New cancer breakthroughs, China vs. USA in biotech, and the future of cancer therapy

This week I spoke to my friend Dr. Tiffany Ma (she founded an early cancer detection company, GambitBio, and works for a cancer vaccine company, Infinitopes) about cancer breakthroughs from ASCO, China vs. USA in biotech, and the future of cancer therapy.

Here it is!

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Here’s the transcript from the episode:

[1:39] Tiff: How was ASCO? You went to the biggest cancer conference of the year. It happens annually and is run by the American Society of Clinical Oncology. It was your first ASCO. How was it?

[1:53] Sam: I loved it. I love science, so if you are like me, it is like crack cocaine. Everywhere you go, there is science: posters, talks, and Big Pharma. Eli Lilly is right in the middle, and you can just go and talk to them. It is the latest groundbreaking science, presented for the first time by the researchers themselves. At the posters, you can speak directly to the person who did the work. That person might be the chief executive officer, an academic, or someone else entirely. Chicago is beautiful, by the way.

[2:34] Tiff: That is amazing. Did you go to the Bean?

[2:43] Sam: The mirror thing?

[2:44] Tiff: Yes, the Bean.

[2:45] Sam: Is that what it is called? I should have known that.

[2:47] Tiff: No, it is fine. I think it was being renovated until recently, so you went at a good time.

[2:53] Sam: Yes. You have to go really early, otherwise there are a lot of people and a huge queue.

[2:59] Tiff: In this episode, we thought it would be good to go over some of the highlights from ASCO: the biggest groundbreaking studies, China, and future directions for these therapies.

[3:23] Sam: Exactly. To kick off with the themes of the conference, I thought there were five major themes at ASCO this year. The first was pancreatic cancer. The major news was daraxonrasib. I can say that now that it has been talked about so much.

[3:48] Tiff: Daraxonrasib. I love the name, because “on” refers to the on state, “RAS” is the target, and “-ib” means it is a small-molecule drug.

[4:00] Sam: Exactly. Daraxonrasib was the major news. It increased overall survival in second-line metastatic pancreatic cancer compared with chemotherapy. It also improved quality of life, reduced pain, and did this with almost half as many serious adverse events.

[4:19] Tiff: It got a standing ovation from the crowd. I saw your tweet. It went viral.

[4:26] Sam: Super viral. Very exciting. I loved it. That was the main news, but pancreatic cancer had more than one breakthrough. Daraxonrasib stole the show, but there were many other therapies: antibody-drug conjugates, and a really nice bispecific T-cell engager. There is an antigen that pancreatic cancer sometimes expresses called claudin 18.2.

[4:55] Tiff: Very specific.

[4:57] Sam: Yes. It is also expressed in some gastric cancer cells. If you target claudin 18.2 and CD3 to recruit T cells, and give that to pancreatic cancer patients, that also looks like quite an effective approach.

[5:10] Tiff: That is amazing. There was not only one breakthrough in pancreatic cancer. There were several. For years, even decades, there have only been incremental improvements in pancreatic cancer, which has a very poor five-year survival rate of around 10%. Suddenly, there has been a lot of progress announced within one year. I thought that was really interesting.

[5:45] Sam: It is. Revolution Medicines is the company behind daraxonrasib, but now there are many companies with RAS inhibitors, and they are approaching it from every direction. Big Pharma is there, small biotech is there. They are developing pan-RAS inhibitors, KRAS G12C inhibitors, KRAS G12D inhibitors, on-state inhibitors, off-state inhibitors, and different combinations.

[6:08] Sam: This week, there was an impressive combination of daraxonrasib plus another new drug in pancreatic cancer, and it improved survival even further on top of what daraxonrasib does.

[6:23] Tiff: That is incredible.

[6:24] Sam: What I think we are going to see is daraxonrasib becoming the foundation, or bottom layer, of therapy, and then being combined with other therapies.

[6:32] Tiff: For that specific mutation or subgroup.

[6:36] Sam: Exactly. I did not think we would see this layering of therapy so quickly, given that it has only been two weeks since we saw the data in the first place. But this week we are already seeing it start. The company I am talking about is Tango Therapeutics. They are working with Revolution Medicines to build this combination therapy.

