Hello, everyone. Next up is Nuvation Bio, and we're pleased to have, David Hung, CEO of Nuvation Bio, here to give us a presentation, and we'll follow up with a Q&A.
Thanks, Lee. Thank you all for coming. Nuvation Bio is a late clinical stage global oncology company. We have four clinical programs, one late, one middle, and two early. You'll hear about them in a lot more detail, but taletrectinib is our ROS1 inhibitor, safusidenib is a mutant IDH1 inhibitor, and then NUV-1511 is the first candidate we have from our DDC program, and NUV-868 is our BD2-selective BET inhibitor. We had a robust cash balance of $577 million, and we just presented some pivotal data from our pooled TRUST-I and II studies, which will form the essence of our NDA filing next quarter. Looking at our programs, taletrectinib has a dataset that's being filed for an NDA in the fourth quarter. We plan to commercialize this asset next year.
Safusidenib is in a phase II study, and we are preparing to design a pivotal study, which we hope to take forward sometime next year. 1511 started in the clinic in March and is in a phase I/II study that's ongoing, and then 868 also is in a phase I/II study, and we're gonna evaluate that in context of the recent pelabresib data, which was quite positive. Focusing on taletrectinib. Taletrectinib is a next-generation ROS1 inhibitor. We have breakthrough therapy designations in first and second line in both the US and China, and we believe that our profile is potentially a best-in-class. We've shown very durable responses and prolonged progression-free survival. This drug is highly brain penetrant and active against the most common resistance mutations.
This asset was in-licensed from Daiichi Sankyo to AnHeart, and as you know, we acquired AnHeart a few months ago. We maintained global rights, except in China and Japan, where the rights to the drug have been out-licensed. If you look at the market of ROS1-positive non-small cell lung cancers, non-small cell lung cancer is about 80%-85% of lung cancer, and ROS1 represents about 2% of non-small cell lung cancer cases. So if you look at the United States, that's a number somewhere between 2,000 and 4,000 patients. There are three other therapies that are currently approved for the treatment of ROS1 lung cancer: crizotinib, which was approved in 2016, entrectinib in 2019, and repotrectinib was approved last year. We just finished presenting data from two pivotal studies.
One's called TRUST-I, a China study that was comprised of 173 patients, and then TRUST-II, a global study comprised of 153 patients. Combined, this is an over 300-patient dataset, one of the largest datasets compiled in the ROS1 space, and this will form the basis of our NDA filing in the fourth quarter. The dose that we're using is 600 milligrams a day. The pooled dataset is about 337 patients, of advanced patients with ROS1-positive lung cancer. If you look at the essence of the data that was presented at ESMO, we show our data on the left compared to the three other approved agents on the right.
So on the far right, entrectinib and crizotinib are both first-generation ROS1 inhibitors, and you can see that the overall response rate is about 70%, 68% for entrectinib, 72% for crizotinib. If you look at the median PFS for entrectinib, it's about 16 months. If you look at crizotinib, it's about 19 months. You can see that repotrectinib, to our right, has an overall response rate of 79%, and the median PFS is about three years. So a significant improvement over the first-generation TKIs. But on the far left, you can see the recent taletrectinib data, which we just presented, which will comprise the basis of our NDA filing next quarter. Our overall response rate is 89%. These are all confirmed responses, and our median PFS is almost four years.
A pretty robust and durable response from this second-generation TKI. Intracranial response rates were high, nearly 80%. And then just to give you some context for how long this PFS is that we were seeing with taletrectinib. As you know, Xtandi revenues really started to ramp, and we started to get stacking when the PREVAIL trial showed a 20-month PFS. Olaparib also has done extremely well with a 19-month PFS, and our taletrectinib data that we just presented now at 46 months, we believe is one of the more durable responses that we've seen in the TKI space. And we're quite excited about what that means to the possibility of revenue stacking in the future. If you look at the second-line setting, so these are now TKI pre-treated patients. In the middle, you'll see repotrectinib's data.
