I want to make sure Lance. Where is the crossover? Because if you're not steeped in clinical trial design, that phrase might not mean much at all. Let me explain it. Because it's actually one of the most important structural critiques of Serena 6. In a randomized clinical trial, patients are split into two groups. One group gets the experimental treatment, in this case, an early switch to camisestrin triggered by the ESR1 mutation. The other group stays on standard care, aromatase inhibitor plus a CDK4-6 inhibitor until their disease visibly progresses on a scan. Crossover is a design feature that allows patients in the control group, the ones who stayed on the standard care, to switch to the experimental drug after they progress. It's both an ethical and a scientific tool. Ethically, if the experimental drug looks promising, it feels wrong to permanently deny it to patients in the control arm just because of which group they were randomly assigned to. Scientifically, crossover allows researchers to observe what happens when the control arm patients eventually do get the drug, providing a second look at its effect and helping validate the findings. Without crossover, when control arm patients progress in Serena 6, they could go on anything, any drug their oncologist chose. That's what Kelly means by dealer's choice. Because those patients scattered onto so many different subsequent therapies becomes very difficult to isolate what effect chamasastrin specifically had. The comparison gets muddled. The absence of a structured crossover also makes PFS2, the second progression free survival period, nearly impossible to interpret cleanly. You're comparing the experimental arms PFS2 and chamasastrent against a control arm that went on completely different drugs. It's not apples to apples comparison. This is one of the core reasons the FDAN ODOC pushed back. Not necessarily because the drug doesn't work, but because the trial wasn't designed in a way that lets you prove it convincingly. Back to Kelly, who has a lot more to say about this.

SPEAKER_05 15:29

Does your CT DNA percentage go down? Does it stay the same? Does it go up? That can indicate really early on whether a treatment's working or not. The FDA has to, I think the sponsors have to. I think we as advocates all have to start learning about how to design trials in a space that's totally new.

SPEAKER_03 15:51

I agree with what you're saying, Kelly, but I also think that one of the main reasons that they did not advise approving this, the FDA technically hasn't ruled on it yet, but usually they follow the committee, is that it did not show overall survival. So as an end point, they use progression-free survival. And that's a different discussion because it seems to me, whereas we do want to know about overall survival. Some trials are only looking at progression-free, some trials are going longer to have the overall survival. They have approved other drugs just based on progression-free survival.

SPEAKER_05 16:31

Yeah, look at the next day. Was it the next day or was it the same day? They uh they approved vep digesterin.

SPEAKER_03 16:37

And I think in that case, vep digestrin is a different kind of drug. Whereas camizestrin, there is another drug of the same classification, the LSER. And M Lunesterin. It's a Me Too drug. Yes, that's true.

SPEAKER_04 16:55

Odak said that there is no clinically meaningful benefit. What did they mean by that?

SPEAKER_03 17:00

Clinically meaningful benefit over already approved drugs.

SPEAKER_05 17:03

But the patients that did the early switch reported improvement in quality of life. And I don't think that was addressed fully. Um, and because it wasn't a primary endpoint, I think it was one of the secondary endpoints.

SPEAKER_04 17:15

Somebody, I think maybe Kelly, you did. You mentioned that the trial design was faulty. So let's talk about this. Serena 6 trial. What do you think the problem was with the trial? And maybe that's one of the reasons why Odak voted the way they did.

SPEAKER_05 17:31

When somebody that did not do the early switch had progression, they could go on dealers' choice of therapy. They could go on anything. I think this would have been a better trial if when someone that was basically on the standard of care arm that continued on their endocrine therapy plus their CDK4-6 inhibitor until they had radiographic progression, something showing up on scans. If they had then been switched to the CAMI, the camizestrant arm, and then they did really well for a long period of time, I think it would have shown that yes, it's camestrant that made the difference. So I think that's one of the issues with this trial. Some of the oncologists that have been commenting on this on Twitter are like, yeah, but it takes so much longer and it costs a heck of a lot more money to do a switch to the investigational drug. And I'm like, you know what? The time factor, I think, is more of an issue. Again, for some people in the oncology space are like, no drug should be approved unless they show overall survival. But think about how many of us will die because some of these drugs are showing years of overall survival. And if the drug's not approved until then, how many of us wouldn't get access and would be dead now? So there is that argument.