[6:56] Tiff: That is so exciting. They waste no time.

[6:59] Sam: They do not. For those who missed it, daraxonrasib doubled survival in PDAC, which is the most common form of pancreatic cancer, with a hazard ratio of 0.4. It decreased pain and side effects, and it is a daily oral pill.

[7:31] Tiff: That is important. People talk about the time burden of cancer therapy. If you are having chemotherapy as an intravenous treatment, you have to go to the clinic.

[7:44] Sam: Exactly. You have to go to the hospital, sit there, and have the intravenous chemotherapy treatment. With daraxonrasib, it is a pill. You take it at home. It reduces the time burden and time toxicity, as well as other toxicity. It does not mean it is completely without toxicities. There were rashes, stomatitis, and one patient in the trial died because of lung inflammation. It is not completely without adverse events, but it is cleaner than chemotherapy.

[8:14] Tiff: That is huge. It is also a cool paradigm shift from the last generation of RAS inhibitors, which tried to target the off state of RAS. RAS is an oncogenic driver of cell division. It is like a gas pedal that is being pressed down all the time, and we have to find a way to stop it.

[8:40] Tiff: The issue with RAS, as we covered in a previous episode before the phase 3 data came out, is that it was considered an undruggable target because there is no pocket in the molecule for a drug to bind to. Revolution Medicines became creative and developed a molecular glue that binds to the chaperone protein cyclophilin A. That creates a complex that can target the on state of RAS rather than the off state. The on state is more susceptible to inhibition, because most of the time RAS is on in human cancer cells rather than off. So you might as well target the on state.

[9:36] Sam: Exactly. If you target the off state, your drug is waiting around for RAS to switch itself off, bind, and then inhibit. But the RAS protein spends hardly any time in the off state. It spends most of its time in the on state, so ideally you target on, not off.

[9:55] Tiff: It is clever. The craziest thing is that this is a pan-RAS inhibitor. In oncology, KRAS is the most common mutated form of RAS, but there are also NRAS and HRAS. Even within KRAS, there are different mutations. There have been developments before in G12C mutations, which means the glycine at codon 12 is replaced by cysteine. In pancreatic cancer, people care a lot about G12D.

[10:37] Sam: Yes, where it is replaced by aspartic acid.

[10:40] Tiff: Now they do not have to worry as much about which type of mutation is occurring in the tumour.

[10:46] Sam: Exactly. That is also one of the future directions. RAS is mutated in pancreatic cancer, but also in colorectal cancer, lung cancer, and other cancers. The big three are pancreas, colorectal, and lung.

[11:02] Tiff: Lung is what Revolution Medicines is going after next in one of their trials.

[11:06] Sam: Exactly. It may not only revolutionise the treatment of pancreatic cancer, but also lung, colorectal, and other cancers. One future direction in cancer is RAS inhibition as a therapeutic foundation.

[11:22] Tiff: That is exciting. Revolution Medicines is a Californian company founded in 2014, and they IPO’d in 2020. Did you look at the stock price afterwards?

[11:34] Sam: Yes. I am in the stock. I think most biotech people are in the stock. Why would they not be?

[11:45] Sam: The market cap is now around $35 billion. People start to think about acquisition: is this going to get bought by Big Pharma? But if the market cap is $35 billion, Big Pharma has to pay a premium, so they would have to pay $40 billion or $50 billion.

[11:59] Tiff: They use the current stock price as a benchmark.

[12:03] Sam: Exactly. As Big Pharma, how do you spend $35 billion, $40 billion, or $50 billion on one company? That probably means it is too big to get taken out now, which is interesting.

[12:15] Tiff: The biggest deals we have seen in the past year have been around $10 billion.

[12:20] Sam: This is much bigger. Some companies could technically take it out, but it would be a huge swing.

[12:27] Tiff: I can see smaller deals being made. Maybe not the whole company, but licensing one asset or one indication to another Big Pharma company.

[12:38] Sam: Exactly. There is another company called Erasca with a molecule that is basically identical to Revolution Medicines’ daraxonrasib. If you look at the chemical structures, they are almost the same, so there is a patent concern. If you are Big Pharma and want to buy something similar more cheaply, maybe you take out Erasca.