Their overall response rate is 38%. Their median PFS is nine months. The most common resistance mutation for ROS1 TKI is a mutation called G2032R. You can see that repotrectinib's response rate is 59%, and their intracranial response rate, because a lot of these patients develop brain mets, is 38%. You can see that compared to repotrectinib, our overall response rate is quite favorable. We have a 56% response rate compared to the 38%. Our PFS is ten months versus their nine months. Our resistance mutation overall response rate is 62% versus their 59%, and our intracranial response rate is a bit higher at 66% versus their 38%. There's been some talk about Nuvalent's drug zidesamtinib, some data of which were presented recently.
That data set is relatively small, so the only data that we know of in the Nuvalent portfolio is in the second-line setting. We have not yet seen first-line data. So if you look at the second-line setting in that study, ARROS- 1, there are only 20 patients that we have data on. To make it completely apples to apples, if you look at crizotinib and entrectinib failures and the response rate of those 17 patients, the response rate is 53%. We have a significantly larger data set. Our N is 113 patients, so almost 10 times larger than the ARROS- 1 data set. If you look at our confirmed overall response rate, it's 56%.
If you look at the repotrectinib failure response rate, out of the three patients in ARROWS 1, there were zero responses. So we think that our data show, you know, again, very competitive efficacy, overall responses in the second-line setting. We have not yet seen durability of responses in the ARROS- 1 study. If you look at resistance mutations, the most common one being G2032R, again, as I said, our response rate is 62%, which is identical to Nuvalent's 62%. But if you look at intracranial response rates, Nuvalent's drug shows a 50% response rate so far, and ours is 66%. So I think we stack up pretty favorably even in the second-line setting. If you look now at safety and tolerability, you know, well, there are...
The most common adverse event seen in taletrectinib is liver function test abnormalities, but oncologists are very familiar and well-schooled in how to manage LT elevations. And so the bottom line for us is that we look at discontinuation rate. If a drug is not tolerable, it'll be stopped. If it's tolerable, it'll be continued. And if you look at the discontinuation rate, we're the green bar on the left. You can see that our discontinuation rate is among the lowest of the TKIs, almost half the discontinuation rate of crizotinib, which is the best-selling TKI in the ROS1 space. If you look on the right, the tall blue bar is the CNS toxicity of repotrectinib.
One of the major liabilities of repotrectinib, and I think what has really hampered their launch, is a really high rate of CNS toxicity, including dizziness and even behavioral changes. We've heard about Mihail talking about psychosis, ataxia, lack of proprioception, falls. I think that that is one of the reasons why repotrectinib has not really managed to get entrenched, and I think that's gonna be a very challenging safety profile to get wide adoption. If you look at the green bar to the left of that, we have less than a third of that, those CNS, that CNS toxicity, and most of our CNS effects are grade one.
I would say that, you know, compared to Repo, we think that our safety tolerability profile compares quite favorably, and as I just went through with our efficacy profile, we think that we're well-positioned there as well. We are gonna be submitting our NDA in the fourth quarter. I mentioned we have breakthrough designation in both first and second line from both U.S. FDA as well as China's NMPA, and we have priority review of two NDAs in China for taletrectinib. We will be launching this drug ourselves in the United States. I recently hired a number of my commercial team from Medivation, so we are quite well-positioned. We feel very confident in our ability to execute a good launch. Yeah. We also have license agreements, royal...
We'll be getting royalties from Innovent for the commercial launch in China and from Nippon Kayaku for the commercial launch in Japan. Our second drug is a mutant IDH1 inhibitor called safusidenib. I think this is a very interesting molecule. Clearly, a brain tumor called glioma, there's a very, very large unmet need, and only very recently in August, was the first drug vorasidenib, the Agios Pharmaceuticals drug, approved to treat glioma. If you look at Royalty Pharma, they just paid $905 million for a 15% royalty stream to vorasidenib, which we think places a significant price tag on that program. If you look at our program, which I'll show you data on in a second, we believe our data are quite encouraging.
