第185期——2026年6月5日

You're listening to Biotech Hangout, a live and unedited weekly discussion of the latest news in our industry with a group of biotech leaders and experts. I'm Yaron Werber along with my co-host today, Tess Cameron, SamFazeli, and Brian Skorney. For more information about our guests and speakers and to listen to the most recent episodes, please go to biotech hangouts.com.

So, Sam, as you were just saying, we're coming off ASCO. ASCO is always—even when you think it's not going to be super busy—inevitably a very busy meeting. There's a lot to discuss and a lot of fireworks.

Before we get to it, maybe first: What's going on in biotech? AI is hot, and biotech, almost by derivative, is not. We're all seeing on our screens the upcoming SpaceX IPO at a $1.8 trillion valuation. About 25% of the stock looks like it's going to go to retail, and so the question is: Is that going to lead to a market sell-off, or is it going to lead to more momentum at that kind of valuation?

Let's look at some of the parameters. We pulled it earlier today, and these are staggering numbers. Year to date, the Nasdaq is up 13%. To extend that theme, the Qs, the QQQ, are up 18%, and SMH, which we all know is a semiconductor index—shaking my head—is up 66%. The S&P, as I mentioned—or I haven't mentioned—is up 10%.

How is biotech doing? Large-cap biotech, where the IBB is up 1% and XBI is up 8%. If we just look at the last month, XBI is down 4%, the Nasdaq is down 2%, the Qs are down 2%, and SMH is flat. It looks like we're definitely seeing a little bit of migration. Tess, do you want to kick us off? Is biotech not hot because AI is hot, or what's going on out there?

Yeah, it's a really good question. I think we have to remember the huge Q4 run-up we had in biotech. That was a lot of recovery after really being beaten down earlier in 2025. I think that's important to remember. Things don't look so great if we look at them on a year-to-date basis—certainly not on a month-to-date basis—but when we look at the past 12 months, it's like, wow, that performance has actually been very strong, driven by market recovery and a lot of the M&A we've seen.

It's important to keep that longer view in context. It's hard not to wonder if some of that is coming from demand for some of these big AI companies. I also think uncertainty around rates is having an impact, wondering if we're actually going to be in more of a rate-increase environment instead of what I think everyone was expecting a couple of months ago, which was heading into rate decreases.

Those are a couple of macro things that are likely having an impact. But, big picture, looking at the past 12 months, we've definitely seen a big sector recovery.

Yeah, great points, and a good tip about looking at the last 12 months.

I know it's hard. We all remember yesterday and the past week.

True.

Biotech looks pretty good when we compare it with April of last year.

Yeah, absolutely. Brian, what do you say?

Yeah, I think it's funny if you look at the year-to-date chart. You could make the point that the S&P is now outperforming XBI and NBI, but you actually look at our indexes, and they're not that volatile. It's actually the volatility of the S&P that's really driven the relative outperformance. A month and a half ago, we were really outperforming the S&P, and that's just come back; we really haven't moved anywhere.

Certainly, you have to attribute a big part of that move to the AI trade. The S&P, I think, had 10 straight-up days. Today, you're seeing a bit of an unwind on the S&P with the jobs report out and concerns about escalating interest rates. But XBI is only moderately underperforming, and I'm not hearing big freakouts about interest rates, although it's certainly on people's radar.

Look, I think it's just interesting that XBI, which we think of as one of the most volatile indexes, given how these companies can report and be up 150% or down 80% on clinical-trial data, has been remarkably stable and is up. That's the best we can hope for: Fundamentally, you're just seeing more green days than red days, and I kind of like where we are.

Yeah, absolutely. Sam, what's the sentiment in Europe? We were getting a lot of generalist calls from Europe. They haven't quieted down—I don't want to say they've quieted down, but they've quieted down a little bit. It doesn't mean much to me, but what's the sentiment on the sector there?

Well, to be honest with you, Yaron, I've literally just come back, so I haven't quite felt it. We've had this setback in the share price of ABIVAX. I want to qualify it that way rather than necessarily their trial, and that's one of the biggest European names at the minute. There's Genmab there, too, and we're going to talk a little bit about their competitive landscape with petosemtamab at some point.

So I think, in general, biotech investors are reflecting exactly what you guys have just been talking about. They're being whipsawed by whatever happens in the AI space: If money needs to flow there, it comes out of health care, pharma, and biotech; if money comes out of there, it comes back into these sectors.

But it's important to also remember that the old industries—anything outside of the Mag 7 or Mag 8; I don't know if I include Micron, and it depends on whatever companies you want to put in there—have picked up a bit. I think there's a lot of people who believe there's value in those non-tech sectors, which, of course, would be the next game to play.

How do we perform relative to the standard S&P 500 in terms of the general older industries? Not much different.