[13:02] Tiff: Then they have to deal with the patent disputes, not Big Pharma.

[13:09] Sam: That was the first theme: progress in pancreatic cancer.

[13:15] Tiff: The second theme was other innovative therapies. What else did you see?

[13:21] Sam: Daraxonrasib was definitely the most important one, but there were lots of others. One was ivonescimab, a bispecific antibody.

[13:29] Tiff: PD-1 and VEGF.

[13:30] Sam: Exactly. It is a PD-1/VEGF bispecific made in China, with trials done in China. In lung cancer, it beat PD-1 immunotherapy on its own. PD-1 immunotherapy is one of the biggest drug classes in the world, but if you use a bispecific that also blocks VEGF, it improved overall survival in lung cancer.

[13:53] Tiff: That is incredible. It is good synergy. PD-1 is the checkpoint inhibitor part of the drug, and the VEGF part is supposed to promote a more normalised vasculature. Then immune cells, especially T cells, can reach the tumour and kill tumour cells. When VEGF is overexpressed by cancers, the chaotic vasculature can prevent immune cells from getting to the tumour.

[14:25] Sam: Exactly. The trial format at ASCO is fascinating. In the plenary session, the lead investigator presents the trial, and then someone else puts the trial in context and criticises it. So the lead investigator is sitting there while someone else says, “Yes, but...”

[14:49] Tiff: It is like a lab meeting in front of thousands of people.

[14:53] Sam: Exactly. The main criticism was that all of the data were from China. The data are strong, but from that perspective, it only really applies to the Chinese population. If we want to show that ivonescimab can beat Keytruda, or pembrolizumab, in a broader population, we have to do the trial in the US. That is happening.

[15:22] Tiff: It has to be tested across different ethnicities. The same statement can be reversed as well. American therapies that want to enter the Chinese market, which is obviously huge, also have to do trials in China. That is happening too. It goes both ways.

[15:42] Sam: It does. But it was interesting that this was the main criticism. Ivonescimab is definitely a major breakthrough. We might actually be able to beat PD-1.

[15:55] Tiff: I hope they are working with MD Anderson or another major centre to test it in a Western population.

[16:00] Sam: They are running at least 15 massive global trials with that compound.

[16:08] Tiff: Amazing.

[16:09] Sam: Another innovative therapy I liked was for cancer cachexia. We talked about this in our first pilot episode. This is one of your favourite proteins: GDF-15.

[16:22] Tiff: Exactly.

[16:23] Sam: Cancer cachexia is a wasting syndrome in advanced cancer. Patients lose muscle and weight, lose appetite, and feel miserable. There are no good drugs. It seems to be driven by a stress-induced cytokine called GDF-15.

[16:42] Sam: This new study, also from China, tested a GDF-15 antibody as a bispecific with an IL-6 blocking antibody. It reduces inflammation and blocks the cachexia-driving factor GDF-15. I spoke to the person presenting the poster, and they told me that the main complaint from patients in the trial was that they were gaining too much weight.

[17:08] Tiff: That sounds like a champagne problem.

[17:14] Sam: With this bispecific antibody, they were gaining too much weight. Some gained around 25% of their body weight.

[17:20] Tiff: That is amazing.

[17:23] Tiff: That is such a cool synergy: block GDF-15 and block IL-6. What does blocking IL-6 do here? Does it just reduce inflammation? Is that because blocking GDF-15 might increase inflammation?

[17:46] Sam: I think one of the mechanisms by which GDF-15 is induced is probably systemic inflammation.

[17:53] Tiff: So you block GDF-15 directly, but also suppress its induction by suppressing systemic inflammation. To be honest, I do not know. It is just cool. I wonder how they make these decisions about what to pair in a bispecific.

[18:11] Sam: As we have discussed many times, suppressing chronic systemic inflammation is generally a good idea. People with advanced cancer have high inflammation. If you suppress it, you probably make them feel better. They also say it increases appetite, increases muscle, increases weight, and improves quality of life. It is generally good to control inflammation.

[18:32] Tiff: We could have a whole other episode on inflammation. I know it is one of your theses.

[18:40] Sam: It is definitely a thesis.