This is a program that was also in-licensed by AnHeart from Daiichi Sankyo, and Daiichi retains Japanese rights, but we have all rights to everywhere else. If you look at the market here, the IDH1 mutant glioma market is about five times the ROS1 market. So a ROS1 is two to four thousand patients, even let's say three thousand. This is thirteen to eighteen thousand. So about, if you take the middle point of that, it's about sixteen thousand patients. So it's about five times the size of the ROS1 market. About two-thirds are low grade or Grade 2, about one-third are high grade or Grade 3. Also interestingly, these patients are on drug for a long time, almost twice the duration that we've even seen for even our robust data in with taletrectinib in ROS1 lung cancer.
We believe that the commercial opportunity of IDH1 mutant glioma is really quite substantial. We have a data set right now that's about 100 patients based on a phase I and II study in Japan and a global phase II study that Nuvation Bio is sponsoring. And I mentioned that if the Royalty Pharma deal values vorasidenib somewhere in the range of $5.5 million. And if you look at our data set compared to vorasidenib, vorasidenib's data is on the right, our data is on the left. So if you look at the far right gray bar, the response rate of vorasidenib in low-grade gliomas in the phase II study was 18%. In the phase III study, their approval study, was about 11%.
You look at the left gray bar, in our phase II study, safusidenib's response rate in low-grade glioma was almost three times what was seen in the phase III study for vorasidenib, 33%, and Daiichi will hopefully be presenting some more data later this year or early next year on the responses of safusidenib in glioma. If you look to the left of the right gray bar where it says zero, the response rate of high-grade glioma to vorasidenib was zero. And if you look at the left green bar, the response rate of high-grade glioma to safusidenib is 17%. So we think this is a pretty encouraging signal, and we are now truly trying to figure out will we go into a pivotal study for Grade 2, Grade 3, both?
We're gonna be looking at the Daiichi data when it's presented next and trying to finalize the details of our pivotal study that we hope to enter into next year. Our third program is what we call the DDC or Drug-Drug Conjugate program. And this is a pretty interesting program because it it's similar in some ways to ADCs, which I'm sure you're all very familiar with. So an ADC is an antibody-drug conjugate, where you take a small molecule warhead, you couple it to a targeting antibody, and the data that have been generated for several of these ADCs, like Enhertu or Trodelvy, are really quite spectacular. And I would say that there are some limitations of ADCs, mainly because of their size. They have to be given IV.
Their targets are really confined to extracellular targets, whereas many targets in a cancer cell are actually inside the cell. And because it's an antibody, it's you know, significantly more complex and expensive to make than a small molecule. So we've pioneered a new field, where we use two small molecules, and we call these drug-drug conjugates or drug-drug fusions, where we take a small molecule targeting agent and fuse it to a small molecule warhead. And we've shown that by doing that, we can create molecules that are bioavailable, both orally or IV. We've shown that they can bind to intracellular or extracellular targets or both. They're highly membrane permeable, and because they're small molecules, they're a lot simpler and cheaper to make.
So the concept here, if you take drug X against target X and drug Y against target Y, we can find a way to fuse those drug X and drug Y without messing up their active sites to create a bispecific small molecule. That's the basis of the DDC program, so to show you, the first molecule we've taken to the clinic, this is called fifteen eleven. We have disclosed some details about this program for competitive reasons, but if you look at the black line, and on the left is a prostate cancer model, on the right is a breast cancer model, and the black line at the very top is no treatment, so these cancers are very aggressive. They grow rapidly.
The gray line right below that is what happens to the tumor when you take the targeting small molecule and just give that, so it really has very minimal activity. The third darker blue line is what happens when you take a well-known chemo agent and give it the maximum tolerated dose of that. You can see it has some efficacy, but it's not really striking. And then if you look at the very bottom lighter blue line, when you fuse the gray molecule and the dark blue molecule to create a targeted warhead, you can see significantly better efficacy. We've also shown that we have interesting pharmacokinetics and durable responses with this approach. This is an experiment just showing that in the top, you can see what happens when you just, you know, give no, no treatment.
The tumor grows rapidly, but if you look at the very bottom dark blue line, when we give NUV-1511 for just a couple of days and then stop dosing, you can see that a month later, the tumor is still completely inhibited. So we can achieve some very interesting pharmacokinetic and pharmacodynamic effects by the way we mix and match our warheads and targeting agents to give, you know, durable responses that, in some ways, you know, would almost resemble an antibody without the antibody. So I think this is a kind of an interesting observation. So, as I said, we're in the clinic with this program. We're targeting five indications. The first is breast cancers who've failed in Enhertu and Trodelvy, a very large unmet need.
The second one are HER2 negative metastatic breast cancer. Third is Xtandi-resistant prostate cancer. Fourth is platinum-resistant ovarian cancer, and the fifth, advanced pancreatic cancer, for which there's really no effective therapy. So this program has been in the clinic for a few months, and we think that towards the end of the year, we should be approaching a therapeutic level, and we'll look forward to reporting data when we get it. Our last program is a BD2 selective BET inhibitor. So BET inhibitors have had a kind of a long and checkered past. I think the scuttlebutt in the field is that, the tolerability issues and perhaps even the efficacy issues have been related to a lack of specificity for the two subdomains of bromodomain four, which are called BD2 or BD1.
There's some literature that suggests that making a BD2-selective compound could be more tolerable, and so we've done exactly that. If you look at the very top, 868 is the most selective BET inhibitor in development. It has a selectivity of about almost 1,500-fold for BD2 over BD1. If you look at the early first-generation BET inhibitors in the red, you know, they've had a very difficult history. We believe that may be related to their lack of specificity for BD2. Interestingly, the third molecule down, pelabresib, is also a BD2-selective compound, even though it's not quite as selective as ours. It's about 5- to 6-fold selective for BD2. But as you know, pelabresib and MorphoSys recently published a very robustly positive myelofibrosis trial comprised of 430 patients.
If you look at the intermediate risk subgroup, which is four hundred of the four hundred and thirty patients, that group hit both its primary and secondary endpoints. Even though that was missed in the high-risk subgroup, which is only thirty patients of the four thirty, we think that was quite an interesting signal. We're kind of waiting to see what Novartis does with that program, and, you know, they've had some issues have been raised about the potential of leukemia transformation, potential imbalance in the groups, and so we're kind of waiting to see what FDA says about that. But we are kind of holding our breath until we see what they decide to do with the program, but we are contemplating the possibility of going to NMPA or other potential indications.
There's also interesting data suggesting that BET inhibitors also play a role in inflammation and inflammatory pathway, so we're really thinking about a number of possibilities. You know, this program's been in phase I/II for almost two years, so at least the first thesis that, you know, the drug might be more tolerable because of its BD2 selectivity appears to have played out. It took us a long time to hit an MTD, but we have identified that, and now we're trying to figure out the best indication to take it into. So, you know, just to summarize, we have four clinical programs. Taletrectinib is a pre-commercial program. We are filing the NDA next quarter, and we'll be commercializing the drug next year. Safusidenib is poised to enter a pivotal study.
We're waiting for some data to finalize the details on the pivotal study. NUV-1511 is in a phase I/II study that's ongoing, and NUV-868 is also in a phase I/II study, and we're just waiting to figure out what indications we'll pursue with that molecule. As I mentioned when we started, we have a robust cash position, about $577 million as of our last Q, and I think that we are, you know, very excited about taking these programs forward and getting to the next level. With that, I'm happy to take questions.
Great. I guess I can start with a question on ROS1. How are you thinking about this commercial opportunity? Obviously, it's a niche market, and you got approved agents out there. It's nice that you have, you know, some of the best-in-class data in hand, but what do you need to do in order for you to gain market share?
So I think that, you know, part of the skepticism I think that exists on the street about ROS1 is because of repotrectinib's relatively poor launch. I think they booked something like $14 million in the first half, two quarters of this past year. If you look at crizotinib and entrectinib, first-generation TKIs, which have a PFS of about, only about a year and a half, between the two drugs, they still sell almost $500 million a year worldwide, and the majority of which is in the ROS1 space. So I think the market exists, and those are first-generation TKIs, which have significantly lower efficacy.