SPEAKER_00 18:46

Yeah. This idea of a trial being powered to answer a particular question, that goes back to the study design. And to me, one of the biggest issues that was missing was the quality of life data. Um, whether we call them patient-reported outcomes or we just call it quality of life data. It's not just the outcomes, it's also our experiences of receiving these medications. And that to me was not captured in the way that it should have been in this particular trial.

SPEAKER_04 19:16

And we do know that the patients who switched reported the improvement on their quality of life and the pure side effects after the switch.

SPEAKER_03 19:27

We're dealing with this with Locestrin as well, that Locestrin was approved only for people who showed that they had the ESR1 mutation, even though it still worked in people who didn't have the mutation. And again, dealing with improved quality of life. There's many of these endpoints that just aren't clear, and it switches. It depends on the trial, it depends on the study design, depends on the month and the day of the week that these are being approved, it seems.

SPEAKER_05 20:04

One of the things the SURDs are showing, whether it's fulvesterin, the injectable SERD, or whether it's these oral SURDs, is there's a lot less of the joint pain and things like that that accompany the AI. And I think that's why the patients had the improved quality of life on the switch to canvas esterin' because they got rid of all that joint ache and pain.

SPEAKER_04 20:24

We haven't heard from Linda or Jill or Janice. You guys have nothing to say.

SPEAKER_01 20:28

I have plenty to say, in fact, I have two pages of notes, but I did them in a little bit of a pros and cons on the ODAC decision because it's easy to see both sides. I think there's trial design flaws that Kelly has already mentioned and you've already talked about that were pretty significant with this trial. Do I think that this is a potentially practice-changing trial? Absolutely. Because we're going towards precision medicine. We're looking at more biomarker-driven trials and so forth. And that's the smart thing to do. I just think that we don't have the full picture. And that's part of what's missing and concerning for me. We have work to do before we can get the answers and the data that we need. I agree with what everybody else said in the metastatic setting, regression-free survival, it's a really important endpoint. Like Kelly said, maybe overall survival, by the time these drugs get to market, we're not going to be alive to try them anyway at that point. Or some people will not. But one of the biggest questions I had was does the early switching improve the PFS2? Does it, if we start using this as a measure outside of clinical trials in practice, where I'm already hearing of oncologists that are switching patients' treatment lines? And this is in the newly diagnosed setting. Based upon CT DNA rising alone, based upon signatura testing. And I think the problem with that is that they were not planning on doing any imaging. That huge knowledge gap that we know exists between the academic oncologists and the community oncologists. We need to make sure that we're doing the right thing for the patients at the right time. And I do worry that does the early switching, I know that there was a significant, what was it, a 6.8 benefit in the PFS between the two arms? That's clear. That was like a, I don't know, 56% of benefit that was seen in Serena 6. But what does it mean long term for metastatic patients? Are we just going to burn through treatments quicker? We know that with each subsequent line of treatment, or it's my understanding with each subsequent line of treatment, the progression-free survival starts declining. So what do these early switches mean? And I think that Serena 6 didn't really answer that, or maybe hasn't answered that yet. What does it mean? So that's really my point of view. On LinkedIn, I saw a researcher that we all know, Adrian Lee, posted his opinion on there. And it was really quite compelling as to why he felt the decision was probably not the best decision. But at the same time, I still think we have questions that are not answered so far, not yet.

SPEAKER_06 23:32

I have two questions. One is I saw one statistic, I think it was time to drug failure or something. Is that the same as progression three survival? I read something where they were offering that as a better surrogate, and I wasn't familiar with it.

SPEAKER_05 23:51

Since we've always thought of progression in terms of either symptomatic progression or radiologic progression, I think we do have to define a new term if you're going to be looking at molecular progression. Yeah, maybe that's it.

SPEAKER_04 24:04

When you see the ESR1 mutation developing on uh liquid biopsy, does that mean that the drug has failed? I don't think so. It means that it's still working, but eventually it will fail.

SPEAKER_05 24:17

And there may be populations of cells where you still are super endocrine sensitive and your AI is going to work in your lung and in your bones, but maybe it's not working so great in your liver. Yeah. So we don't know that. I think that was one of the comments I saw from some oncologists commenting that we don't know how long somebody might still have done well on their AI plus their CDK4-6 inhibitor. And as Janice mentioned, you burn in lines of therapy. I think Kami is a great drug, it has its place. And again, I'm a little not quite flabbergasted, but questioning like why were they so down on camisesterant, but they approve VEP digesterin? And you look at the PFS, the PFS in the Serena 6 was, I think, double what it was in the Veritac trial with VEP digesterin. Yeah.

SPEAKER_06 25:08

Here's my second question. And by the way, that other surrogate was TDF or something, time to drug failure. So I want to keep looking for more information. Then my second question is do we have any opportunity as advocates to give input before there's the final vote? Since this is so controversial. And should we get organized to do that if there's an opportunity?

SPEAKER_04 25:34

But what would you what side are you on? What would you like to see happen?

SPEAKER_06 25:40

Anytime they're taking an opportunity, if this was phase two, does that mean it's dead in the water?

SPEAKER_05 25:48

Serena 6 was a phase Serena 6 was a phase three trial.

SPEAKER_06 25:52

So is it dead in the water? And that kind of pisses me off.

SPEAKER_05 25:56

No, that there's some other Serenas. There's a couple of these Serenas floating around. Serena 2, I think, is one. They're looking at it in combination with other agents. So I don't think it's dead in the water. I think it's a definitely a speed bump.

SPEAKER_04 26:11

Camestrin itself, like LS estrant and imblunct, will be approved as a monotherapy, probably with the ESR1 mutation or something. But the bump is with this early switch, clearly.

SPEAKER_06 26:26

I think as advocates, this is really all I have to say. As advocates, I think we need to be saying, look, if there is an opportunity for sequential use of these drugs like CDK 46s, then we need to be loud about every opportunity matters. And I'm on a BEMA now after Cal Bow and Rabo didn't work, right? So this is not Canada where you only get one shot at a CDK. And the sequential opportunity is huge. And even though it may be diminishing returns, and that I think we need to be screaming about. And I'm not clear what the situation is with these oral surge, but if it is an opportunity, and particularly with the CSR1 issue, that you can go from one to the next in different circumstances.

SPEAKER_01 27:20

I just wanted to add to Linda's point. I honestly didn't see it a vote against the drug itself. Yes. I saw it as a vote against changing practice too quickly without the evidence that there's meaningful clinical benefit. So I don't see it as being dead in the water at all or that it wasn't a good drug. I thought that the side effect profile was pretty favorable with Kami from what I saw. And knowing that the quality of life was improved for the people who did the switch, I really do think somebody else said it too. It's more about that point of switching. When is the right time to switch? And I think it's a great drug. And I'm glad that we already have some oral SERDs for ESR1 mutated hormone positive MVC. It'll be approved. And I think it's going to be a great drug. Like Kelly said, I thought what she said was perfect. It's a speed bump along the way.

SPEAKER_02 28:19

This is Jill. I'll chime in a little bit. Yeah, I think the bump in the road really is surrounding this new definition of what is molecular progression and what does it really mean? And do we have enough data right now to jump into using that as a line changer? So I think maybe in the metastatic space, there's kind of being floated like step-up, step-down therapy where maybe we can add on an additional drug, then really change a full line of treatment. And maybe some of this molecular progression is really where we're gonna see that being used. If certain tumor population within a person is changing, but the rest of it's still susceptible. Should we really fully change a line versus maybe change one piece of a triplet and that kind of stuff? And so to me, that's what I think they were really pumping the brakes on is what truly gets a molecular progression? Are we doing all that? Now, that being said, as a patient, like someone who has gone through a lot of line of treatments and a little bit of time, months matter to me. And so the loss of that drug being approved right now, I was a little upset about because I agree, it seems like it's a good drug that's useful that actually can do well. But since it was so tightly tied to this other piece, they're concerned that we don't really fully understand that that aspect yet.

SPEAKER_05 29:38

And then you look at the Padawan trial, which was another early switch based on emergence of an ES401 mutation and switching from an AI plus palbo cyclib to fulvestrin plus palbo, they've allowed crossover progression. And so they've met their primary endpoints, which are PFS, but they're still the data's nowhere near mature about OS. And again, I think we need that, but do we need to wait for OS?