[18:43] Tiff: What else was there apart from this cachexia drug?

[18:48] Sam: Antibody-drug conjugates were everywhere. They are so hot now. The biggest one is sac-TMT. I think they are running 17 phase 3 trials with sac-TMT.

[19:05] Tiff: It is American now. It is Merck. But it was produced in China.

[19:10] Sam: It was developed in China and acquired by Merck. They are running 17 phase 3 trials. It is a TROP2-targeted antibody-drug conjugate with a topoisomerase I inhibitor payload.

[19:22] Tiff: So it is an antibody-drug conjugate delivering a topoisomerase I inhibitor payload.

[19:31] Sam: Exactly. It also improved overall survival in lung cancer compared with standard of care.

[19:40] Sam: If you add daraxonrasib plus those three innovative therapies, that is the second major theme. The third theme was prevention. I was at ASCO trying to discover what was happening in prevention, because prevention is the best cure.

[20:00] Tiff: Or early intervention.

[20:05] Sam: Exactly. There was a lot on GLP-1s: many observational studies showing that GLP-1s seem to reduce the risk of many different cancer types.

[20:15] Tiff: That is cool.

[20:16] Sam: Basically everything you can think of: breast cancer, colorectal cancer, blood cancers, and lung cancer.

[20:22] Tiff: Somehow, it does not come as a surprise that they could have those effects.

[20:26] Sam: Obesity is a risk factor for cancer, so GLP-1s obviously reduce that risk factor. But there must be something else going on as well.

[20:37] Tiff: Maybe inflammation. I do not know the effects of GLP-1s on inflammation.

[20:44] Sam: Systemic inflammation definitely drives cancer, so suppressing inflammation is likely to be one mechanism.

[20:55] Tiff: So far, these are observational studies, because there is now so much data on GLP-1s and researchers can correlate them with other datasets. The next step is randomised trials to support this.

[21:12] Sam: What is amazing about the conference is that Eli Lilly’s oncology team is just standing there. Lilly makes tirzepatide, so you can go and ask them what they think. I asked whether they were going to run randomised trials with GLP-1s to prevent cancer. They said no, but if you look deeper, Lilly actually is running relevant trials.

[21:39] Sam: There is a randomised trial with tirzepatide where liver cancer is at least a readout. There is another trial with retatrutide and tirzepatide, the dual and triple agonists, looking at whether all-cause cancer risk is reduced. Cancer is not the primary endpoint, but it is an exploratory endpoint.

[22:03] Tiff: There is another trial happening in breast cancer for primary and secondary prevention with a GLP-1. These are already underway.

[22:13] Sam: Yes. We will have readouts in a few years.

[22:17] Tiff: It feels like everyone is going to be on a GLP-1 soon, for one reason or another.

[22:25] Sam: What is fascinating is that everyone knew overweight and obesity were bad, but GLP-1s have shown us they are worse than we thought. Obesity contributes to so many diseases, and when you suppress it, many things improve.

[22:42] Tiff: It feels like a holy grail, with obvious caveats and side effects.

[22:52] Sam: Do not worry about side effects.

[22:53] Tiff: Pancreatitis, which you disproved.

[22:55] Sam: Yes. No pancreatitis, actually. That was the third theme. The fourth theme was cancer vaccines.

[23:03] Tiff: One of my favourites. The big Moderna and Merck vaccines are personalised vaccines in phase 2. The phase 2 trial took five years to finish. It was in resected melanoma, using the vaccine plus pembrolizumab. It was around 72% versus 49% progression-free survival.

[23:50] Sam: It is definitely bullish. There is also a Chinese company running a trial in oesophageal squamous cell cancer with a personalised vaccine. Oesophageal cancer has miserable survival, and they got strong results. I was happy because Infinitopes is running a trial too.

[24:18] Tiff: A different kind of trial. You are an investor, obviously. We are doing ours in oesophageal adenocarcinoma. Oesophageal adenocarcinoma and oesophageal squamous cell carcinoma overlap, but they have distinct profiles. Squamous disease mainly affects Asian and Chinese populations, while adenocarcinoma mainly affects Western populations.