Okay. Well, one of the things that's been going on—I know it was discussed recently—is the recent BMY news. They had a pretty good ASCO. But one of the things that's been going on is the recent BIOSECURE Act, bipartisan legislation, which explicitly adds to the COINS coverage.

Of course, the COINS Act, as we remember, has to do with a U.S. outbound-investment-screening regime, including countries of concern like China, in terms of prohibiting or requiring notification of U.S. capital flows. That framework came up in December of last year. And now, of course, there's a joint BIOSECURE proposal expected, but we'll have to see if it's actually going to go through.

Tess, do you want to comment on this? I know that was discussed last year, and you definitely have an opinion.

Yes, absolutely. Happy to.

I think, first, just in terms of what's happened, you shared this BIOSECURE proposal, and we also had a letter from John Moolenaar, who's the chairman of the Select Committee on the CCP. Maybe just stepping back and talking about COINS: What was the purpose of COINS in the first place?

A lot of the motivation behind COINS—and COINS is really focused on technology, semiconductors, and AI—was around not transferring expertise. It's kind of like capital flows, but even more than capital flows, it's expertise: things that American investors may have learned from all of their work on AI in the U.S. not benefiting or going to China.

The letter that Moolenaar put forward actually went quite a bit further than COINS, because under COINS, licensing is allowable, right? But what Moolenaar is actually calling for is drawing attention to licensing deals as well and calling for making such licensing deals more difficult. He's calling for something that would be a significant expansion of COINS.

When we saw the letter come out, Peter and I, along with some other members of our team, really thought through: Let's start with what our north star is, which is what's best for American patients. Let's start there and think about this legislation and what impact it would have. Ultimately, what it would do is slow down access to new medicines.

And what the legislation would also do is make it very difficult for U.S. funds to do anything.

It would make it very difficult for US pharma to do anything. But if I’m a European investor, I’m like, “Absolutely, put that COINS Act in.” That’s great because, guess what? If I’m a European investor, my deals with Chinese biotech are going to become that much cheaper, right? Or if I’m a European pharma, it’s like, “Well, awesome. Now maybe my US peers can’t get these China licensing deals, but game on for me,” right?

So it’s interesting because it’s actually a gift to European funds and European pharmas that could essentially put them in a really strong leadership position to continue working with Chinese innovators and bring those medicines globally, including to the US. There’s nothing in COINS that says a drug discovered in China can’t make it to the US, right? It’s just saying US funds can’t go there, US biotechs can’t go there, and, based on what Moolenaar was suggesting in his letter, it could potentially just make straight licensing deals beyond equity investments more challenging.

So there are really a lot of unintended consequences associated with the legislation that’s being proposed. Peter, our colleagues, and I were really heartened to know that we’re certainly not the only people in the sector who see this as really against American interests and against US patient interests. Bruce Booth also had a great article, “Patient First, America First: The Case for Global Collaboration,” arguing that we really have to look at everything with the north star of what is best for patients. There were a number of other investors—Rod Wong and Chen from TCGX—on X and LinkedIn really describing the importance of staying grounded in what our sector does, which is bring medicines to patients and do that in a way where we’re bringing the best medicines and doing that efficiently, so we can deliver high efficacy and safety. That’s really what we’re looking for.

Peter and I also addressed in our article that there are actual valid security concerns, right? Manufacturing is an absolutely valid concern that we should be looking to resolve. If we separate out the physical supply chains for the manufacturing of drug product from the innovator supply chain, which is more about ideas and molecules, we should really be thinking about security and taking more action on the manufacturing side. We should be thinking about how we ensure the supply of not just the end product—the finished drug product—but also drug substance and some of the inputs to drug substance. These are supply chains where we’re heavily dependent on China and some other countries, and it’s something that we should really be looking to resolve.

But the conversation hasn’t gone that way. Instead, it’s been more focused on money going to China and how that threatens US biotech, and we’ve got to let money go where money will go. The US should compete by having a more efficient system where innovators can spend more money in the US to develop their drugs.

Got it. It’s a good point. Maybe, Sam, do you agree? I don’t mean to put you on the spot. Some people will say a lot of what China does well is copycat. We see an antibody in the US, we see another targeted antibody, we’ll put them together into bispecifics, and they do this at industrial strength.

It makes things a little uninvestable, because do you really need 10 best-in-class bispecifics or antibodies? So do you agree? What’s your view, and what do you think is going to be the European response? At the national level, are they going to try to protect their own pharmas?

So, on the first point, I would say we’re going to come and talk about PD-1 bispecifics in a minute. I remember Chris Bard at the AACR pre-event conference saying that nobody would have invested in a PD-1 bispecific. Now we’re going to discuss whether there’s real data here, or whether we have an issue with this PD-1/VEGF bispecific in the West versus China. But the reality is, they did it, and that’s where I think China can currently do things that we don’t have the appetite for.