SPEAKER_04 30:04

Shall we talk about another surrogate endpoint that was introduced in this particular trial? That I don't know if I'd ever seen it before in any trial designs, PFS2. So, what exactly is PFS2? And obviously it was falsely because of the crossover issue. But what do we think about it in the future trial designs?

SPEAKER_05 30:28

It's also not PFS2, because the people that had the early switch, that's their second drug. That's PFS2. So when they progress and they switch, that's PFS3. So you're comparing PFS2 to the people that stayed on their AI plus their CDK4.6 to PFS3. So there were some concerns about that. But again, if you also look at the Sonia trial, which just recently showed that frontline addition of a CDK4-6 inhibitor to endocrine therapy is not necessarily the be-all and end all that it has been purported to be. I think we have a lot of confusing data and we need more trials. I would love to see these kind of correlatives done with every single trial that's out there. Let's do CTDNA, let's see what happens. Let's see if we can find predictive biomarkers on who can just be on an AI for six years. One of us was. Who needs an AI and a CDK4-6 inhibitor from the get-go? We just need so much more data. And we need that kind of basic correlative biomarker-driven data.

SPEAKER_01 31:40

I would agree, Kelly. I think that is really key and where we're moving, but we're not there yet to be able to determine which patients really need that CDK4-6 inhibitor in first line versus just endocrine therapy only. And the same with all of these. Which patients are the right patients? Which ones are the ones that I don't know what the biomarker would be, but maybe it's a more aggressive hormone-positive breast cancer that isn't going to respond to any line of treatment as long as what you see the data coming out from the clinical trials. And I think finding those biomarkers to know which patients are the right ones to switch with molecular progression versus the ones who may get an extra six months to a year out of that current treatment that they're on. Maybe they're having some rise in their ESR one mutation or CT DNA or whatever, but maybe it's not the same as somebody else's, and that other person would benefit by that earlier switch. Like you said, Kelly, there's just so much that we don't know yet. And I think that they thought of this as when comparing to Pata 1, it was a much smaller trial, right? It was phase two, wasn't it? Wasn't it a phase three? I thought it was phase two, but maybe around. It could have been. It could have been, but it was a smaller trial. I think with having a Serena 6 being a much larger trial, having more participants, some might think, well, that's going to lead to stronger data. But it all depends on what the questions are that you're asking and what your endpoints are and what you're really looking for in that trial.

SPEAKER_04 33:18

So I have a question for you, actually, as a follow-up to what you're saying, Janice. It sounds like what you are saying is that most of the decisions made by our medical oncologists will be CT DNA driven soon enough. So do you think we're ready for prime time for this? And if we are, how often do we expect people to be tested?

SPEAKER_01 33:42

The big answer for that is, and we hear it at every single scientific conference. They may not say the words, we're not ready for prime time yet, but in clinical practice, the majority of the people who are running trials and the academic oncologists, they're a little hesitant to really jump into that space of using CTDNA or molecular progression as the point of switching. I think we're seeing it in other spaces where oncologists maybe they don't know all the ins and outs of what does that mean if we switch earlier based on molecular progression. Do I think eventually that it will be based upon biomarkers such as CT DNA? I think they'll definitely be a companion tool in clinical practice. We don't quite have all the answers there either. And what we don't know, especially for surveillance and monitoring, it might be good right now for monitoring response to treatment, but whether or not it can replace imaging at some point, I think we're a ways away from that, personally. Yeah.

SPEAKER_04 34:54

And we haven't really talked about the insurance issues right now. Not everybody's readily eligible. I think maybe garden 360 is more widespread and more available than Signatera.

SPEAKER_01 35:09

But the truth garden uh reveal would be more similar to Signatera because it's just looking at CT DNA. Right, because they're about tumor-informed testing, they require tissue.

SPEAKER_05 35:22

Which one? Garden reveal does not.

SPEAKER_04 35:25

Garden 360 does not, Signatera does, right?