[24:45] Sam: That is a good point. It is useful that they are running the squamous trial in China, where it is more relevant. It would be interesting to see whether any antigens overlap between the two types. Their trial is personalised, whereas Infinitopes is doing semi-personalised, off-the-shelf vaccines. It is a different approach, but as proof of concept showing that you can improve survival in a difficult cancer with a vaccine, it is very bullish for Infinitopes. That is why I was happy to make that discovery.

[25:17] Tiff: Watch his face, everyone.

[25:21] Sam: That was the fourth theme. The fifth theme is that, with the exception of daraxonrasib, a lot of the most innovative work we discussed came out of China.

[25:35] Tiff: China biotech is on the stage.

[25:40] Sam: China biotech is doing amazing work.

[25:45] Tiff: I was surprised. China is no longer just doing me-too therapies. They are innovating and coming up with their own ideas. You said you had some stats to back that up.

[26:04] Sam: Some criticism of China is that it is doing me-too therapies and fast follows. That is happening, and China is also the pharmacy of the world. But they are also doing innovative things: ivonescimab, sac-TMT, and the cachexia bispecific we discussed.

[26:21] Sam: Last year, there were 5,000 new trials started worldwide for innovative therapies. Half of them started in China. In 2015, it was about 10%. There were about 2,000 trials started globally and 200 in China. In 2025, it was 5,000 globally and 2,500 in China. China went from around 10% of innovative trial starts to 50%.

[26:53] Sam: Not only is the number of innovative trials increasing rapidly, showing that science is speeding up, but China is also playing a bigger and bigger role.

[27:07] Tiff: How many of these do you think are sponsored by American or European Big Pharma companies? A lot of them partner with Chinese pharma because they get access to the Chinese population, which is a major market.

[27:27] Sam: That is a good question. This year so far, for the first time ever, most biotech deal value is going to China. Around 70% of biotech deal value is going to Chinese companies. In 2021, it was 4%.

[27:50] Tiff: That is huge.

[27:52] Sam: It has gone from 4% to 70%, stepping up over time.

[27:59] Tiff: Why do you think that is? Is it because the companies are cost-effective, the trials are cheaper, and the trials are faster?

[28:07] Sam: Exactly. It is cheaper and faster. The cost per patient in a trial in the US is around $65,000. In China, it is around $20,000 to $25,000. It is also much faster to recruit patients, about three times as fast. It is roughly a third of the cost and much faster.

[28:30] Tiff: Those are basic business fundamentals. What is faster and cheaper gets you to the end goal faster.

[28:39] Sam: Exactly. If we want to reverse the trend of all this money going to Chinese companies, we have to fix the fundamentals in the US and Europe. I think that is doable. We need to lean more on artificial intelligence.

[28:55] Tiff: We also need to look at the architecture of the regulatory bodies. Part of the speed of running trials in China may come from the NMPA enabling cross-border trials to happen quickly. I wonder whether it gets criticised as being less stringent than the FDA. Is that why trials can be run so fast? Is that why people are going there? Is the data reliable? These are questions some founders have asked. As a founder myself, I do not see an obvious reason to stop me from going to China and running a trial there.

[29:56] Sam: To prove the concept quickly, China is an amazing place to do it. But to get your product approved in Europe, the US, or both, you still have to run the trial in those regions as well. You still need to show that the results apply to the relevant broader population.

[30:20] Tiff: Now it feels like China is becoming a proof-of-concept ground for proving therapies quickly. Once the proof of concept has been shown in China, companies can bring the therapy back to the West. It swings both ways and uses the best of both worlds.

[30:44] Sam: Exactly. In general, as I said on TBPN this week, if you are on the side of new medicines and patients, more competition is better. Competition is good for patients. If China is just as good as the US, or arguably even better, at doing this, that is great. We will get more medicines faster, which is better for patients, saves more lives, improves lives, and helps eradicate disease.

[31:17] Tiff: That is the end goal. One good thing about medicine and science is that they are cross-border. As you saw at ASCO, researchers fly in from many different countries. That is a beautiful thing about science.

[31:36] Sam: It is like music. It is not contained within one country.

[31:43] Sam: That was the China theme. I also wanted to say something about the future, given what we have discussed.

[31:52] Tiff: I am excited.