On the other hand, the hardcore innovation—all of these examples fit in this conversation, right? That came out of 2 companies in the US thinking through matching their efforts together, at least with Revolution bringing the RAS mechanism in. So I want to see more evidence of really completely new ideas and technologies coming out of China, and I have to say I doubt that won’t happen in the next 1 or 2 years. These big deals that you see happening with Hengrui and Innovent will involve new science and new biology.

I don’t think this is a trend that’s going to be stoppable. There’s no reason why Chinese innovation is going to be any worse. They already lead in materials science and chemistry by far in terms of their share of new ideas and idea generation. It’s going to happen. So, from the European perspective, we have to make a decision, as Tess was talking about: Do we want access to that innovation, or do we want to stifle the access our companies have to it?

I don’t think AstraZeneca, GSK, Roche, or Sanofi are going to be able to escape any major changes to rules that happen in the US. At the end of the day, that is the country where they currently make most of their profits, and I think that will cause a very interesting conversation at the board level. If they’re able to get away with it, then I think it gives them an advantage versus US large pharma, because, let’s face it, those are the groups we’re talking about: large pharma, right? I don’t know if they’ll be able to get away with it if this becomes legislation, which I hope it doesn’t.

Brian. Yeah. What about you? I don’t know if you’re seeing a lot of competition coming from China in your coverage.

Yeah, look, I think it’s always been a competitive area, whether it started with an attack on it and bringing similar molecules to things that are patented in the US more quickly, to now what we’re seeing—to Chris’s point on PD-1/VEGF—there’s a novelty there. It’s not 2 novel targets, but the concept of doing a bispecific is novel, right? I’m sure we’ll just continue to see more innovation there.

Look, I think it’s ridiculous. We don’t go around saying, “We’re all going to make our own PD-1 antibody, and if you can’t make it in your house, you shouldn’t have access to it,” or that you shouldn’t be able to provide it to other people. But that’s the political climate that we deal with right now, right? It’s sort of this attack on globalization versus the need to retain jobs and retain scientific IP.

I don’t know that there’s a great answer. I’m probably more in favor of global collaboration than not, but there are a lot of ins and outs and nuances in that argument. Eventually, it’s just inevitable, right? You have to deal with that inevitability, and I think you have to embrace it to some extent.

Maybe I’ll just make 1 quick other comment because I know we have a ton of ASCO stuff to cover. For the fast-follower argument and the copying argument that you made, we have IP. If someone makes an actual copy, guess what? They’re not going to be able to commercialize that in the US, so it’s not very valuable.

But is China really good at getting around patents and figuring out, “Here’s something that’s interesting and potentially better that builds off of a patent from maybe a US biotech”? Absolutely, right? But I also view that as fair game, right? There’s a lot of that that maybe a lot of US biotechs could have played 5 years ago. Now that’s a hard pitch for a US biotech to sell, because I think everyone knows there are probably some more efficient fast followers that are going to come out of China. So it does raise the bar on what I think US biotechs need to work on to get funded in terms of making that fast-follower approach more challenging.

But under the patent system that we have, that's a totally fair game: to come up with something that's new and potentially better, and that builds off existing IP that a company has put out.

Yeah. I mean, I guess the question is—look, the other side of the argument, maybe I'll take that for a second. At the end of the day, we're talking about a global industry that is very U.S.-centric, or we're losing our edge. You can argue that China has historically protected the biotech industry and subsidized it. Many of the scientists were trained here.

If you look at the end of the day—whether it's semiconductors, shipping, increasingly electric vehicles, or, obviously, the tech and AI sides—there is a global competition going on. We can hear the argument about patents, but you can also argue that some of the electric cars out of China are incredible, and U.S. consumers would probably love to buy them. You do need to have a certain degree of protectionism when it comes to equal trade and equal competition, and I think that factors into the argument as well. I guess the question is—

Is there enough innovation in China that we don't have here?

Can I just add one quick thing here? One thing that I would really hope we don't see, because I think it actually increases the risk in my view, is companies remaining in stealth and not filing IP. I think that's quite risky, because that assumes that China—or anywhere else in the world—will not be on the same track of trying to get intellectual property in a new area.

Tess would probably be perfect to deal with this, because you were also involved very much in early-stage companies and private VC-type companies. If you hold your cards too close to your chest and someone else plays their card on the IP front, you've lost that initiative, because you're no longer the innovator. That's going to be a very interesting game to play. Whoever does that needs to be very careful and very sure that they are absolutely at the leading edge of this and everyone else is eons away. That's just one last thing, because I hear that a lot, too.

Okay, perfect. Let's move on. We have a lot to get through, and I think we're going to have to do a little bit of rapid fire because we have some other non-ASCO topics as well.