SPEAKER_01 35:30

Signatera limits the pool of people that can use it. But it's not looking at treatment response person. I think garden reveal is more in the MRD than the minimal residual or molecular residual disease. I think it's more in that space. But you're right, Victoria, and that's a good point. Not everybody has insurance that will cover any of these tests. And some of the platforms are a little bit more forward in helping patients by maybe whatever insurance doesn't pay, or if the insurance doesn't pay, they write it off. But not everybody's, I mean, I know a lot of people paying out of pocket for these tests.

SPEAKER_05 36:06

Most of the time, these tests will be covered, like a Garden 360 will be covered when there is progression. Medicare covers it. Most insurers will therefore cover it, but they're not covering it in the Serena 6 paradigm, just to routinely monitor. And I know that's something that some of these companies are pushing for in rules that would allow for Medicare and therefore the private insurers to follow to cover that.

SPEAKER_01 36:33

Yeah, and if they're not going to pay for the testing, chances are they're not going to approve a switch in treatment based upon that. I would think. I don't know that for a fact. I'm just thinking that might be the case. If they're not going to pay for the testing to use as evidence for switching treatment, are they going to pay for the next line of treatment if they don't have radiologic progression as noted? I don't know.

SPEAKER_04 37:00

I've also heard something that may have changed in the last year that a lot of community doctors are not comfortable with reading the results of these CC DNA tests and they don't base their decisions on what they see. What does that mean? We have a two-tier system now. We have those of us who are treated by uh forward-looking oncologists in the cancer centers versus local general oncologists. That's a problem as well, right? If there are no general guidelines, it's harder for people to make decisions based on something they don't quite understand.

SPEAKER_05 37:38

We've had a two-tier system for a long time based on where you get your care and what the color of your skin is and gender and everything else. I'm not quite as pessimistic about Helen that it won't change. It hasn't changed yet. I don't think it's going to change in the next couple of years. And that's again where we as advocates and voices in our community have a role to educate the newly diagnosed, to educate the people that are under-resourced, to educate and to give people the tools to ask for this testing. Because in 2026, to not be offered a liquid biopsy upon progression is, I am sorry, it is malpractice.

SPEAKER_01 38:18

And unfortunately, it happens all too frequently. Yeah.

SPEAKER_05 38:24

But in terms of this whole idea of the switch, and Janice is right, people are doing it. They are asking their oncologists, they're getting routine monitoring, they're having treatment switch. And I don't think it should be done outside of a clinical trial. And I think we should make more clinical trials more accessible to more people so we get these answers faster.

SPEAKER_04 38:44

Kelly, you're saying that people are asking. Who are those people who are asking? People who are knowledgeable about it. And there are so many who have no idea what we're talking about right now. So I'm hoping that having this discussion and putting it out there will give some education to people to ask the right questions when they go next time to their oncologists. But we still have a lot to unpack.

SPEAKER_05 39:10

We at MetaVivor are working on a biomarker education piece. Excellent. It will live on our website. There'll be some webinars later on this year about biomarker testing. What is a biomarker? Frankly, a blood pressure is a biomarker. Anything to assess what's going on in our bodies is a biomarker. But we're really focusing on what we're talking about now: biomarkers in terms of circulating tumor cells, C T DNA, and then what to do with it, when to get it, what platforms, in what situations. Hopefully, more and more people will become aware of it and have access to it.

SPEAKER_06 39:42

That's sending me back to this question about as advocates, what are we saying and when should we say it? And who should we be connecting with? I'm curious who was out there in the advocacy space influencing clinical child design. To me, this whole discussion begs the issue of how do you find a progression? How do you define progression? What you guys were saying. And then the whole back to the surrogate endpoint thing, like, where is our voice being incorporated? That's such a good point.