As I mentioned, only a 70% response rate versus our approximately 90% response rate, and with a durability of almost, you know, two and a half fold less than our. You know, we, our PFS is about 240% higher than first generation TKIs. So the way I look at it is, if you look at, you know, the market, the number of patients with ROS1 per year in the U.S. only, it's 2,000 to 4,000 patients. So if we take the middle point of that, let's say 3,000 patients, and you multiply that times the repotrectinib price, which is about $29,000 a month, so $350,000 a year, that's about $1 billion.
If you captured 100% of patients in any one year, it'd be about $1 billion. But what's important is that because of our durability of response, I'm not saying we would capture, you know, anything close to a hundred percent, but if you look at EGFR, ALK, and some of these spaces, what we have seen with drugs in those spaces, like osimertinib, you know, they tend to be a winner-take-all situation. So there are dominant drugs in those spaces. When you have a drug that's effective and tolerable, we've generally seen kind of a winner-take-all situation. Now, I don't know how big a market share that would be. Clearly, it's not gonna be 100%, but we think it could be substantial.
So if you look at our durability of responses now, you know, we have a PFS now almost four years. Let's say we in the first year, we multiply three thousand patients times the repotrectinib price, that should be about $1 billion. Year two, you'd get the same number of patients, plus you still get the stacking of the first year's patients. That's about $2 billion. Third year, you get about $3 billion. The fourth year, you get about $4 billion. So that's if you got 100%. So if you apply, you know, you apply whatever fraction you believe is reasonable for market share, and you can kinda get an idea of what that market size is.
You know, we think that that's a sizable opportunity, and we look at osimertinib, which only, by the way, has a 19-month PFS. Their stacking, and if you look at, I mentioned extended PFS of 20 months, even that stacking was enough to allow for a pretty, you know, significant and robust revenue ramp. We think our 46 months, you know, would probably position us pretty favorably for a reasonable revenue ramp, so it's just a matter of how much market share we can get. And we believe that our data, if you look at our efficacy, there, you know, there is no metric in efficacy, whether it's response rate, durability, intracranial response rate, G2032R resistance mutation, response rate, there's no metric where any other TKI exceeds our numbers.
We are. We have BTD in the first- and second-line setting, so we believe that we're well-positioned. You know, Nuvalent has a third-line BTD, so, you know, we're really focused on the first-line setting. So we think that it's a really significant market opportunity. We think we're well-positioned with our efficacy and our safety profile, you know, as I said, the lowest discontinuation rate of any of the TKIs. So I think we think this is a significant opportunity, and we have the right team to do it, so we're looking forward to that.
Can you talk a little bit about the timeline to markets? Do you anticipate priority review, and then how big of a commercial team?
So I mentioned that we did have, we do have breakthrough designations in both first and second line, in both the U.S. and China. I think that just kind of gives you a flavor for how the agencies view this drug, and I think that sets us up very favorably. We believe that we will get a priority review, and we, you know, we think that, you know, compared to the other TKIs, our profile has enough advantages that we consider the currently marketed drugs to represent still an unmet need that we can help to resolve. So we think that we will, that will go well.
We've had many discussions with the agency, which we think are going very well, and we know we're, as I said, we're very confident in our approval next year or our launch next year. We're still sizing, you know, the team that we would be putting together for this launch. This is a, you know, a lot of these patients are identified in the community, but they quickly go to key academic sites that are familiar with ROS1. So we're, you know, it's not a, it's not going to be a massive sales force because they tend to go to these academic centers. We have relationships with many of them, and we think this is a very targetable indication, very, you know, reasonably targeted.
So I think that, you know, and as I said, we're, we've hired our senior leadership from, for our, our launch, some, many from Medivation that we, I have a great deal of confidence in, and, we'll probably be, you know, looking to bring on reps, closer to launch. I think it's a little too early right now, but, given how many inbound, inquiries we've had from reps, I think that we'll have a very easy time.