We started talking about VEGF bispecifics, so, Sam, it's a great segue. There were kind of 2 things to talk about back to back. We were in the same sessions: the PD-1/VEGF bispecifics, and then it's going to carry us right into RAS, essentially in the same session at ASCO. One set of data got a clapping ovation—totally appropriate, absolutely expected—the PDAC indication. This is going to be one of those ASCOs we'll all remember.

The other one had amazing data and a very critical reviewer on the value and translatability of HARMONi-6 from China to the global patient population. Do you want to take that on?

Sure. I know we were both there. Ivonescimab is a drug that Summit licensed from Akeso, a Chinese company, and it is developing it in the U.S. HARMONi-6 is the study we've all been waiting for to tell us whether there's a chance that Summit can succeed in the West.

HARMONi-6 was a Phase 3 trial of a PD-1/VEGF bispecific in squamous non-small-cell lung cancer. This is important because VEGF antibodies usually had a bit of an issue in quite a lot of lung cancer, but specifically in squamous disease, in that the risks outweighed the benefits of using them. The idea has always been that if you're going with a bispecific, you might be able to make the drug more conditional in terms of its activity and therefore get a better side-effect profile. We're seeing that in most cases. I can't say that every single bispecific is doing this, but HARMONi-6 worked.

I know the discussant, Dr. Julie Brahmer, had a very hard job discussing the data. It worked in the population that was tested. We have a meaningful increase in overall survival and a meaningful reduction—34%—in the risk of death in the trial. This was a pretty well-followed trial, although there's still quite a long way to go. This is interim overall-survival data, and the data has been published in The Lancet. It worked in the various subgroups, so that's another good signal.

There were 2 particular things. One we knew about was the imbalance of women in the trial. We also knew that there was a data set for the over-65s and under-65s, and we saw some of that split at ESMO last year for the progression-free-survival data. Here, in the overall-survival data, when you look at the data, the trial pretty much benefited folks under the age of 65.

The question now is, okay, this is great as it is for the China trial and the population in China. I'm pretty sure the drug will be—it’s already approved in China—so I'm assuming that it will be approved on the back of this data because it's a successful Phase 3 trial. The question, which I think everybody in the room was trying to second-guess, is whether it's translatable to the U.S. So, Yaron, I pass it on to you to tell me what you think about that.

Well, I mean, it was fascinating because, in general, there's a growing body of evidence suggesting that this combo really is doing something, both in response rates and a little bit on durability. We've always known there were biological differences, for whatever reason, in EGFR populations between China and ex-China, and it's probably smoking.

Squamous disease, which is what this study covered, also has a very high component of men. As the presenter said, it's the male, heavy-smoker population in China. That population looks like it's potentially a little different from the Western population, certainly by age. Potentially, non-squamous disease is going to be fairly predictable.

Based on our analysis, when you looked historically at data for ivonescimab, let's say from Phase 1 in China to the Western population, the data is essentially identical. So we might just end up having some differences for nuanced reasons. It might ultimately be mutation-based and related to smoking, for whatever reason, but the totality of the data is increasingly suggesting that this bispecific really is doing something, and it could be conditional within the tumor.

BioNTech's BNT327 had data as well. This is from the lead-in part of their Phase 3, their global Phase 3. This was sort of from Part A of the study. They showed slightly better response rates—about 63% overall and 64% in non-squamous disease. To give you a sense, ivonescimab from Akeso and Summit does about 50% to 54%. By the way, Pfizer's PD-1/VEGF drug does 68%, so there are subtle differences. These are smaller cohorts, but ultimately our KOLs are increasingly beginning to believe that there will be a difference. They want to see about a 25% reduction in the hazard ratio for survival in frontline non-small-cell lung cancer for that to really be the new standard.

They're continuing to get a little bit more excited, frankly, about triple-negative disease. Now there was actually data on colon cancer, too, from Summit that looked really interesting in the frontline setting with chemotherapy. When you compare that data to Avastin plus chemotherapy in the past, again, ivonescimab looked better. So we're beginning to see that all across the board. Remember, of course, that PD-1, as we all know, has no real activity in colon cancer. We have our fingers crossed, and we're obviously following closely.

Let's talk about the other one, which was really memorable and incredible: the data on PDAC from Revolution Medicines that got a standing ovation. Sam, go for it.

Yeah. I think that particular comment you just made kind of sums it up. PDAC—pancreatic ductal adenocarcinoma—everybody knows about pancreatic cancer being an awful thing to get because there has pretty much been no improvement in the standard of care.

Now we have daraxonrasib, which works by that mechanism I mentioned earlier: by bringing another molecule into the vicinity of the RAS molecule and then leading to inactivation. There's very little to quibble about as the lines separate in terms of overall survival, or drugs, or whatever way you want to call it. It is a significant advance for this disease.

Overall survival jumped to 13.2 months versus 6.7. Median progression-free survival was better, overall response rate was better, and disease-control rate was better. Frankly, a lot of people focused on the side-effect profile, which is absolutely right to do, because there's no point getting 6 months, 7 months, or 8 months—remember, we're talking medians here. There are people in this subgroup who would have lived a lot longer, and of course the opposite is true as well.

The control arm is chemotherapy. That's not a walk in the park either; it's just that people have, for want of a better phrase, gotten used to dealing with chemotherapy side effects. Whereas here you've got rash. Maybe you could say that, from the EGFR world in lung cancer, we've gotten used to it, but these are slightly different types of rash. Stomatitis, mucositis, and diarrhea are also issues.

This is not a drug without side effects, but I think people would take the risk and take the drug because you can also reduce the dose. You can do dose reductions and dose interruptions. Discontinuations were not as much of an issue as far as we're concerned, but there were obviously dose reductions and dose interruptions, which is one way of dealing with the side-effect profile.

So now what's left is: what is the group here that benefits most? The trial is tough to answer that because about 80% of the patients in the trial had G12D/V mutations, and another 30% had G12 mutations in this RAS molecule. So what you've got is a very concentrated distribution, more than you would see in the standard real-world distribution of mutations.

The question now ends up being: if I come with a more directed G12D or G12V inhibitor, will I be able to compete and do better than daraxonrasib? Or if I come with a pan-KRAS versus a pan-RAS, can I manage the side-effect profile? All that has to be proven.

But you cannot take it away from Revolution Medicines that they have set the bar now, and they have opened the door for all of these things to be tested, with patients having an option better than just chemotherapy. So I'm really excited by it, and I think the standing ovation clearly showed that.

Okay, so there's so much to talk about. Let's move to breast cancer. The one area that I always struggle to keep my thumb on the pulse is the ER area. There was more data from persevERA from Roche, which actually failed, but we had an update on it, and there was a slew of other updates. Do you want to—let's talk about SERDs, and then we'll move on to the PI3K area as well.

Yeah, sure. Giredestrant is the drug here, which was being tested in first-line HR-positive, HER2-negative breast cancer, and it didn't meet statistical significance. There was a numerical improvement in progression-free survival, but it didn't quite make it. Why is that? Well, it could be the size of the trial, that it wasn't sufficiently powered.

When you look at the differences, overall survival was slightly different. Obviously, overall survival is a tough one because you get post-progression therapy. Median progression-free survival was 33 months versus 28 months, and unfortunately, the hazard ratio crossed 1. So you think maybe if you had 1,400 or 1,500 patients, it could have done better.

Everything was numerically in favor of the drug, but obviously you set your parameters for these trials. You set the number of patients based on what you think is going to be the success criteria, and it didn't work out. So that's where that is.

But what does this mean for others? The other one that most people are focused on is camizestrant from AstraZeneca, which is reading out in the second half. The SERENA-4 trial is a similar trial to the persevERA trial, and AstraZeneca talked about this at its analyst meeting. We're going to have to wait and see how that pans out. Obviously, people are going to worry about that readout.

The reason I mentioned the 1,400-patient number is that they have a larger trial. They're running a 1,392-patient trial versus a 992-patient trial, so a good 400 patients more. That might help them just squeeze the statistics in on the right side of 1. Of course, it's a different molecule, and the design may have some differences, but you also have to remember that some of these patients are coming from different subgroups. There were subgroups that seemed to do better in persevERA, so we wait and see.

The last one here I want to touch on is Olema. We liked what Olema showed, and frankly, the data is looking pretty positive here. So we think Olema has time to potentially adjust its trial to try to deal with these things, with this knowledge in hand. That's going to be quite interesting to see what they do going forward, with regard to what they've learned from persevERA and, obviously, what they will learn from AstraZeneca in the second half.

I mean, so does that mean that SERDs should be ESR1-mutant drugs? Because the second-line data actually looked good in combination with the CDK4/6 inhibitor?

That's right. That's right. But I'm not convinced that it's as straightforward as that in the first-line setting. So I think it's more than a conversation we're going to be having today. But the data did suggest that, in ESR1 wild-type metastatic disease, maybe additional mechanisms may be driving that.

I think we need the detailed data from more than 1 trial to try to figure that out, because I don't know how different these molecules are with regard to that particular population.

Okay. Okay. Incredible. So let's actually, before we jump to PI3K, since we started talking about CDK4/6 inhibitors, let's talk about CDK4, which is a new area. Recall that there are 3 CDK4/6 drugs currently on the market from Pfizer, Lilly and Novartis. They're dominant; it's really Lilly and Novartis' game. The Pfizer compound has kind of fallen by the wayside over the years because it did not show a survival benefit.

Increasingly, these drugs do cause neutropenia, and emerging data suggests that CDK6 modulation potentially does not confer much benefit and might be the detrimental part that causes neutropenia. So naturally, companies have now developed what's known as CDK2/4/6 inhibitors. CDK2 as a single agent has also become a little less promising because it hasn't shown dramatic clinical activity as a single agent. It's thought that maybe it can reduce resistance to the CDK4/6 inhibitors, but increasingly, the evidence suggests that CDK4 modulation is really the sweet spot.

There are 2 companies now working in phase 3. The first one is Pfizer with atirmociclib, and the second one is BI, which is now in phase 3. We saw updated data from essentially both of them, and the data looks really good.

BI really did the full unveil, and they went right into a phase 3. They started the program about 3 years behind Pfizer, and they're probably a year behind now. That's how fast they're able to move on a global basis. Their compound showed a 63% confirmed response rate and a 74% unconfirmed response rate. This was in combination with endocrine therapy, letrozole.

They did not have any neutropenia, which is critical, so they can ultimately combine with other mechanisms down the line. They did have some GI toxicity, which was mostly grade 1 and 2 once they gave the drug with food. Atirmociclib has a response rate that's up to the 60s, so it looks like potentially BeiGene is getting a little bit more response rate. BeiGene has now started enrollment, and in the meantime, Pfizer has completed enrollment.

This is an area that's super interesting to watch. They're both actually going to go head-to-head against the CDK4/6 inhibitors in combination with endocrine therapy. Historically, CDK4/6 inhibitors with endocrine therapy give, let's say, a 50% to 55% response rate and 2-year progression-free survival. As we just mentioned, the Pfizer compound gives you about 10 points higher, and BeiGene potentially gives you 15, maybe even 20 points higher.

The question becomes whether that's going to be enough to beat them head-to-head, and those studies are ongoing. These are 1,000- or 1,100-patient studies that take about 3 years to read out. So these things are ongoing.

What's really interesting now is to shift over to the PI3K axis. About 15% of patients have what are known as PIK3CA mutations in breast cancer. Relay, along with Pfizer, is going to specifically focus on that cohort in the frontline setting. They'll test Pfizer's CDK4 inhibitor along with a PI3K inhibitor and endocrine therapy next year, and that's going to go head-to-head against CDK4/6 inhibitors.

That strategy is fairly compelling because you're doing 3 drugs versus 2 in patients who have mutations, and you're giving them a PIK3CA-mutant inhibitor, which is very effective and is frankly in phase 3 on its own in the second-line setting. So that regimen is going to start phase 3 next year.

Let's move to Tess to talk about Grail at ASCO.

Yeah, absolutely. I'm happy to talk about Grail. I think this was probably a pretty disappointing readout for a pan-tumor, multicancer early-detection test, but there were a lot of interesting points here.

First, let's start with what they showed. They had a study looking at a reduction in stage 3 and 4 deadly cancers at a 3-year follow-up, and they missed this by a pretty big margin. That was the primary endpoint. The IRR was a little over 1, and they had about 706 patients in the intervention arm versus about 700 controls, so it was pretty well balanced.

There was a 14% reduction in risk for the stage 4 cancers, but, interestingly, an increase in the stage 3 cancers. This was a pretty challenging thing to read, just in terms of understanding if there's a real signal associated with these multicancer early-detection tests.

The question is whether these tests may be helpful from the standpoint of understanding your cancer, but are they really going to change mortality and outcomes? I think that remains a question. On the positive side, they did show that it was a well-run, well-balanced trial.

They did have a reduction in emergency presentations, right? So again, maybe that points to, well, people at least know what they have, right, and maybe that helps in emergency situations, but maybe it's not really changing mortality outcomes.

Then the test performance actually looked pretty good, right? Again, for these multicancer early detection tests, I think the positive predictive value was about 52%, with really high specificity. So, very helpful in terms of knowing and helping screen for cancer, but the question is what that actually means for outcomes and mortality.

Some of that may be a function of what the associated interventions can be when you learn about cancer at an early stage in this pan-tumor way. I think Grail is taking an approach of looking at pan-tumors, looking across a lot of different cancers. I think in this trial there was more of an impact in CRC.

This may be something where we have to look at it on a cancer-by-cancer basis and understand how knowing about cancer early changes how you are treated and what patient care looks like, so that it can result in an improvement in mortality and outcomes. More to do in the MCED space, but it's important to at least see that the test data is looking good. Now we have a lot more work to do on interventions.

Amazing. That was great, Tess. So, I clearly got cut off, and I don't know where I was when I got cut off. Any hints?

You were talking about—I think you were getting on to the CDK4 area.

Okay. All right. I'll keep it brief because I know we have a lot to get through. The CDK4 area is super interesting. CDK4/6 inhibitors are the dominant drug class; they sell about $15 billion. But it's thought that CDK6 modulation probably does not do a ton for efficacy and adds to the neutropenia.

There are 2 companies now with CDK4 data in Phase 3. The first one is atirmociclib from Pfizer, and the second is a drug now in Phase 3 from BeiGene called BGB-43395. Atirmociclib from Pfizer is in a frontline study, fully enrolled, and gives you about 60% response rates. The big Achilles' heel is that it does cause neutropenia, and neutropenia is a little bit of an issue when you're trying to combine this class with other classes.

BeiGene has managed to move very quickly. They're now showing between 63% and 74% response rates. They don't have neutropenia. They do have some grade 1–2 GI effects—nausea and a little bit of diarrhea—which is just frequency. That's been much better now that they're taking the drug in a fed state.

Pfizer's fully enrolled. BeiGene was about 3 years behind. They're probably only about 1 to 1.5 years behind now because they moved really quickly and started enrolling their Phase 3. The big question is whether these drugs can actually beat the CDK4/6s head-to-head in frontline. They do give you between 10% higher response rates on the Pfizer side to maybe 15% to 20% higher on the BeiGene side.

Just to give you a sense, the existing CDK4/6s give you about 2 years of PFS, and those studies are ongoing now. It will take about another 2 to 3 years to get the data. In the meantime, Relay, which has a PI3K inhibitor, is moving to a Phase 3 next year with Pfizer and atirmociclib in frontline.

This will be in patients who have PIK3CA mutations—about 15% of patients—and they're going to test the CDK4 inhibitor with their PI3K inhibitor in that setting, head-to-head against the CDK4/6s. That's probably a more elegant way to de-risk a Phase 3 study because you really should be able to beat CDK4/6 alone with a PI3K inhibitor, given that Relay showed really good data.

They're actually running a separate Phase 3 in second line with their drug in these patients with these mutations, and we're expecting positive data probably sometime in early 2028 for that regimen. So, lots going on in that space.

The other big data at ASCO was VIKTORIA-1 from Celcuity, and they have a PI3K/mTOR inhibitor that showed very good data, doubling PFS. This was in a PIK3CA-mutant population and in the second-line setting. They went to 11 months from about 5.5 with a triplet against a doublet.

Physician feedback is that this is going to become standard of care. The only Achilles' heel is that you have to take an IV infusion 3 out of 4 weeks, and it does cause some mucositis and some inflammation of the stomach lining. Physicians are fairly optimistic and hopeful that once Relay has data from its oral inhibitor, which is better tolerated, that will provide another really good option for patients. That's probably another 1.5 to 2 years away.

There's really a lot going on in breast cancer. Maybe, Sam, over to you on in vivo CAR-T. It's a huge, hugely important area, with data from myeloma that led Lilly to buy Orna for up to about $7.5 billion, with $3 billion upfront. Can you maybe address that? And Legend's about to have data next weekend in lymphoma with its in vivo CAR-T.

Yeah, sure. I'll do the myeloma, and I'll pass on to you for lymphoma. The trial data was exactly the sort of thing that we love digging into: the abstract had 6 patients, and the actual presentation had 18 patients. This is Orna—Lilly, Orna, I mean, whatever we want to call it now—in relapsed/refractory multiple myeloma patients, with in vivo CAR-T targeting BCMA.

So, we're all going to compare it to everything else that's going on: CARTITUDE-1, which was obviously autologous—that's Carvykti, autologous CAR-T—and AstraZeneca's got the EsoBiotec CAR-T. ESO-T01 is the name of the molecule.

The Orna data showed 100% ORR and 100% MRD negativity, but then there were a couple of things that, of course, you don't necessarily want to see with CAR-T. The devil will be in the detail when we see all this. All patients achieved MRD negativity, and then 4 out of 6 patients with follow-up over 4 months reached complete response, which is the direction you want to see data go.

But at month 3, 1 patient relapsed, and another patient turned MRD-positive. These early signals are kind of a little shadow on durability, but you want to know the details in those patients. Remember, these are 3 to 5 lines of therapy, and of course it's a bit dangerous to compare them to, say, CARTITUDE-1, where the range was 3 to 16.

Let's just temper excitement there a little bit. We need to see the characteristics of these patients. Were they triple-hit cytogenetics, really high risk? Had they had every line of therapy available? Did they have proper plasma-cell extramedullary disease, for example, plasmacytomas? Those are the questions that I think need to be addressed because even the autologous CAR-Ts are not one-and-done.

All that needs to be something to look at. It's very promising still. The number of patients has gone up, and I'm really excited about that. Of course, on the side-effect profile, you still see some immune effector cell-associated neurotoxicity syndromes, including 1 grade 3 event, but no delayed neurotoxicity. This is only 2.8 months in terms of median follow-up, so I'm excited by it.

I think we're going to see more evidence that this is a real future thing that could be competing with autologous CAR-T, which, of course, the autologous companies are all working on. I'll pass it on to you.

Yeah. Legend is going to have data at EHA, which is next weekend, not this weekend. This is in 12 patients. This is in vivo again. As you know, you just give the patient an IV infusion that has lipid nanoparticles and essentially a whole construct inside, which then goes into the blood and actually transfects T cells to make CAR-T in the blood.

There's no conditioning, and there's no waiting or long vein-to-vein time to make the cells and enrich them outside the body. The data looked really good at 2 dose levels. The higher dose level had essentially a 100% response rate and 83% complete responses. At this point, the follow-up is only 2.2 months, and there's no real ICANS or major toxicity other than grade 1–2 CRS.

The bar in general is sort of in the 70%–80% range based on ex vivo response rates, so 100%—and this is in 6 patients at the second dose level—is promising. Of course, what we need to ultimately see is that this is going to be sustainable, so we'll wait for that.

I'm also going to flag that there's a lot going on in head and neck these days between Genmab, Bicara, and J&J on the EGFR side. Super-promising programs. J&J has now filed Rybrevant, and biotech investors were really looking at Merus, which got acquired by Genmab, and Bicara, and were discounting J&J. J&J came from essentially nowhere to filing Rybrevant ahead of everybody else.

So, lots going on by the end of the year, and then we'll continue to talk about that over time. But we want to leave time. Abivax had its long-awaited maintenance data in ulcerative colitis.

The efficacy looked very good, but there were essentially 7 cases of cancer at the high dose versus 1 at the lower dose and 1 on placebo. The stock was down 45%, and I think it has recovered about 30% of that loss so far. Sam, what do you think? Should the stock have been down this much or not?

I mean, look, on the efficacy side, I think it outperformed what most people were looking for. It was bigger than the best hoped-for result, which was 30% placebo-adjusted. I don't know what you guys were looking for, but it did better than that. So the efficacy side looks good.

On the 50-milligram dose, in terms of the concentration of malignancies that they reported, it just optically scares you. The company has detailed it. The KOLs on the call, and the conversations with KOLs, seem to suggest that maybe it's not related to the disease or the drug. We know that this patient population has a higher risk, and we know that other drugs in the space, such as the JAK inhibitors, do carry a black-box warning for malignancies. But it still scares you when you see it concentrated in the higher dose versus 1 signal in the lower, 25-milligram dose.

So I think it's going to be an overhang because of worries about this. The stock has recovered. It hit 70%. I mean, it looked pretty bad on the day that the data came out, and it's recovered. Some people have come out in support of it, so we'll see. It will come to the FDA, and we'll get an outcome. A lot of this, I'm pretty sure, will be discussed there.

We'll see. I don't know if there's an obvious mechanistic explanation for this, but we'll wait and see. That's as far as I can go.

Yeah, fantastic. Brian, over to you. We had 3 topics, but we have about 3 minutes left. Maybe let's take on the FDA rare disease roundtable meeting that was held on Wednesday with the new acting commissioner. What were your takeaways from that?

Yeah, there was this roundtable, as you said, that included a number of senior leaders at the FDA. We talked a little bit about this last week and some of the feedback that's come in on Kyle Diamantas, who is the acting commissioner right now after Marty Makary's departure.

I think this is a continuation of what I commented on last week. The feedback on him, even looking at his CV, wouldn't make you say, "Oh, this guy has a clear, great background for an acting commissioner." But he seems to be saying and doing the right things. He seems willing to be deferential to the voice of industry and the voice of the patient.

He had this roundtable, and as we've discussed throughout the last year or so of Makary's tenure, there's sort of been this lip service to flexibility, particularly in orphan disease, but actions have not reflected what he was saying in meetings or what Prasad was saying in meetings. Now, with that sort of leadership gone, he's saying many of the same things, but it does seem like he's less likely to interfere directly.

Comments from the meeting that I think are particularly important and positive for the orphan side of things include talking about the importance of regulatory flexibility and the importance of the patient voice. Personally, one of the things I liked most that he said was that he intends to bring back many more advisory committee meetings. He wants to rely more on career staff as well as external experts than the prior leadership did.

One of my favorite parts of the job is historically going to the advisory committee meetings, and more recently listening to the Zoom advisory committee meetings that the FDA holds. I kind of love bringing everything to light and seeing people debate it out.

I think it's definitely at least an incremental positive, especially for these orphan areas that a number of us cover, where you can't really run full 500-patient, dual-arm clinical studies to show efficacy. This flexibility is required, but we'll see. I think there's cautious optimism that the political interference we saw under the last leadership will not be the case here.

A lot of people heard Makary's comments when he first came on and also said the same thing: "This guy sounds really flexible." So we'll have to see. From my perspective, this does look like at least an incremental change in a positive direction for these types of stories.

All right, terrific. This was a little bit of a tour de force. A lot to cover. We had a good amount of discussion and debate in the beginning and then a rapid-fire drill through.