SPEAKER_05 40:12

Yeah, voice should be there. And I'm very fortunate in that I'm speaking at two big meetings this year on precision medicine, on endpoints, on biomarkers. Would you like to tell us what those meetings are? So I'm speaking at ESCO, and I'm in a clinical science session that's a special session, so it's not just a specific cancer type. And the focus of it is endpoints that are meaningful to patients, and it's in the big hall. Wow. There could be nobody in the big hall, or there could be thousands of people in the big hall, but it's in the big hall. And Ethan Bosch is the chair. And one of the points that I'm going to be making in terms of the different endpoints is that we've got to include quality of life measures, heroes, needs to be primary endpoints. And that if we involve trained patient advocates in the design of the trials from the get-go, in the design of the phase one trial, not just the phase three, not just commenting on something after IRB approval, that we can help improve all this. We can help pick these endpoints. We're talking here about how we all think that the quality of life should have been a primary endpoint in Serena 6, because the improvement that people reported in their quality of life with the early switch was pretty darn compelling. And I think if that had been a primary endpoint rather than a secondary endpoint, maybe that would have swayed that. And again, we don't know. Granted, yes, this was a 6-3 vote by ODAC. The full FDA usually, but not always, follows the ODAC recommendations. So the full panel could go, yeah, we think this should be approved. We think this is interesting. But again, patients need to be involved in the design of these trials and in choosing what are the endpoints.

SPEAKER_04 42:06

At the ODAC session, the FDA came to talk about their concerns. So they clearly have a lot of concerns about this trial.

SPEAKER_05 42:15

And remember that this is not the first time AstraZeneca was hearing this. Like back in 2021, 2022, they have these meetings with the FDA. And sometimes they're real meetings, sometimes they're virtual meetings, sometimes it's an exchange of information back and forth. But they get a letter that says, here's what we think, and here's where we think you should make changes. I've been involved in a meeting with the FDA, not with the big thing like this, but on a smaller scale, where I've been in a room with the folks at the FDA when I was doing some consulting for a pharma, and we were responding to FDA concerns about a trial design. And it became clear that there was no way in hell that the FDA was going to go for this, partly because the company didn't respond to the concerns that the FDA had continued to raise for a couple of years. Yeah. That's so true. If the company had gotten us involved a few years earlier, we would have said, no, you need to change this. AstraZeneca had multiple opportunities to make some tweaks to the design of this trial.

SPEAKER_04 43:24

Do you actually think it's arrogance on their part that they don't listen to what they're being told?

SPEAKER_05 43:29

I think on both sides there's arrogance. Again, this is something totally new. And I agree with the comments that people have made that the FDA is a little too stuck in the mud and not thinking outside the box, like, whoa, this could be super promising. How do we integrate this into the regulatory framework? And I also think on the part of the pharmaceutical companies, that they're like, we love our idea and we think our idea is great, and we're not going to change. So, yeah, there's some arrogance on both parts.

SPEAKER_06 43:59

Yeah.

SPEAKER_04 44:10

All right. I want to hear from everyone. What are your parting thoughts?

SPEAKER_01 44:15

Just say that as we move closer and closer to truly practicing precision medicine, I think molecular progression is scientifically extremely exciting. And I find it to be a more patient-centered approach. And I'm all for it. I have been very vocal about using these types of biomarkers and so forth outside of clinical trials. But I think at the same time, we have to be patient because we still have a lot of questions that are unanswered. And that really is my parting thought. It didn't dampen my excitement about where we're going. I still think we're making great progress when it comes to biomarkers and precision medicine. I think Serena 6 was a bit of putting the cart before the horse. It's like we have the data, but we don't necessarily know what to make of it or what to do with it. Or we just don't have the big picture. We don't have all of the evidence that we need to say, hey, this is practice changing today. Very well put. Thank you.

SPEAKER_02 45:19

I'm just going to make a plea that I heard of involving patients in trial design upfront because that's when it matters. Because once the cart has started on a trial, it's hard for it to change as it goes on. And so the planning phases, the proposals, that's when it matters. And the second plea being decentralizing trials so they can actually reach broad people across the country.

SPEAKER_05 45:43

Kelly, how about you? I know you have something to say. Janice summed up things quite well. However, I think an unexplored thing with Serena 6 is do we change treatment the second a biomarker emerges, the second a mutation emerges? Do we watch it? Do we see if it shows up at a low level and then increases? I think looking at tumor allele fraction is more important than yes or no in terms of how much of the mutation is there. I think is going to be where this can go.

SPEAKER_04 46:29

I have to stop us here one last time. Because Kelly just mentioned something I have to be honest. I had to look up myself. Tumor allele fraction. Let me explain it. Because I think once you understand it, Kelly's point lands much harder. When a liquid biopsy detects an ESR1 mutation in your blood, most people think of it as yes or no result. Either the mutation is there or it isn't. But that's not the whole picture. Every liquid biopsy also measures what percentage of the DNA fragments in your blood actually carry that mutation. That percentage is the tumor allele fraction, sometimes called variant allele frequency or VAF. Think of it this way: imagine your bloodstream contains a thousand pieces of tumor DNA. If two of them carry the ESR1 mutation, your tumor allele fraction is 0.2. If three months later 150 of them carry it, your fraction has jumped to 15%. That trajectory, that rise, tells a completely different story than a simple positive test. A tiny, newly emerged mutation at a very low allele fraction might mean resistance is just beginning to develop. A rapidly rising fraction means the resistance cell population is taking over. A falling fraction after a treatment switch might mean the new drug is working. What Serena 6 did was trigger a treatment switch based on the presence of the mutation alone, without accounting for fraction or trajectory. Kelly's argument is that this is too blunt an instrument. Not every positive result is the same. How much of the mutation is there? And is it growing? That, she's saying, is where the science needs to go next. And on that note, back to our panel for closing thoughts.

SPEAKER_03 48:35

What I wanted to add to this is that one reason not to act immediately upon a new mutation is that we know that there are false positives in these tests as well. So waiting and learning, there are trials going on currently that are going to answer some of these questions not too far in the future. And that's really going to help.

SPEAKER_06 49:00

Linda. I just want to go back to what Jill said and echo what everyone else has said. But I do want to point out, and I can't help but be left with this feeling of, oh my gosh, where does this really leave us for this one decision? But imagine if really informed patient advocates had been at the table and this trial design had not necessarily happened. How much further ahead would we be? Think of the investment in this trial and what we get is a little bit of a messy decision. So I'm going to echo the plea that Jill made bring really smart patient advocates to the table who know their stuff. Perhaps some of the people on this call, not myself, but others on this call. Being way too modest. And let them give input at the beginning, and then we might not end up with however much money was sunk into this, and then end up with this mess at the end. So that's my last thought.

SPEAKER_04 50:02

And I want to say something I think is worth mentioning, and we touched upon it all throughout this panel that this particular vote, we don't think is the vote on the drug itself. We think it's the vote of a new way of testing for mutations and changing treatment. As we say that it might be a paradigm change in the future. But the drug itself is good. And we think it's going to get approved. And as Kelly mentioned earlier, that there are, I think she said that there are four ongoing trials on this drug. And we have every expectation that the drug itself will be approved at some point. So I think it's important for our listeners to know that. I think we're good. And that brings us to the end of today's panel. I want to take a few minutes to bring everything together because we covered a lot of ground, and I don't want you to leave without the clearest possible picture of where things stand. So the main takeaways. The ODA vote on chemisestrin was not a verdict on the drug itself. Our panelists were unanimous on this. Chimestrin appears to be a good drug, and the 6-3 vote was a verdict on a question Should detecting an ESR1 mutation in a blood test before anything shows up on a scan be enough to switch treatments. Odox said not yet. Not with the evidence we have. The trial design matters as much as the drug. Serena 6 had real structural problems. No crossover for the control arm, quality of life as a secondary rather than primary endpoint, and a complex PFS2 comparison that was difficult to interpret cleanly. These weren't minor quibbles. They made it impossible for the FDA to draw confident conclusions, even when the early data looked promising. Molecular progression is the future, but we're not ready to act on it alone. The concept of switching treatment based on arising ESR1 mutation before radiographic progression is scientifically compelling. But as our panel made clear, we don't yet know which patients to switch, when exactly to switch them, or what the long-term consequences for subsequent lines of therapies will be. The field is moving fast, but it hasn't caught up with the biology yet. Patient advocates belong at the table from day one. Perhaps the strongest consensus in this conversation was this. If trained patient advocates had been involved in Serena 6 design from the beginning, the trial might have been built differently. Quality of life as a primary endpoint, a crossover, better capture of what actually matters to patients, that is a fixable problem. And it starts with pharma and researchers opening the door earlier. Access and equity are not afterthoughts. The promise of liquid biopsy and precision medicine means nothing if testing isn't covered by insurance. If community oncologists aren't trained to interpret the results, and if patients who aren't plugged into major cancer centers never know to ask, the two-tier system Kelly described is real, and it will determine who actually benefits from these advances. Okay, so now a few words about the trials referenced in this episode. Serena 6, the central trial of this discussion, a phase 3 randomized study by AstraZeneca testing chamasestrin and oral surge in patients with HR-positive HER2-negative metastatic breast cancer on first-line aromatase inhibitor therapy. Patients were randomized at the point of ESR1 mutation detection before radiographic progression to either continue standard care or switch early to chamasestrin. The trial met its primary endpoint of PFS, showing a roughly 6.8 month benefit. ODAC voted 6.3 not to recommend approval, citing concerns about trial design, the lack of overall survival data, and the absence of a structured crossover. PIDA1, a French phase 2 trial that also explored early switching based on ESR-1 mutation emergence. Patients on palbocyclip plus an aromatase inhibitor were monitored with liquid biopsy. Those who developed a rising ESR1 mutation were randomized to either switch to fulvestrin plus palvocyclip or continue their current therapy until radiographic progression, with crossover allowed. Pada 1 is smaller than Serena 6, but is considered better designed in some respects precisely because of that crossover provision. It helped establish proof of concept for the early switch strategy, though its data on overall survival remains immature. Sonia, a Dutch phase 3 trial that tested a different but related question. Does it matter whether you use a CDK-4-6 inhibitor in the first line of treatment or the second? Sonia found that starting with a neuromatase inhibitor alone and adding a CDK-4-6 inhibitor at the second line, produced similar overall survival to starting with both up front, challenging the assumption that CDK-4-6 inhibitors must always be part of the first line therapy. Kelly referenced this as an evidence that the field has more confounding data than it realizes, and that the optimal sequencing of these drugs is still genuinely unsettled. Serena 2, an earlier phase 2 dose finding an efficacy study for chamasesterin and previously treated HR-positive HER2-negative metastatic breast cancer. It established chamasterin's activity and helped determine the doses used in Serena 6. Kelly references several ongoing Serena trials as evidence that chamestesterin's development continues despite the ODOX setback. Veritac or Veratac 2, the trial referenced when discussing Webtidestrin, an investigational protoc protein degrader against fulvestrin in adults with advanced or metastatic breast cancer. Veritac 2 tested web tidestrin in ESR1 mutated metastatic breast cancer after prior endocrine therapy and CDK4 inhibitor treatment. Its approval for a later line, more specifically defined population, is what prompted Kelly's question. Why was web tidestrin approved while camisestrian was not? The answer lies partly in the population studied and partly in the narrower, better defined claim web tidestrin that was approved for. I want to close by thanking the extraordinary women who gave their time, their experience, and their candor to this conversation. Thank you to Kelly Shanahan, patient advocate, meta-viver, president, and one of the sharpest voices in the metastatic breast cancer space on biomarkers, trial design, and what precision medicine actually means for patients. Thank you to Janice Cowden, whose two pages of notes and careful balanced thinking set the tone for the nuance this topic deserves. Thank you to Ellen Landsberger for consistently bringing the conversation back to what the data actually shows, and for the important reminder that endpoints and approvals are never as straightforward as they seem. Thank you to Abigail Johnston for articulating so clearly while trial design that ignores patient experiences fundamentally incomplete. And thank you to Jill Tirabasi for the plea about decentralizing trials that I hope researchers and sponsors heard. And thank you to Linda Weatherby for calling in from the road, asking the questions many listeners were thinking, and reminding us that sequential access to these drugs is not a technical footnote. It's someone's life. This conversation happened because a boat was taken on a Friday and we got everyone on a call by Monday. That is the metastatic breast cancer advocacy community doing what it does best. The information discussed in this episode is intended for educational purposes only and does not constitute medical advice. Clinical trial data, regulatory decisions, and treatment guidelines evolve rapidly. Some detail discussed may have changed since the time of recording. Nothing in this episode should be used as the basis for any personal medical decision. Please consult your oncologist or qualified healthcare provider regarding your individual treatment options. The views expressed are those of the individual participants and do not represent the positions of any organization, institution, pharmaceutical company, or regulatory body.