[31:56] Sam: These are basically syntheses of what we have already said. First, RAS inhibition is going to become a foundation of therapy in several cancer types: pancreatic cancer, colorectal cancer, and lung cancer.

[32:19] Sam: Second, we are going to see many more antibody-drug conjugates. When I spoke to some of the pharma teams and asked what the most exciting product in their pipeline was, the Lilly team told me about a new antibody-drug conjugate. It does not only target topoisomerase I, like many antibody-drug conjugates do, but also targets ATR.

[32:44] Sam: That takes me back to our PhD days. It inhibits both ATR and topoisomerase I. If you do that, you disrupt DNA replication, which is disastrous for the cell and can kill it.

[32:57] Tiff: That makes sense. Remember the problem we had in our PhDs? This is a niche reference. ATR is not essential for the cell to live.

[33:10] Sam: Is that right? Do you mean in terms of inhibition?

[33:14] Tiff: No, I am confusing it with ATM. ATM is not essential. My morning coffee has not kicked in. Does targeting both make it more specific?

[33:30] Sam: I think so. To be honest, the product is preclinical. They acquired it. If you inhibit topoisomerase I, ATR helps repair the topoisomerase I lesions.

[33:44] Tiff: So they are synthetic lethal.

[33:48] Sam: Exactly. It is a synthetic lethal or synergistic relationship.

[33:53] Sam: The second future theme is many more antibody-drug conjugates. The third is radiopharmaceuticals. When I asked what they were most excited about in the pipeline, they also mentioned radioisotopes.

[34:07] Tiff: Targeted radiopharmaceuticals.

[34:10] Sam: Exactly. It is similar to an antibody-drug conjugate, but instead of using chemotherapy, you use a radioisotope, such as an alpha or beta particle. You link it to a tumour antigen and use it to kill cancer cells.

[34:25] Tiff: That is a creative payload. There have been a few more biology-physics convergence therapies coming out.

[34:34] Sam: The third future theme is radiopharma. The fourth is prevention.

[34:41] Tiff: That is your job. I am working on it.

[34:46] Tiff: Thank you for being an investor in both companies.

[34:54] Sam: The fifth theme is that daraxonrasib has shown that things we thought were undruggable are not necessarily undruggable. There will now be a wave of supposedly undruggable things being drugged. My two top examples are MYC and p53. Both have companies focused on drugging them, and I think we will see them drugged.

[35:24] Tiff: I completely agree. It is about being creative. You do not have to drug the target directly. You can drug its interaction partners.

[35:38] Sam: Exactly. That is one way people are trying to target MYC. Another is degraders, such as PROTACs. You do not need a little small molecule. You can use a PROTAC.

[35:51] Tiff: We now have much more context around disease biology. With RAS, we now know to go for the on state and not the off state. The same principle will apply to MYC, p53, and other previously undruggable targets.

[36:10] Sam: I am really excited.

[36:13] Sam: Whenever we talk about therapies, we also have to say that prevention is best. Early detection and prevention are much better than treating metastatic disease. We have to combine these approaches.

[36:22] Tiff: That is why we have early detection technologies. They make existing therapies work better.

[36:30] Sam: Exactly. You have to jump in before the disease becomes metastatic.

[36:38] Tiff: You are working on that, and we will keep people updated on the progress.

[37:59] Sam: One last thing. There was an interesting All-In Podcast episode this week. They had someone from EcoR1 Capital, which is a biotech hedge fund.

[38:17] Tiff: Very nerdy name.

[38:21] Sam: He gave a stock pitch for a company called Aktis Oncology. Do you know what they work on? Radiopharmaceuticals. Radiopharma is definitely one of the major up-and-coming themes.

[38:37] Tiff: Now that cancer vaccines have matured, the next new shiny thing is radiopharmaceuticals.

[38:46] Sam: There are already two approved radiopharmaceuticals, including one in prostate cancer. But there are only two, so it is still very early. It is definitely a direction for the future.

[38:57] Tiff: Exciting. I am glad you had a good time. Let’s go next year.

[39:01] Sam: Come next year and we will do some chatting, interviewing, or something like that.

[39:08] Tiff: More standing ovations.

And the Youtube video: