NUVB

Hello, welcome to Nuvation Bio's first quarter 2026 financial results and corporate update call. Today's call is being recorded, and a replay will be available on the company's website. All participants are currently in a listen-only mode. A brief question and answer session will follow the prepared remarks. I'd like to turn the call over to JR DeVita, Vice President of Corporate Development and Investor Relations at Nuvation Bio. Please go ahead.

Thank you, good afternoon, everyone. Earlier today, we issued a press release summarizing our financial results for the quarter ending March 31st, 2026 and providing a business update. The press release is available on the investor section of our website at nuvationbio.com. Today's call includes forward-looking statements, including statements about the therapeutic and commercial potential of Ibtrozi and safusidenib, our plans for safusidenib development and future data presentations, the components of our anticipated product revenue, expected milestone payments, and our cash runway. Because such statements deal with future events and are subject to many risks and uncertainties, actual results may differ materially from those in the forward-looking statements. For a full discussion of these risks and uncertainties, please review our quarterly report on Form 10-Q, which we filed with the U.S. Securities and Exchange Commission today.

Joining me on today's call are our Founder, President, and Chief Executive Officer, Dr. David Hung, our Chief Commercial Officer, Colleen Sjogren, and our Chief Financial Officer, Philippe Sauvage. I'll turn the call over to Dr. David Hung. David, please go ahead.

Thanks, JR. Good afternoon, everyone, and thank you all for joining us. Today, I'm excited to discuss the progress we've made across our business in the first quarter. Following the line-agnostic FDA approval of Ibtrozi in June 2025, we entered 2026 focused on continuing to build a successful commercial launch in ROS1-positive non-small cell lung cancer, with specific focus on educating physicians, supporting patients, and generating new clinical evidence that reinforces Ibtrozi's differentiated profile. Overall, we are very pleased with our continued execution, highlighted by strong demand for Ibtrozi and our ability to significantly increase the percentage of new patients treated in the first line setting. We successfully treated approximately 200 new patients with Ibtrozi in the first quarter, which makes 3 consecutive quarters of about 200 new patient starts, bringing our total to over 600 since launch.

We see a growing trend of more new patients coming from the first line setting, and in turn, a lower percentage of patients coming from the third line setting or later. In fact, for the first time since launch, more than half of the new patients who started Ibtrozi in the quarter were TKI naive. Given the changing dynamics of patient mix and moving from later line to the first line setting, and considering the significantly increased durability of Ibtrozi in earlier versus later line settings, we are just beginning to see revenue stacking this quarter, as Philippe will shortly discuss. This revenue dynamic is the most important metric for the launch going forward. Therefore, at some point in the future, we will focus on revenue and no longer report new patient starts.

This has meaningful implications for the long-term opportunity for our medicine, especially now, given that based on a recent new analysis presented at AACR, Ibtrozi has now extended its median duration of response to 50 months in TKI-naïve patients in the pooled results from the pivotal TRUST studies. When patients are treated earlier in their disease course, they are often in a better position to realize increased benefit from a therapy with durable efficacy and generally favorable tolerability. Over time, we believe this can build a larger, longer duration base of active patients on Ibtrozi and support more substantial revenue growth. Since launch, our discontinuations have been driven primarily by disease progression in later-line patients. This is expected in any oncology launch, as these patients have already progressed through other approved therapies.

From the data that we see, discontinuations in earlier line patients or for adverse events are consistent with clinical trial results that remain relatively low. As a reminder, and as detailed in Ibtrozi's prescribing information, 6.5% of the 337 patients with advanced ROS1-positive NSCLC in our pivotal TRUST studies discontinued therapy due to any adverse reaction. As we have previously presented, only 1 of these patients, or 0.3%, discontinued treatment due to any of the 6 most common adverse events, including liver enzyme elevations, diarrhea, nausea, vomiting, or dizziness. The feedback we continue to receive from both key opinion leaders and our sales organization has been highly consistent.

Physicians are impressed with Ibtrozi's clinical profile, citing the durability and tolerability, and our real-world experience is giving physicians increased confidence to both keep patients on therapy longer and to choose Ibtrozi when considering a preferred first-line treatment option. This response further supports our belief in both consensus net revenue estimates for Ibtrozi in 2026 and its long-term potential. We are also encouraged by the addition of Ibtrozi to the latest CNS NCCN guidelines as a systemic therapy option for ROS1-positive NSCLC patients with brain metastases. We believe this is an important recognition of Ibtrozi's demonstrated intracranial activity and further supports its differentiated position in the ROS1 treatment landscape. Turning to our recent abstracts and publications, we were thrilled to present updated pooled results from the August 2025 data cutoff of the TRUST-I and TRUST-II studies at the American Association for Cancer Research Congress, or AACR.

These updated data continue to reinforce the strength of Ibtrozi's profile. In TKI-naive patients in TRUST-I, as recently published in the Journal of Clinical Oncology, median duration of response and median progression-free survival have both now increased to approximately 50 months or more than 4 years. As presented at AACR in TKI pre-treated patients, the median duration of response was nearly 20 months in TRUST-II, and the overall survival in the pooled TKI pre-treated population showed a median of nearly 30 months, which is unprecedented in this space. With this longer follow-up, Ibtrozi continued to demonstrate a manageable and consistent safety profile, including low rates of neurologic adverse events and no new safety signals. We believe these durability data matter not only clinically, but commercially.

Drugs that combine deep and durable efficacy with a favorable tolerability profile are well-positioned to become the therapy of choice for TKI-naïve patients and that is exactly the trend we are seeing in our launch. With approximately three years of follow-up in the pooled analysis and more than four years of follow-up in TRUST-I, we believe these data further supports Ibtrozi as an effective, durable, and tolerable treatment option for patients living with advanced ROS1-positive NSCLC. At AACR, we also presented preclinical data which continues to build on our broader scientific understanding of Ibtrozi's differentiated profile. As I discussed on our last earnings call, Ibtrozi is designed to achieve deep and durable inhibition of ROS1 while maintaining measured activity against TRK-B. Our presentation showed two important points. First, taletrectinib has nearly complete coverage of ROS1 fusions at clinically relevant concentrations and is effective against ROS1 resistance mutations.

Second, taletrectinib has partial yet biologically meaningful inhibition of TRK-B while being sufficiently balanced to avoid significant CNS-related adverse events as seen in our clinical trials and real-world experience. Of note, in the same experiment, a TRK-B sparing agent failed to control tumor migration and markers of invasion and metastases, which were well-controlled by taletrectinib. These data support the concept that some degree of TRK-B inhibition may be required to inhibit systemic progression, prevent the migration of lung cancer cells, and protect against metastases to the brain. This analysis showed that our medicine may have a mechanistic profile which we believe leads to a potential impact on tumor invasiveness and metastatic behavior in patients while limiting neurologic adverse events.

This balanced approach and ability to prevent resistance could ultimately play an important role in the long-term durable control of ROS1-positive lung cancer, as demonstrated in Ibtrozi's median progression-free survival of over 4 years. At ASCO in June, we will be presenting additional data from our TRUST program on patient-reported outcomes and our ongoing TRUST-IV study in the adjuvant setting. Turning to safusidenib, we remain very excited about the potential of this program and the opportunity it represents for patients with IDH1 mutant glioma. Beyond its potential clinical importance, we believe safusidenib could address a broad segment of the glioma market and therefore represent a meaningful long-term value opportunity for the company.

safusidenib is currently being evaluated in the ongoing Phase III SIGMA study for the maintenance treatment of patients with IDH1 mutant astrocytoma who have high-risk features following standard of care and in a non-pivotal cohort with Grade 3 oligodendroglioma following surgery. In Phase I and Phase II single-arm studies, safusidenib has shown very encouraging efficacy signals, including durable responses and prolonged progression-free survival across both low and high-grade IDH1 mutant gliomas. We think about the glioma market as a pie with 4 parts: low-grade, low risk, low-grade, high risk, high-grade, low risk, and high-grade, high-risk tumors. Today, the only approved glioma drug, vorasidenib, is approved in the low-grade, low-risk glioma setting, and prior data have shown limited activity in enhancing our high-risk, high-grade tumors. In contrast, safusidenib has shown significant activity in clinical studies across all 4 subgroups of IDH1 mutant glioma.

The safusidenib SIGMA pivotal trial will target 3 of the 4 pieces of the glioma pie, enrolling high-grade, high-risk, high-grade, low-risk, and low-grade, high-risk IDH1 mutant glioma patients. We're also exploring potential studies to further develop safusidenib in the final piece of the pie, low-grade, low-risk glioma, and we'll provide an update on our plans later this year. I'd also like to highlight that a November 2025 publication in Neuro-Oncology summarized the phase II study of safusidenib patients with chemotherapy and radiotherapy-naive grade 2 IDH1 gliomas as of a March 10, 2023 data cutoff. Strikingly, as of February 2026, 12 of the 27 patients evaluated in this study remained on treatment with a median follow-up of more than 5 years. We believe these data continue to support the potential of safusidenib in patient populations with significant unmet need and limited or no FDA-approved targeted treatment options.

Importantly, in April, we acquired exclusive rights to safusidenib in Japan from our partner, Daiichi Sankyo. With that agreement now complete, we plan to expand the pivotal phase III SIGMA study into Japan, continue to advance the global development program, and pursue presentation and publication of longer-term phase II data so the scientific community remains current on these findings. Finally, we remain on track to provide an update on our drug-drug conjugate platform by the end of the year. Overall, the first quarter confirmed important points for our 2026 outlook. We are seeing solid new patient demand, improving mix toward first-line use, and continued confirmation of Ibtrozi's encouraging efficacy and tolerability profile in the real world. We believe these trends position Ibtrozi well for long-term success while we continue to advance a broader pipeline designed to address significant patient needs and create additional future value.

With that, I'll turn the call over to Colleen.

Thank you, David, and hello, everyone. We continue to see strong momentum in the launch of Ibtrozi, and we are particularly encouraged by what we have accomplished in just three quarters, especially when viewed against relevant targeted therapy launch analogs. Based on our internal data, we have generated more new patient starts than the prior ROS1 launches combined over the same time period. We believe this early success reflects the compelling clinical profile of Ibtrozi and the focused execution of our commercial team. In addition, it represents a strong foundation for long-term value creation. As David mentioned, new patient starts remained robust at approximately 200 for the third quarter in a row, and this included a greater proportion of patients initiating treatment in the first line setting.

Importantly, our internal data sources indicate that for the first time, over half of new patient starts in the quarter were TKI naive, compared to approximately 30% in the first full quarter following launch. This continued shift from later line to front line use is one of the clearest indicators of the strength of the launch and is in line with what we would expect based on typical uptake trends with new oncology agents. This gives us confidence in Ibtrozi's long-term trajectory because these patients respond at a higher rate, have the potential to remain on therapy for years, and contribute to a more durable, active patient base over time. This dynamic is also important in understanding the discontinuation patterns we have observed, as we are encouraged by how Ibtrozi's clinical profile has translated to the commercial setting.

Discontinuations continue to be concentrated among later line patients, which is expected given the more advanced disease in this population and exposure to multiple prior therapies. As we discussed last quarter, most discontinuations are driven by disease progression in later line patients rather than tolerability. This dynamic can introduce some variability in near-term revenue even when new patient demand is steady. Importantly, adverse event-related discontinuations remain low and in line with what we observed in clinical trials, reinforcing the strong overall clinical profile of Ibtrozi, including its favorable tolerability. Taken together, these observations, along with feedback from both patients and physicians, reinforce our view that Ibtrozi is well positioned to serve patients across the ROS1 lung cancer treatment landscape and has not changed our view of the potential for Ibtrozi in this setting.

This increasing strength in patient mix and positive real-world feedback on Ibtrozi's treatment profile is matched by expanding adoption across both academic and community settings. We are especially encouraged by the pace of uptake we are seeing, particularly given that ROS1 is a rare disease and the prescriber base is relatively broad. Our commercial efforts continue to translate into strong physician awareness, which we believe is a meaningful indicator of successful launch execution. Based on our most recent market research, aided awareness of Ibtrozi among target physicians has reached 97%, underscoring the breadth of our commercial reach and the growing visibility of Ibtrozi in the market. We understand that academic and community customers have different needs, and we have been deliberate in aligning our commercial strategy with the distinct value drivers for each setting.

As a result, 100% of the top 50 historical TKI accounts in the country have prescribed Ibtrozi. Our broad account adoption is another important indicator of launch strength. When paired with favorable placement on pathways and formularies, it reinforces our belief that institutions recognize the differentiated clinical profile of Ibtrozi. We believe the launch progress we have seen to date also reflects the strength of a team that knows how to win in targeted oncology. We are seeing our efforts translate into meaningful account and physician traction. The result, an appreciation for the durability that Ibtrozi has to offer and the openness to partnering with Nuvation Bio. Taken together, we believe this positions us well to continue building momentum and capture the full ROS1 market over time.

Lastly, we believe there is meaningful opportunity to increase the number of ROS1 positive patients who are diagnosed and treated with a ROS1 TKI today. Publications and data from the field suggest there should be approximately 3,000 patients with advanced ROS1 positive non-small cell lung cancer diagnosed annually in the U.S. based on DNA testing. As the field shifts to using RNA and DNA-based testing together, which may detect an additional 30% of fusions, the annual addressable population could expand to approximately 4,000 patients. Unfortunately, although effective testing is better in most academic centers, it is currently significantly lower in parts of the community, including below 50% in some centers. To combat this, we have implemented several initiatives to partner with and educate the community on the importance of testing for oncogenic drivers.

We strongly believe all patients should have the opportunity to benefit from the prolonged durability and high response rates Ibtrozi has shown in the first-line setting, consistent with the NCCN guidelines issued last year. Improving patient identification is the right thing to do for patients and will be a key driver of long-term value for Nuvation Bio. Overall, we are encouraged by the level of demand we are seeing, the shift towards earlier-line use, and the strength of the launch execution to date. The medical community recognizes that Ibtrozi's long durability gives physicians an important tool and offers patients the potential for long-lasting benefit with a generally favorable safety profile, so they can stay on therapy for years. With an experienced commercial team, a clear strategy, and disciplined execution across the launch, we believe we are well-positioned to continue building momentum and support the long-term success of Ibtrozi.

Now I'll turn it over to Philippe.

Thanks, Colleen, and good afternoon, everyone. For detailed first quarter 2026 financials, please refer to our earnings press release, which is available on our website. Now I will align to a few key points from the quarter. In the first quarter, we generated $83.2 million in total revenue, including $18.5 million in Ibtrozi net U.S. product revenue. This represents 18% growth in net product revenue from the prior quarter, which was not only driven by yet another quarter of about 200 new patient starts, but importantly, from a growing population of active patients remaining on Ibtrozi due to increasing frontline use. As you can see on this slide, the number of patients starting Ibtrozi in the last three quarters has been consistent.

However, due to the percentage of first-line patients increasing from approximately 30% in the 3rd quarter last year to approximately 40% in the 4th quarter last year to now more than 50%, net product revenue has grown from $7.7 million to $15.7 million to now $18.5 million, in spite of an expected uptick in gross to net. We expect this trend to continue and also expect the number of new patient starts to increase as more U.S. physicians become aware of Ibtrozi and testing rates in the community continue to improve. As previously mentioned, our long-term success will be driven by the exceptional duration of response of Ibtrozi in the first-line setting, and we are pleased that a growing number of TKI-naive patients have started on medicine since the early months of our launch.

This trend, combined with our ability to grow revenue despite later-line patients dropping off Ibtrozi, demonstrates the potential impact of revenue stacking going forward. Lastly, as I noted, while we did see an expected uptick in gross to net discount at the start of the year, we still expect our gross to net expansion to gradually stabilize from here. In addition to product revenue, we recognized $64.7 million in collaboration and license revenue in the quarter, including an upfront payment of nearly $60 million from Eisai pursuant to our partnership, which was announced in January. We also received approximately $1.7 million in royalty payments from our partnerships in Japan and China, both of which are exceeding initial expectations on a new patient start and net revenue basis.

As a reminder, taletrectinib was listed in China's National Reimbursement Drug List, or NRDL, in January. Since then, sales from Iovance launch have increased rapidly. We believe this significant commercial uptake is due to a greater appreciation for effective testing in China and also believe this rate of adoption will translate to the U.S. market as patient identification improves over time. We continue to invest in our business and in our programs, resulting in total operating expenses of $73.5 million for the quarter. R&D expenses were $35 million, driven by increased investment in the SIGMA and TRUST clinical studies. SG&A expenses were $38.3 million, primarily driven by commercialization activities. Turning to the balance sheet, we ended the quarter with $533.7 million in cash equivalents, and marketable securities.

In addition, $50 million remains available under our existing term loan agreement with Sagard Healthcare Partners through June 30th. We also expect to receive a milestone payment of approximately $30 million from ASI upon the approval of Ibtrozi in Europe in the first half of 2027. Lastly, on the business development front, we announced our partnership with ASI in January to commercialize Ibtrozi in Europe and other territories outside of China and Japan, which we discussed on our previous earnings call. In April, we also announced an agreement with Daiichi Sankyo to acquire rights to safusidenib in Japan. This transaction made sense to us from a strategic and financial perspective, as it allowed us to fully secure global rights to safusidenib, including ownership of all clinical data and rights to future publications and data generation, without changing our expected cash run rate. Acquiring full global rights will reinforce our speed of execution and now allow us to expand our commercial reach to Japan. I'd like to thank Daiichi Sankyo for their efforts in developing safusidenib and for their confidence in us to take the program forward to our potential global regulatory approvals. Overall, our capital position continues to provide us with the flexibility to support the Ibtrozi launch, advance our pipeline, and evaluate additional strategic opportunities, all while maintaining a disciplined approach to spending. We continue to believe we are well-positioned to execute on our priorities without the need for additional external financing, given our current revenue trajectory and operating plan. I am now turning back to David for closing remarks.

Thanks, Philippe. As we move through 2026, we remain focused on disciplined execution, continuing to build on the momentum of the launch, advancing our clinical and scientific understanding of IBTROZI, and progressing our broader pipeline. I want to thank our team for their continued commitment, and our investigators, partners, shareholders, and most importantly, patients and their families for their ongoing support. I'll now ask the operator to open the line for questions.

We will now begin the question-and-answer session. Please limit yourself to one question and one follow-up. If you would like to ask a question, please press star one to raise your hand. To withdraw your question, press star one again. We ask that you pick up your handset when asking a question to allow for optimum sound quality. If you are muted locally, please remember to unmute your device. Please stand by while we compile the Q&A roster. Your first question comes from the line of Farzin Haque with Jefferies. Your line is now open. Please go ahead.

Thank you. Congrats on the progress, and thank you for taking my question. Can you comment on whether the growing first-line patients are coming from the academic or the community settings? What specific educational field force initiatives are being implemented to accelerate adoption in the high-volume community settings?

Hey, Farzin Haque, it's Colleen Sjogren. I'll take that one. You may have heard me mention that first of all, we're very encouraged. We have about 97% awareness right now, you know, across. This is uniform adoption of Ibtrozi across both academic and community. Most importantly, when we look at it historically, the top ROS1 accounts, which we have a historical list of about 50 of those accounts, 100% of them, in fact, have prescribed. We're seeing broad adoption across all channels, academic, IDN, and community. Really, we believe that that just speaks directly to the oncologists that are driven by the clinical evidence and Ibtrozi's TRUST data. It's so compelling that in each channel, we're seeing really good uptake and adoption. On your second question, you asked about specific initiatives.

Are you talking about adoption there? Do you want me to go in more of that? Which kind of initiatives are you looking for me to answer?

Right. Adoption and basically use over the chemo agents.

Yeah. You know, I would say that one of the things, Farzin, that we really are focused on is testing rates. You know, this is a real challenge, and I'll say that we're not dismissive of it, but we're also not passive about this. The gap between really academic and community testing is very well documented. Frankly, in some of the community centers, we're seeing testing rates that still remain below 50%. In our opinion, that's unacceptable from a patient care standpoint, and it represents just a really meaningful community opportunity. What really gives us confidence is that we do have a targeted strategy in place. We're partnering directly with community oncology practices. We're investing in a lot of educational initiatives.

We're also directly working with testing platforms to make sure that, in fact, comprehensive molecular testing is the standard of care and not the exception. We believe in this market. We believe in the size of the market. We do believe and have acknowledged that we have an issue with testing that we're addressing directly.

Hi, Farzin, this is David. Just to add a little more precision to the question you asked. You know, the use, getting first-line patients really depends on them being diagnosed. As Colleen mentioned, while we have great awareness in both community and academic centers, the testing rates are higher currently in academic centers than community centers. Therefore, the diagnosis of new patients are right now higher in academic sites because that's where more testing is being done. We've already seen significant improvement in multiple community centers, and we are very heartened by that improvement in testing rates and the awareness that there's a drug that's, you know, highly efficacious, durable, and well-tolerated to use when those diagnoses are made. We're pretty excited about this change.

We've seen in first line percentage, as we mentioned, you know, 20% or 30% in the first quarter after launch to about 40% now to over 50%. You know, that's a pretty exciting growth trajectory for us because we think that's gonna allow us to meet our consensus, you know, guidelines for the year if that were to continue. Thank you so much. Congrats.

Your next question comes from the line of Leonid Timashev with RBC Capital Markets. Your line is now open. Please go ahead.

Thanks guys for taking my question. I wanted to follow up on that a little bit. Just maybe trying to better understand the dynamic of the new patient starts. I mean, it seems like it's been 200 for the past 3 quarters. And you've laid out a lot of reasons why there should be growing awareness, better testing. I guess I'm just trying to better understand why that hasn't pulled through into more new patient starts yet. For example, why you aren't seeing why the proportion is changing towards 1st line, but you're not necessarily also seeing more of the later-line patients coming on as well. I mean, whether there's a bottleneck somewhere, if this is something that can be helped by expanding the sales force then hitting more prescribers.

You know, just if you can talk about the dynamic, that'd be great. Thank you.

Yeah. It's a great question, but the main reason is because remember in our early quarters of our launch, we're getting mainly late line patients, third line, fourth line, fifth line patients. Those patients can discontinue therapy in literally a month or two. When you see very late line patients, they drop out very quickly, unfortunately, to pursue other therapies or they unfortunately pass away. The reason that you see right now what appears to be a plateau, it's not. It's just that the late line patients are dropping out very quickly. We're getting new line patients, but those are incidents. Remember that the prevalence pool has already been diagnosed, when they enter the study, they are much easier to find because they've already had a ROS1 diagnosis.

They've already been on a therapy, but they don't stay on very long, and they drop out very quickly. The new patients are newly diagnosed. I mean, the first line patients have to be newly diagnosed, and that's an incidence pool, which obviously takes longer time. When you see what's happening now, the fact that we're getting from 30% to 40% to now over 50% first line, we are finding those first line patients, but the 3rd, 4th, 5th line patients are dropping off rapidly. That should stabilize because eventually we're gonna deplete that whole pool. In fact, we think we've already captured a significant amount of the late line patients. Now that's why we're really focused on first line.

That's all that really matters given the fact that we now have a PFS or DOR of more than four years, 50 months, which is, you know, there's no drug even within a year of that. We think that that's gonna lead to revenue stacking that will really start to kick in, and we're just seeing that this year. Even in spite of a quarter with roughly the same number of new patient starts and in spite of an increase in GTN, revenue still went up 18%. We're just starting to see the beginnings of that, but we think that if we were just to keep the same growth rate in first-line patients that we've seen in the last from Q3 to Q4 to Q1, we think that we should make our consensus for the year comfortably.

Your next question comes from the line of Kaveri Pohlman with Clear Street. Your line is now open. Please go ahead.

Yes. Good evening. Thanks for taking my questions. So maybe a question on, you know, the repeat prescription. I believe any details you can provide on, you know, you know, the previous call mentioned the academic was 70% versus 30% distribution for academic versus community. Today's call also mentioned that 100% of top 50 accounts have prescribed Ibtrozi, which I assume are mostly community-based. Any insight you can provide there. You know, if you can also tell us, you know, how this NCCN CNS guideline inclusion helps you get more of the first-line adoption. Then, you know, I, my follow-up question is quick on the previous comments you made regarding lower testing rates in the community setting.

Are these rates simply lower because of lack of awareness regarding the importance of testing, or there could be some other hurdles that could take longer period for changes to happen? Thank you.

Thank you.

Hey, Kaveri. It's Colleen. What I can tell you, a couple things that I think we need to keep in mind. When we look at across these top historical accounts and we're looking at 100% of those 50 accounts have now written, we see a much greater, I would, I would say, usage by community, IDN, and now academic. And you're right. In the first one, we first launched, we saw real fast uptake in the academics. Now we're seeing just as much strength in the uptake across other channels, especially in the community. You know, one of the things that we've seen when we first launched, obviously the academic oncologists, right, they're driven by the clinical evidence, Ibtrozi's TRUST data speaks to that directly. We look now at the community oncologists and what they need, right?

They need the practical support, the reimbursement pathways, patient support programs, and the confidence of their patients can tolerate the therapy over time. They're now seeing all of that. They're seeing the surround sound of NuvationConnect. They're seeing reimbursement pathways that have now taken effect. They're seeing our patient support programs. We believe that that's directly linked now to the channel of community really increasing their uptake in identifying patients. The other thing you asked about was the testing. You know, one thing I want to say is that we know that our accounts are increasingly prioritizing the flagging of these mutation statuses. As RNA-based testing continues to gain ground alongside with using DNA, we know that more ROS1-positive patients are starting to be identified each month and every year.

We're laying that groundwork in terms of education, and we know that's now positioning Ibtrozi to benefit as these, you know, identification rates improve. We're seeing the educational part of our efforts really taking traction in the community. I will also say we're educating on effective testing rates, making sure that our oncologists are waiting until they get all the oncogenic driver testing back to make a treatment decision. That's what we talk about influencing effective testing rates.

Thank you, Kaveri. Let me add one more thing to add to your question about the NCCN CNS guidelines. The reason that's so important is actually it turns out that one of the most widely used previous TKIs for ROS1 is crizotinib. crizotinib doesn't even get into the brain. We have guidelines from the NCCN that specifically call out the CNS profile of Ibtrozi, and at that contrast even more starkly against crizotinib's complete absence of brain penetration. As you know, 36% of ROS1 begins in the brain at first diagnosis, and then another 50% will progress in the brain upon first progression. It literally would be medical malpractice to give a drug that is not CNS penetrant.

Not only is Ibtrozi highly CNS penetrant, if you look at our integrated response rate, even in the second-line setting, even in the most difficult to treat patients, our integrated response rate is 66%, which is so far the highest recorded integrated response rate of any TKI in the pre-treated space. That's independent of our unmatched durability and response in the first-line setting. We think that the new NCCN CNS guidelines make it even more imperative that doctors need to give patients the right therapy, which is Ibtrozi.

Thank you, Kaveri. Just to add on that, to put an exclamation point on that point by David, we've already received early feedback from HCPs that this will only enhance Ibtrozi's profile and really impact their treatment decision.

Very helpful. This has a lot of exclamation points. Thank you so much.

Your next question comes from the line of Gregory Renza with Truist Securities. Your line is now open. Please go ahead.

Greg, good afternoon, David and team. Congrats on the progress and results today, Thanks for taking my question. David, maybe I'll just stay with Ibtrozi and add another question on this topic. A competitor recently presented some data suggesting activity in patients previously treated with taletrectinib, is there. I'm just curious, how would you expect treating physicians to interpret such results? Would you see this influencing sequencing decisions or the positioning with Ibtrozi as compared to competing or potential agents in the market? Thanks so much.

Yeah, I think it actually does have some implications. First of all, you know, we are delighted that new treatment options are becoming available for patients as they fail therapy. If you look at Ibtrozi's efficacy with a response rate of 90% and now a PFS of more than 5, you know, more than 4 years, almost 50 months, there is nothing close to it in the first-line space. Repotrectinib's PFS is 36 months, so you're still talking about almost a year and a half difference. If you look at the second-line setting, you know, now with our, with a DOR approaching 20 mon...

at 20 months, and again, a response rate in second line of 56% without excluding any oncogenic drivers and an integrated response rate of 66%, again, without excluding any oncogenic drivers, there are no agents today that can claim any numbers that match those. When a competitor has data in the third-line setting showing responses after Ibtrozi fails in the second-line setting, we're delighted that patients have another option in the third-line setting. I will refresh your memory. I think the competitor you're referring to actually got breakthrough designation in the third-line setting while Ibtrozi got breakthrough designation in the first and second-line setting.

We think things are playing out the way FDA initially saw them, which is that Ibtrozi will be used in the first and second-line setting. We think other agents are needed in the third-line setting. We welcome that because that's what patients need.

That's great. Thanks, David. Appreciate the color.

Your next question comes from the line of Mayank Mamtani with B. Riley. Your line is now open. Please go ahead.

Yes. Good afternoon, team. Thanks for taking our questions. Maybe just to build on the prior point of how Ibtrozi is being now considered relative to crizotinib, and maybe the entrenched position could be protected with additional market entry. How much is the development of new CNS meds relevant to the clinicians you talk to? If you are able to comment also on those interruption reductions that are tracking in the frontline patients versus what you may have seen in the later lines. Then I have a follow-up.

That's a great question. ROS1 non-small cell lung cancer is a really aggressive disease, not only because the tumors grow aggressively, but because where they go. More than a third of the time, they already are in the brain when you even make your first diagnosis. 50% of the cases, upon progression, the brain is the first site of tumor metastasis. That makes it imperative that you get CNS coverage as quickly as possible with an agent that has proven and long-term efficacy. As I said, the intracranial response rate of Ibtrozi in the second-line setting is 66%. Our duration of response in the second-line setting is 20 months with the now overall survival of almost 3 years.

In the 2nd-line setting, there are no agents today that have published any data that come close to that. In the 1st-line setting, it's completely a, you know, universal difference. There's no agent remotely within Ibtrozi's 90% response rate and 50-month PFS. I think CNS is important and because CNS is so important, that's the reason that Ibtrozi is being adopted so quickly, especially in the 1st-line setting, is clinicians know they need an agent that covers the brain. They need to see proven data that this drug has durability, and our 50-month durability is unprecedented. That's the reason that we're getting such adoption in the 1st-line setting. And also still significant use in the 2nd-line setting. You know, as I said, we've probably captured the majority of patients already in the 2nd-line plus setting.

I think that's, you know, that would be expected, and that's what we're seeing. Now, to get onto your question about discontinuations and interruptions, the great thing about this drug is it's pretty well-tolerated. As we said on the call script, we are not seeing anything new that we haven't seen in the clinical trials. That's really important because the thing you always worry about with any drug is that will real-world experience parallel your clinical trial experience? Oftentimes in the clinical trial experience, when you're under the careful supervision of your principal investigators and you know, they may control those patients better. Sometimes in the real world setting, you don't see metrics that exactly parallel what you would hope for based on your clinical trial.

In our case, we have seen no new developments. What we are really encouraged by is that tolerability of Ibtrozi is pretty much exactly what we saw in the clinical trials. Our dose reduction interruption rates are pretty much what we saw in clinical trials. Our efficacy is too early to see now how long these patients will last. We expect them to last 50 months in the first-line setting, 20 months in the second-line setting, just like reflecting clinical trials. Overall, you know, the great news for us is no surprises. We feel very confident in what we're seeing, and what we're hearing from physicians echoes that.

I think that the uptake that we've seen and the growth in the first-line setting we're seeing are all consistent with the fact that our data in the real-world setting are as good as they were in the clinical trial setting.

Very helpful, David. Thank you for that comprehensive answer. Then just on a go-forward basis, I understand new patient adds not a very relevant metric. What should we focus on? Should we get more updates on the proportion of, you know, first-line patients? Would you have some information on durability? I understand gross to net, you have some thoughts. Just help us think about, you know, the modeling beyond 2026. I understand everyone's focused on 2026, I just wanted to get some color on how you're thinking about metrics on a go-forward basis. Thank you for taking my question.

We're very excited by the dynamic there. I think what we've said again and again is that we see a profile which is very similar to our clinical trial, which means that patients, especially first-line patients, will stay on board for a very long time. That's why we shared some more information on this because we think this is really the driver of our long-term potential. If you look at our story there the past two quarters, I mean, we grew this first-line patient number by 35% from Q3 to Q4. We grew again by 35% quarterly, Q1 to Q4. If we keep increasing at that rate, we will hit consensus. If we do better than that, if we accelerate further, we'll beat consensus.

Everything there is really happening as we thought it would, which is really, really encouraging. To the question that I heard earlier about the stability you can see, well, it's because you have, like, two different mechanisms going on, right? You have those first-line patients increasing again and again, as I said, 35% from Q3 to Q4, 35% again Q4 to Q1, and we expect it to keep increasing over time. At the same time, we have this pool of late-line patients where unfortunately many of them will not stay on drug. This pool is limited, and that's why this is, as a total, relatively stable.

Looking ahead and looking forward, really, what is important for us is really this buildup of first-line patients, and we'll keep talking about that because we know that's where is the promise of Ibtrozi. Incredible tolerability, incredible durability, and all of that together to help patients stay on drug for a long time and to help ourselves progress quarter after quarter. That's really what we see. We think that's what's gonna drive our sales forward further. To your point about GTN, I think again, we hinted about that in our past quarter. Q1, typically because of our price increase, you will have a rise of GTN driven by the fact that Medicaid, and 340B price are stable, as we know. When you're higher than inflation, and we were, that drives your GTN a little bit higher.

You also see in the launch as a 340B used gradually progress a little bit until it stabilize. That's typically an oncology launch. For all of these reasons, our GTN has raised a little bit by a few percent this quarter. We still believe it's gonna stabilize and this is nothing, you know, abnormal there. Again, as I said, no surprise. No surprise on our GTN, no surprise on our patients, no surprise on our OpEx. Everything is happening exactly like we said.

Very helpful. Thank you for that.

Your next question comes from the line of Yaron Werber with TD Cowen. Your line is now open. Please go ahead.

Great. Thank you so much, and thanks for all the detail. Just a couple of questions. If we're looking at number of patients, let's say, that you started each quarter, like the 30 and then 40 and let's say greater than 50% who are new, it looks like a really increasing number of patients now are going to be sort of in the naive setting, right? Or, or treatment naive patients. Can you, can you give us, can you give us maybe a sense kind of what percentage of those now are treatment naive as a percentage of the total? Just some thoughts. Gross to net, should we sort of assume that you're going to be in the high twenties, and that's kind of where you're going to stabilize this year, Philippe?

I think it was kind of in the 25% last quarter. Thank you.

On your first question, yes, that's exactly what you're saying. Increase of first-line patients quarter after quarter. We expect this, you know, first-line patients to come on drug to keep increasing over the year. As I said, if we stay on the same rhythm of +35% roughly every quarter, that takes us to consensus. If we go beyond that will help us to beat consensus. That's the dynamic here. To your point about patients on drug today, you know we have limitations with our data, it's kind of hard to answer to that question. You know, you can run your own estimate based on our first-line patients. It's a very good tolerability profile, plus what we said about late line versus first line. To the point about, I think your second question was about GTN.

Yes, it's pretty mechanical if you think about it. You have a increase of 340B. If you look at the CPI-U, the index rate for inflation between June, the time we launched, and December, you can see it's pretty much aligned. For all of 340B and Medicaid patients, this basically drive our gross to net higher by the amount of our price increase. That makes sense to you all. If you think about that, yes, we will be around 30, and we expect to stabilize around that level as gradually inflation start to ease on our inflation penalties, if that makes sense. I can elaborate if it's not clear to you where we are. That's where we are, and we think again, it's very much aligned with what we said in the previous quarter.

Really no surprise there.

Your next question comes from the line of Boris Peaker with Jones Trading. Your line is now open. Please go ahead.

Great. Thanks for taking my questions. Just want to understand, how is the duration of therapy in some of these first-line patients compare to your expectation based on the clinical trial results?

I mean, it's still early now. You know, They're clearly staying on way longer because that's why our revenues are going up, that's why our, you know, our as we would expect. You know, we expect them to be on for an average of over 4 years. We won't know until we get to the 4th year. I think we feel very confident that if you look at the discontinuations, as Colleen said earlier, almost all of our discontinuations are from late line patients, not early line patients. Just as we would expect.

As we mentioned earlier.

Got-

You know, side effects profile is exactly aligned, there is no reason for a said patient to stop the drug.

Got it. With the recent addition to NCCN guidelines, can you see an inflection with that? Like, can you see how much that really benefited, or is that kind of just in the background, and it's not something that could be noticed?

You know, I think that it's just there's always lag in this stuff. You know, the first NCCN change was a year ago, and it took a while for practices to actually realize that IO is actually contraindicated in this disease. We're just starting to see some practice shifts there. That's, you know, that's a year after that guideline came out. These CNS guidelines are great. The awareness was already pretty high that ROS1 is a brain tropic disease. I think the guidelines, the impact of these guidelines might be appreciated a little bit earlier than the original ones. IO, with IO is a pretty ingrained practice in many centers, but everyone knows that when you get a brain met, you're not gonna do well. I think I'm guessing that the NCCN guidelines will be appreciated maybe a little sooner.

It's all good direction for us because everything the NCCN is saying is basically take control.

Great. Lastly, do you expect to issue annual sales guidance sometime this year?

You know, I think we're getting to the point where we now have hundreds of patients under our belt. When we see growth the way we're seeing it, I think we would probably be willing to issue guidance at some point in the future.

Great. Thanks for taking my questions.

One

Your final question comes from the line of Sylvan Turcan with Citizens JMP. Your line is now open. Please go ahead.

Hey, how's it going? This is Josh on for Sylvan. Thanks for taking my questions, and congrats on the results here. Seems like we have gotten a lot of color on the CNS efficacy, but maybe could we get the team's perspective on the comparison of taletrectinib and CNS maybe to emerging clinical candidates rather than what's already been improved? What do we know here? Maybe not to be too repetitive, but how does the CNS NCCN guideline reinforce the benefit here?

Well, I mean, the nearest competitor that's not yet approved has so far an intracranial response rate of 45% while excluding oncogenic drivers. Ours is 21 percentage points higher than that at 66% without excluding oncogenic drivers. That's all I can say about the CNS data that are available today for competitors. If you look at our intracranial responses compared to the approved TKIs, Ibtrozi is far higher than that. Even compared to up-and-coming competitors, as I said, there's no one close so far on intracranial response rate in the second line setting.

Your next question.

Great. Thanks.

Your next question comes from the line of Michael Yee with UBS. Your line is now open. Please go ahead.

Hey, guys. This is Matt on for Mike. Thanks for squeezing us in. I just wanted to ask a quick one on the IDH1 program. Could you just remind us what the standard of care is there in that high-grade glioma setting? Speak to what PFS would be clinically meaningful, both in the broader population and then also on that ORR readout that could come maybe next year in a subset of patients. What would a good result look like, and what could next steps be in that smaller subset? Just turn us through any kind of nearer-term milestones for the IDH1 program. Thanks so much.

You know, the SIGMA trial is a placebo-controlled study. Given the fact that there's absolutely nothing approved for the management of high-grade glioma, the management of high-grade glioma today is surgery for tumor debulking, radiation, and chemo. As you know, the patients don't do well when they have multiple surgeries. You can't just keep debulking the tumor since it's in the brain. Chemo and radiation are just not effective with very low response rates. For a response rate, we would be looking anything north of 20%, you know. We think that anything north of 20% for an indication that has absolutely no other therapies would be certainly a response where we can go to FDA and have a discussion about approval pathway.

We feel pretty good about that, especially given the data we've presented so far. For grade 3 oligodendroglioma, those are less aggressive than the grade 4 astrocytomas, which are GBM. We would expect response rates to be even higher because it's an a little bit of an easier indication to treat. Again, I would say anything north of 20%, we would think the FDA would be pretty interested given the fact there's nothing even in grade 3 oligodendroglioma. We think anything in that range would be potentially an approvable pathway.

There are no further questions at this time. I will now turn the call back to David for closing remarks.

Well, we just wanted to thank you all for your support. We're really excited about what we are seeing with the Ibtrozi launch, it's gone pretty much the way well we'd hoped we continue to, you know, we can't wait for our next quarter 'cause we'd love to report our next quarter earnings we hope that you'll follow up with great enthusiasm. Thank you very much.

This concludes today's call. Thank you for attending. You may now disconnect.

Hello, and welcome to Nuvation Bio's Fourth Quarter and Full Year 2020 Financial Results and Corporate Update Call. Today's call is being recorded, and a replay will be available. [Operator Instructions] Now I'd like to turn the call over to JR DeVita, Executive Director of Corporate Development and Investor Relations at Nuvation Bio. Please go ahead.

Thank you, and good afternoon, everyone. Welcome to the Nuvation Bio Fourth Quarter and Full Year 2025 Earnings Conference Call. Earlier today, we released financial results for the quarter and year ending December 31, 2025, and provided a business update. The press release is available on the Investors section of our website at nuvationbio.com and a recording of this conference call will also be available on our website following its completion. I'd like to remind you that today's call includes forward-looking statements, including statements about the therapeutic and commercial potential of IBTROZI and safusidenib, the components of our anticipated product revenue, expected milestone payments and our cash runway. Because such statements deal with future events and are subject to many risks and uncertainties, actual results may differ materially from those in the forward-looking statements. For a full discussion of these risks and uncertainties, please review our annual report on Form 10-K, which we filed with the U.S. Securities and Exchange Commission today. Joining me on today's call are our Founder, President and Chief Executive Officer; Dr. David Hung; our Chief Commercial Officer, Colleen Sjogren, and our Chief Financial Officer, Philippe Sauvage. David will provide an overview of our key achievements in 2025 and other business updates, Colleen will provide details on the commercial launch of IBTROZI and Philippe will discuss our financial, partnering and operating updates. David will then conclude with closing remarks. Now I'll turn the call over to Dr. David Hung. David?

Thanks, JR. Good afternoon, everyone. Thank you for joining us. 2025 was a pivotal year for Nuvation Bio, and I'm pleased to discuss our full year and fourth quarter results with you today. Our most significant achievement occurred on June 11 with the full U.S. FDA approval of our first therapy IBTROZI, indicated to treat people living with advanced ROS1-positive non-small cell lung cancer, or NSCLC. Since then, we've been working tirelessly to bring IBTROZI to patients with this aggressive disease. And based on the number of patients who have started our therapy, and the confidence we have in this differentiated profile, we believe that IBTROZI is becoming the new standard of care for ROS1-positive NSCLC. By the end of 2025, 432 new patients started IBTROZI, including 216 in the fourth quarter. For IQVIA data, patients are being prescribed IBTROZI at a rate that is approximately 6x faster than the 2 prior ROS1 TKI launches over their first 2 full quarters following approval. Our fourth quarter patient starts also reflect an increase the 204 new patient starts in the third quarter during the time of year that may be impacted by seasonal factors. We continue to see a steady cadence of new patient starts in the first 2 months of 2026 from those who have filled a TKI, those currently on a TKI, who have switched to IBTROZI, and those naive to therapy. This broad patient mix further highlights the strength of our launch and collective belief in our medicine. Feedback from key opinion leaders, daily interactions with health care providers and results from our market research have consistently been overwhelmingly positive. Since launch, we've learned that IBTROZI's efficacy profile resonates strongly with physicians and equally important, its safety profile, especially limited CNS toxicity may allow earlier line patients to remain on therapy for years. An essential factor in a space for long-term duration therapy is paramount. As I mentioned, and consistent with this, we continue to see switches to IBTROZI from all 3 of the other therapies approved for ROS1 positive lung cancer. The reasons for these switches include disease progression, tolerability challenges, brain penetrants and physician confidence in the strength of IBTROZI's clinical data, particularly in the durability of response. I'm thrilled with how our team has executed despite the fact that rare disease launches always provide a variety of challenges. Their efforts have resulted in significant impact and most importantly, patients, but also on how providers choose to treat this disease. Colleen and Philippe will provide more detail on launch dynamics and net product revenue later in the call. Looking ahead, we are focusing on increasing our prescriber base and identifying more newly diagnosed first-line patients to be treated with IBTROZI. We believe that treating these patients will significantly increase the collective time our active patient population stays on therapy while we continue to simultaneously treat patients in the later line setting, who are in urgent need of our medicines. We also plan to present additional long-term IBTROZI data at multiple medical conferences in 2026. As a reminder, on our prior earnings call, we reported that as of August 2025, IBTROZI's median duration of response has now reached 50 months in a pooled analysis of TKI-naive patients in the TRUST-I and TRUST-II pivotal studies, population of which IBTROZI has previously shown an 89% confirmed overall response rate or ORR. We believe these long-term IBTROZI data represent the greatest patient benefit seen to date in ROS1 positive NSCLC. And unlike ongoing studies of other ROS1 TKIs, our pivotal study did not exclude patients with other concomitant oncogenic mutations making the results with IBTROZI, we believe, representative and applicable to real-world patients. We look forward to providing more clinical analyses from the August 2025 data cutoff in the first half of this year. Our scientific updates in 2026 may also further characterize IBTROZI's unique balance of activity against 2 important targets: ROS1 and TRKb. IBTROZI is 11 to 20-fold more selective for ROS1 and over TRKb and remains strikingly potent against ROS1 with picomolar level inhibitory activity. But importantly, IBTROZI also has measured inhibitory activity against TRKb. What is starting to emerge with improved scientific understanding is that the degree to which a lung cancer therapy inhibits TRKb, in addition to its primary oncogenic driver, may play a significant role in not only controlling the growth of the primary tumor, but may also inhibit the ability of that primary tumor to metastasize and grow in distant sites, particularly in the brain. Remember that ROS1-positive lung cancer has a particularly high propensity to spread to the brain, as 36% of newly diagnosed patients present with brain metastases. And in an additional 50% of cases, the first site of disease progression will be in the brain. We believe the ability to control and even prevent brain metastases in ROS1 positive lung cancer may be 1 of the most important determinants of long-term survival and will be reflected in a therapy's durability of benefit. TRKb is an oncogene, meaning that it drives cancer growth and metastasis and the natural ligand for the TRKb receptor is BDNF or brain-derived neurotrophic factor, as the name implies, this factor is expressed at high levels in the brain and can fuel the growth of cancer cells via the TRKb pathway if that pathway is not inhibited sufficiently. However, too much inhibition has been shown to lead to neurological side effects. IBTROZI is far more potent against ROS1 and TRKb, about 20-fold, which may explain why it has such a high response rate and durability in ROS1-driven lung cancer. And yet, while IBTROZI does have adequate activity against TRKb, this inhibition is measured enough that its dizziness rate is similar to that of crizotinib, a drug that doesn't cross the blood-brain barrier. In a recent commentary in publishing the Journal of Thoracic Oncology, renowned thoracic oncologists, Dr. Ross Camidge, Dr. William Phillips, Dr. Rafael Nemanov and Dr. Diana Sitelli, hypothesized that this selectivity could make IBTROZI the best tolerated next-generation ROS1 inhibitor. And we believe IBTROZI's intentional, but well-tolerated TRKb inhibition may contribute meaningfully to intracranial disease control and ultimately survival without introducing the significant CNS toxicity that has limited other agents, to the point Dr. Camidge and team emphasized in their analysis. Separately, published data have linked uninhibited TRKb signaling to larger tumor burden, higher stage disease, increased risk of CNS metastases and poor outcomes across multiple solid tumors, including lung cancer. In our view, IBTROZI strikes a particularly effective balance, deep durable inhibition of ROS1, paired with measured TRKb activity that potentially supports CNS disease control while preserving tolerability. Interestingly, the only other approved TKI to demonstrate longer durability in TKI-naive patients than IBTROZI is lorlatinib in ALK-positive NSCLC, which showed a median progression-free survival, or PFS, of over 5 years in the CROWN study. Lorlatinib has even greater TRKb inhibition than IBTROZI which we believe is likely related to lorlatinib's high rate of CNS events like mood disorders. However, given the high propensity for CNS involvement in ALK-positive disease, Dr. Camidge speculates that it is lorlatinib significant TRKb inhibition that may account for its high intracranial response rate in 5-year duration of response. We do not view the shared prolonged durability of lorlatinib and IBTROZI as coincidental. Taken together, we believe that IBTROZI's ability to strongly suppress ROS1 while modulating TRKb in a tolerable way could help explain durability intracranial activity and safety profile we continue to observe as real-world use increases. We also continue to envision and develop IBTROZI for a broader ROS1 positive lung cancer population. Based on our label, IBTROZI has been prescribed to a significant number of patients in the advanced setting across lines of therapy. And the next step for us is to move to earlier stage of lung cancer. As previously shared, we have dosed the first patient in TRUST-IV, a randomized, placebo-controlled Phase III study evaluating taletrectinib as an adjuvant therapy for patients with resected ROS1-positive, early-stage non-small cell lung cancer. Adjuvant therapy is fundamentally different from treatment in advanced disease and is an area we targeted for study only after garnering support for multiple lung cancer KOLs. These patients have undergone surgery, often feel healthy and are understandably unwilling to remain on our therapy that is difficult to tolerate or interferes with daily life. As a result, only a drug with a manageable and highly tolerable safety profile can realistically be developed in this study. We believe it is particularly meaningful that IBTROZI is the only ROS1 inhibitor currently being studied in the adjuvant setting, and we view this as a further testament to its safety and tolerability profile. Across our clinical database of 337 patients with advanced ROS1-positive non-small cell lung cancer, only 1 patient discontinued treatment due to any of the 6 most common adverse events, including diarrhea, nausea, vomiting, dizziness or liver enzyme elevations. While this does not summarize all adverse events detailed in our prescribing information, this level of tolerability for our most prevalent adverse events is critical when considering use immediately following surgery and why we believe IBTROZI may provide benefit in the adjuvant setting. Lastly, we not only aim to bring IBTROZI to patients across the ROS1 positive disease spectrum, but also the patients and providers around the world. Last year, we received approval for IBTROZI in China and our partners at Innovent Biologics and in Japan with our partners at Nippon Kayaku. In January, we were thrilled to announce a strategic partnership with Eisai to develop IBTROZI in Europe and other ex-U.S. territories outside China and Japan. We are working diligently with Eisai to submit IBTROZI for approval in Europe in the first half of this year. In short, we believe our continued launch performance, the latest updates reconfirming IBTROZI's efficacy and tolerability profile and additional development, regulatory and commercial achievements, all show why we believe IBTROZI is becoming the standard of care for ROS1-positive lung cancer. We also made exciting progress developing our second program, safusidenib. Safusidenib is an inhibitor of mutant IDH1 being developed for IDH1 mutant glioma, a devastating type of brain cancer. Importantly, not only are there very few treatment options available for this disease, but these younger patients are typically diagnosed between the ages of 38 and 45. Clearly, there is an opportunity to make an impact for these patients and their families. IDH1-mutant glioma described using 2 types of terminology, grade and tumor classification. A grade of a glioma indicates the level of risk while the classification describes certain biological features of the tumor. Malignant IDH1 mutant tumors can be defined using grades 2, 3 and 4, and these tumors can be classified as an oligodendroglioma or an astrocytoma. Both descriptors together indicate the level of risk, aggressiveness of disease and estimated time patients may live with their disease. To simplify this, we describe both grade 2 oligodendroglioma and astrocytoma as low-grade IDH1-mutant glioma, while high-grade IDH1-mutant gliomas consists of grade 3 oligodendroglioma, grade 3 astrocytoma and grade 4 astrocytoma. Each year, there are approximately 2,400 new cases of IDH1-mutant glioma in the U.S., split almost evenly between the low-grade and high-grade population. The key difference is that based on published median overall survival data, patients with low-grade IDH1-mutant glioma live approximately 12 to 20 years, while high-grade patients live on average approximately 2 to 12 years. The only targeted treatment option available for patients with IDH1-mutant glioma is vorasidenib, which was approved by the U.S. FDA in August 2024, where only patients with grade 2 oligodendroglioma and grade 2 astrocytoma are the low-grade population. In this pivotal INDIGO study, which included 168 Grade 2 patients with non-enhancing or low-risk disease in the active study arm, vorasidenib demonstrated a median PFS of 27.7 months, a 41% progression rate at 24 months and an ORR of 11%. In a separate Phase I study of 30 patients, vorasidenib showed a confirmed ORR of 0% in a high-grade enhancing population, which is not included in its approved label. In November, results from our Phase II study of safusidenib for low-grade IDH1-mutant glioma were published in neuro-oncology. This patient population was treated with safusidenib following surgery and prior to radiation or chemotherapy. The same types of prior treatment patients received in the INDIGO study. In this study of 27 patients, safusidenib demonstrated a median PFS have not reached a 12% progression rate at 24 months and a confirmed ORR of 44%. As a reminder, in a Phase I study of 35 patients, safusidenib also showed a 17% confirmed ORR including 2 complete responses that lasted multiple years in a high-grade enhancing population. As we've discussed previously, vorasidenib is already approaching a $1 billion U.S. net revenue run rate, less than 2 years after its approval. This rapid commercial uptake underscores both the unmet need and the willingness of physicians to adopt targeted therapies in this setting. While we acknowledge the inherent complexity and limitations of cross-trial comparisons due to differences in study design, patient populations, endpoints and sample size, recently published data in neuro-oncology and data from our Phase I study highlights the encouraging clinical profile of safusidenib and its potential to address significant unmet need in this patient population. In parallel, we continue to learn more about safusidenib's safety profile. While the drug is generally well tolerated, we observed a distinct set of dermatological related adverse events, including alopecia, arthralgia, and skin hyperpigmentation. We believe the presence of these events may be due to a different pharmacological profile of safusidenib, and we continue to investigate if safusidenib may inhibit targets other than IDH1. Importantly, the drug-related discontinuation rate in the Phase II study, which was conducted at the pivotal 250-milligram twice-a-day dose remains low at approximately 8%. The patients, who had discontinued therapy, were able to recover with interruption and appropriate management. Based on data generated to date, we announced in February that we started enrolling our pivotal Phase III study called SIGMA. This global randomized study is evaluating the efficacy and safety of safusidenib versus placebo for the maintenance treatment of high-risk and high-grade IDH1 mutant glioma following standard of care. Specifically, the study population includes 300 patients with grade 2 or grade 3 astrocytoma, who show certain high-risk features in all patients with grade 4 astrocytoma. As an important reminder, these patients have no FDA-approved targeted therapy options. Considering the high unmet need and the exciting profile of safusidenib, we are optimistic about the speed of recruitment in this trial. Due to the sizable population being enrolled to support approval, and the use of PFS as the primary endpoint, we expect this study will read out in 2029. Importantly, we recently announced the initiation of a second nonpivotal cohort evaluating safusidenib in patients with grade 3 oligodendroglioma, a patient population that is considered to be within the lower risk end of the high-grade glioma spectrum. This grade 3 oligodendroglioma study will enroll approximately 40 patients with measurable disease, including patients with residual disease following surgery for those with recurrent disease and will evaluate ORR as the primary end point. Given that we have 31 sites activated in the U.S. already, we estimate that we will be able to provide a full study readout in 2027. Importantly, if we see significant objective response in this study, we will meet with the FDA to discuss the results and potential options for further development, aiming towards an accelerated approval pathway. Patients with grade 3 oligodendroglioma frequently seek alternatives through the cumulative toxicities associated with prolonged radiation and chemotherapy given the relatively young age at diagnosis and median life expectancy of 12 to 14 years. Yet, there are currently no approved targeted therapies for this group either. While there are approximately 400 new grade 3 oligodendroglioma cases diagnosed annually in the U.S., we believe this represents a much larger prevalent population of several thousand patients, who are underserved today and could meaningfully benefit from an effective, well-tolerated targeted therapy. We view safusidenib as an ideal complement to IBTROZI as we now have an approved therapy and a late-stage program that both address a clear unmet need for patients. We look forward to generating updates from our evaluation of safusidenib as quickly as possible. Lastly, our drug-drug conjugate or DDC platform represents a novel modality in targeted cancer therapy designed to conjugate 2 small molecules, a targeting agent and a warhead. While we discontinued development of our first DDC NUV-1511 in the fourth quarter, we were able to gather valuable insights into DDC development and are already applying these learnings to new preclinical candidates in our pipeline. We hope to have updates on the next phase of our DDC program by year-end. We remain confident in our capabilities to successfully execute our program goals, build lasting value and most importantly, serve patients. With that, I'll turn it over to Colleen to provide more color on the launch of IBTROZI.

Thank you, David, and good afternoon, everyone. I'm excited to report that the launches of IBTROZI continues to build what we believe is market defining momentum in a rare disease indication. From our approval in June through the end of 2025, we treated 432 new patients with IBTROZI, which represents a rate that is 6x faster than the 2 most recent TKI launches in ROS1-positive lung cancer. As David mentioned, we continue to see patient starts from 3 distinct populations. Patients who have failed prior ROS1 TKI switches from patients currently treated with ROS1 TKI and newly diagnosed patients who are TKI naive. This momentum underscores that a significant medical need in ROS1-positive non-small cell lung cancer still exists. And it is clear to us that the efforts of our incredible team our tailored strategy and IBTROZI's compelling efficacy and safety profile are well positioned to address this need. By the end of the year, we had engaged all top-tier target accounts and our field-facing interactions reinforce that physicians are quickly gaining comfort prescribing IBTROZI for their patients. Prescriptions have been written in 100% of our 47 sales territories by multiple repeat prescribers and per IQVIA data, we are showing significant growth in market share of new patients treated with a ROS1 TKI. On the market access front, payer engagement continues to be constructive and effective. At this point in our launch, we have achieved broad coverage to label for patients across the country. Finally, our patient support program, Innovation Connect continues to help eligible patients receive support and access to IBTROZI, while reimbursement is secured. Now I'd like to walk you through some of the key dynamics of our launch to further characterize, where we are today and what lies ahead. As we've noted, IBTROZI is being prescribed across both TKI-naive and TKI-pretreated patient populations. With our extremely high response rate in TKI-naive patients, we do expect an overwhelming majority of this population to be treated with IBTROZI for an extended period, which we are now starting to see. Still, it is typical at the beginning of any oncology launch that the majority of patients who start therapy are in need of a third or even fourth medicine and the response and duration of treatment will unfortunately be lower. While we expect IBTROZI to benefit these patients for a relatively shorter duration, meaning most will not remain on therapy for multiple quarters, we view this as an encouraging signal that providers are motivated to offer their patients a differentiated therapeutic option. While we have limited visibility into the characteristics of all IBTROZI patients, we do have some insight into the segment of patients that come through our Innovation Connect support program and specialty pharmacies. Within this group in 2025, we know that about 75% of discontinuations came from later-line populations. We're encouraged that IBTROZI is providing another meaningful option for patients across lines of therapy and the patterns we've observed through this experience have given us 3 important insights. First, discontinuation is strongly correlated with the line of therapy. IBTROZI has been well tolerated by first-line or TKI-naive patients, who have shown extremely high response rates in clinical trials. We also know that median DOR and PFS are much longer in this population than in the TKI pretreated population. Therefore, we expect to see far lower discontinuations as we move IBTROZI upstream in the treatment paradigm. Second, the fact that a significant share of our new patient starts at the beginning of launch were in the third-line plus setting helps explain the gap between an unprecedented number of patients starting IBTROZI and our net product revenue growth from the third to fourth quarter. As I mentioned, this late-line population unfortunately tends to discontinue therapy relatively quickly. And as a result, the majority of these patients are not treated for multiple quarters. which directly impacts near-term revenue trends. By the end of 2026, we expect to see a more direct correlation between growth in new patient starts and growth in our revenue. As a larger portion of active patients treated with IBTROZI shift to those who are newly diagnosed. Lastly, first-line IBTROZI patients are the main driver to our long-term growth. And the reason we are so optimistic about our launch is because we continue to see a meaningful, steady increase in first-line patients starting on IBTROZI in recent months. Our data, including the number of previously treated patients in the market suggest that we are expanding the ROS1 TKI landscape rather than simply competing for a fixed pool of patients. We anticipate this will directly impact the number of active patients on IBTROZI over multiple quarters going forward. And we plan to elaborate further on this trend as we collect more data in 2026. Switching to another key area of our launch dynamics, we continue to see use from providers in both academic and community settings nationwide. As of the end of 2025, approximately 70% of our new patient starts had come from the academic centers or IDNs and 30% from community centers, compared to a 75%, 25% split at the end of the third quarter. It is typical in a rare oncology launch that immediate uptake occurs in the academic setting. That said, this gradual shift towards the community is expected to increase over time, and in turn, will support prescription growth and momentum. This is important because the majority of ROS1 patients will be found and treated in community centers. Looking ahead, we are focused on deepening adoption and continuing to raise awareness of the importance of patient identification. Today, DNA-based testing should identify roughly 3,000 advanced ROS1-positive non-small cell lung cancer patients annually in the U.S. And as the field shifts towards also utilizing RNA-based testing, which publication suggests may help to detect approximately 30% more ROS1 patients, the annual addressable population could potentially expand to roughly 4,000 advanced patients in the U.S. alone. Because of IBTROZI's unprecedented durability, especially in the TKI-naive setting, this small incidence population turns into a substantial prevalence population, generating an opportunity to treat a meaningful number of patients over a period of several years. Finally, I want to commend the efforts of our commercial team. We believe their hard work has positioned IBTROZI as the emerging market leader in this disease. There is still educational work that needs to be done, but I am beyond thrilled we have been able to deliver this therapy to so many patients in need. With that, I will now turn it over to Philippe.

Thanks, Colleen, and good afternoon, everyone. For detailed fourth quarter 2025 financials, please refer to our earnings press release, which is available on our website. Now let's go over some important highlights of the quarter. I'm pleased to inform you that in the fourth quarter, we generated $41.9 million in total revenue, including receipt of the milestone payments, which brings our total revenue for 2025 to $62.9 million. These figures include $15.7 million and $24.7 million in IBTROZI net U.S. product revenue in the fourth quarter and full year 2025, respectively. As Colleen mentioned, we know a significant share of our product revenue was driven by patients, treated with IBTROZI as a third line plus option. And unfortunately, these patients do not remain on therapy for very long. We do expect that over time, the bulk of our sales will be from first-line patients, staying on drug for many years. This trend of more TKI patients benefiting from IBTROZI is what makes us extremely optimistic about our long-term growth. As this occurs, we'll be able to see the true impact of our 50-month median DOR on revenue growth. Still, this dynamic will play out gradually over time, and we will continue to update you on emerging trends. Our channel movements are stabilizing as we expected we would. And today, we believe our specialty pharmacy and distribution partners hold approximately 2 to 4 weeks of inventory on hand. This is standard and shows that our product revenue has been driven by true patient demand for IBTROZI. In addition, our free trial program continues to provide patients with IBTROZI before they are fully reimbursed and this prescription generate full commercial revenue in the patient's second month on therapy at the latest. Our approach to access has been extremely successful and has resulted in broad coverage for patients across the country. As I mentioned on our last call, our level of gross to net will naturally increase as we enter more contracts that allow us to cover more lives. As a result, our gross to net now sits around 25%, and we would expect this to slightly increase before stabilizing long term. This is based on our balance of business with commercial, Medicare, Medicaid and 340B plans and the limited amount of free medicine provided to date. The remaining revenue for 2025 came from our collaboration and license agreements, including milestone payments, royalties, product supply and research and development services. In addition to ongoing royalty revenue from our partner in China, Innovent Biologics, we began receiving royalty revenue from our partner in Japan, Nippon Kayaku following regulatory approval and reimbursement in November, an event for which we received a milestone payment of $25 million. We also continued our mission to bring IBTROZI to as many patients as possible outside of the United States. In January, we announced our strategic partnership with Eisai, covering Europe and select territories outside of China and Japan. As a reminder, commercial rights in China and Japan were previously out-licensed and when those deal values are combined with the Eisai deal, this represents a total deal value of nearly $520 million for most territories outside of the U.S., but still excluding Latin America. Under our agreement with Eisai, we received an upfront payment of approximately $60 million and are eligible for a payment of about $30 million upon European approval. We will also earn up to $140 million in milestone payments upon the achievement of certain sales level, in addition to double-digit tiered royalties up to the high teens on net sales in EIsai's territories. This partnership meaningfully strengthens our cash position, allows us to reinvest in our own programs and allows us to precisely focus on our commercialization efforts in the United States. Looking ahead, we expect to file IBTROZI for approval in Europe with Eisai in the first half of this year. On the expense side, R&D expenses were $34.3 million for the quarter and $115.1 million for 2025. We continue to invest in IBTROZI and importantly, are focused on bringing safusidenib to patients as quickly as possible. SG&A expenses were $40.3 million for the quarter and $151.6 million for 2025, primarily driven by support for commercialization. As discussed in prior quarters, we do not expect material increases in commercial head count going forward. Turning to the balance sheet, we ended at 2025 with $529.2 million in cash, cash equivalents and marketable securities. This cash position has increased by approximately $60 million following the upfront payment we received from Eisai. As a reminder, an additional $50 million remain available to us under our term loan agreement with Sagard Healthcare Partners until June 30, 2026. Our robust capital position gives us a flexibility to invest in our launch and pipeline, while also enabling the evaluation of additional business development opportunities that can create shareholder value, similar to our acquisition of AnHeart. Based on our current operating plan, revenue trajectory and disciplined expense management, we do not anticipate the need for additional external financing to reach profitability. We remain a well-managed and agile organization that is positioned to execute our 2026 objectives. I'll now hand it back to David.

Thanks, Philippe. When I take a step back and reflect on our 2025, what gives me particular confidence is the foundation we've built for what comes next, an increasingly durable commercial franchise, a pipeline with meaningful long-term potential and a capital position that allows us to execute with discipline and flexibility. I'm incredibly proud of the team and grateful for the support of our investigators, partners, shareholders and most importantly, patients as we continue this journey into 2026. With that, I'll ask the operator to open the line for questions.

[Operator Instructions] The first question comes from the line of Farzin Haque with Jefferies.

Congrats on the progress. So you're not providing any revenue guidance yet for 2026. But what are you seeing in 1Q in terms of first-line and second-line plus mix that gives you confidence in meeting the consensus mark of $150 million for the year?

Farzin, thanks for the question. This is David. So we're -- as we said, we feel that the patients are out there. We think that the robustness of the first 2 quarters shows that we are able to capture a lot of -- a significant number of these patients. Just -- if you look at the number of new patient starts, we think the trajectory has been pretty good. As we did say, the majority of our NPS, our new patient starts to date have been later lines, as you would expect. But we are seeing increases in first line news. But we've also made the point previously that we don't have visibility into the majority of these patients. because unless they come to the Nuvation Connect Portal, we don't actually necessarily know -- what we need to know about them to know what line of therapy they are. But what we've seen we do see a majority of our use currently in later lines of therapy. Clearly, those aren't the ultimate price. Those patients, especially in the third-line study, have relatively short durations of response. And so that would lead to a much higher discontinuation rate. In fact, the vast majority of the discontinuations that we have seen are due to these late-line patients. But we are confident that over time, we're going to see growth moving toward to the second line and then to the first-line setting. And so we think that the patients are there and we think that ultimately we will start to see first-line use a much longer durability and then the revenue stack that we've previously talked about.

Perfect. And then for safusidenib, can you provide an update on the current enrollment trajectory for the Phase III? And do you anticipate any interim analysis before the projected 2029 completion?

We haven't commented on our enrollment. Those patients are definitely there. As you know, there's absolutely nothing for high-grade disease or vorasidenib approved only in a subset of low-grade disease. So we think that, that trial will enroll well. But it is a PFS study. So it's going to take a while to get the number of events we need to see it -- to see the results. So that's why we've guided to a 2029 readout for that. But I would say that the patients are there. We feel very confident in the capabilities of our clinical operations and clinical development team. So we think that trial will enroll on target. We will not be any later than 2029 in reading that result out. And also -- I'm sorry, we don't have any plans right now for interim analysis. I forgot to mention that.

The next question comes from the line of Leonid Timashev with RBC.

I just want to ask a little bit more about the IBTROZI trajectory. I guess, in the fourth quarter, there was potentially some seasonality, maybe changes in diagnosis has also been a historically weaker quarter for some lung cancer drugs. I guess how should we think about the seasonal bounce back we should see in the first part of 2026. Is any of those maybe weather-related seasonality is going to pull through into the first quarter? And any kind of payer dynamics that we should be thinking about in the first quarter as well?

The data set that we discussed, the seasonality was still based on just ROS1 TKI use in the last 4 years. So while there was a somewhat lower use in the fourth quarter, I would say, it's hard to know if that would necessarily predict about what's going to happen going forward. We feel confident the patients are there. We know -- we know that from -- just from our interactions with all the centers that we're at, these patients are there. We think that with -- while there's always way to improve the amount of genetic testing, we think that new patient diagnosis will happen. We know there's a prevalence pool of over 1,000 patients who are TKI experience. Clearly, those are the ones that are the -- going to be the easiest ones to identify because they've already been on our ROS1 agent. And clearly, we've already captured a significant number of those. But so I don't really know if the seasonality will necessarily result in a bounce back. It could, but I can't tell. And as you know, we just had a significant blizzard recently. So that was a pretty significant weather event. But, I don't, again, know if that will change anything.

The next question comes from the line of Michael Yee with UBS.

This is Matt on for Mike. I wanted to ask on your expectations just kind of further trajectory cadence of patient uptake for the year, especially with maybe a competitor entering the market in the second-line setting, later in the year. How do you expect to see kind of the market shake out? I know you guys talked about TRKb as an important factor for you guys? Just kind of speak to the longer-term competitive landscape here would be great.

Sure. Well, as you've already seen from the first 2 quarters that we're over 200 new patient starts per quarter so far, and we think that's going to continue. And I've already said that the majority of those are later line therapy. So if you talk about second or third line, we've already captured a significant amount of about 1,000 TKI experienced patients that we believe are out there. So -- by the end of the year, we think that we will have probably captured a significant majority of all those patients. And as I said, what we're looking for is growth in the first-line setting. And given our 50-month duration of response, which is unmatched and our tolerability profile, we would expect to claim the majority of that. So that's what we're really looking for. We're not really looking any more at later-line use because that's -- we've been there and we've actually captured much of that. But we're looking towards the first-line growth, and that's what everyone should be focusing on. I think the one of the most compelling features of our drug is its durability. As you know, patients and doctors decide on therapy based on efficacy and by far, the most important metric for efficacy is how long that drug will work. We think that TRKb is an important factor in durability. If you look at the lorlatinib data, there is no TKI with longer median PFS that lorlatinib in the CROWN study, which is over 5 years. And lorlatinib has significant TRKb activity. And if you look at CNS control rate, it's really high. And as you know, for a cancer like ROS1 lung cancer, which is so CNS tropic, where it starts in the brain more than 1/3 of the time and goes to the brain another 50% of the time. It's really important to have as robust control of the CNS as you can. And we think that TRKb will play a significant role there. And as I've discussed previously, if you look at our intracranial response rate and our second line setting at 66%, that's not been matched. There's nothing close to that. So -- we think that the profile of this drug is extremely compelling, tolerability, efficacy, we're looking to move the first line, and we think that's where the unmet need will persist after we've already taken care of the later lines of therapy, which we are capturing. So we feel bullish. We feel we're just where we need to be and things are heading in the right direction.

The next question comes from the line of [ Mary Coleman ] with Clear Street.

Congratulations on the progress. For taletrectinib or IBTROZI, just in general, how much adoption of TKIs any -- in the first-line setting? Have you observed following the NCCN guideline changes, especially in the community setting or community practices? And what factors or initiatives could further drive first-line use of IBTROZI there? And I have a couple after that safusidenib.

Sure. So we did note that if you look at the other TKIs that before we were approved, we actually did see an increase in scripts in the other TKIs after the NCCN guidelines came out. So I think those guidelines were helpful, and they did increase TKI use. Now since the introduction of IBTROZI to the market after our approval, we've seen clear growth from the little glimpse that we see, we have been seeing increasing first line use, but it's -- again, our glimpse into that window is still limited at this point. I don't -- I can't really speak in detail about it, we'll need to wait until we have maybe a quarter or 2 more under our belt. But we feel that things are going in the right direction. We think the NCCN guidelines are going to be a real benefit. Just the amount of IO/chemo use before those new guidelines was significant. And even after the guidelines, we still think that's a challenge. But I think that now that IO is actually contraindicated, I think that's only going to help drive the appropriate therapy. And as I've said earlier, there is no other therapy that can match our metrics on efficacy or even tolerability. So I think that we are well positioned to capture this. And I think the NCCN guidance will be a significant tailwind. But I think the greatest in the tailwind we have is just the strength of our label.

All right. That's helpful. And for the Phase III astrocytoma trial, what efficacy outcomes would be considered both clinically meaningful and commercially attractive. And -- what is the kind of estimated market opportunity or value that it can provide? And for the other cohort, what was the rationale for adding the oligodendroglioma patients as a separate cohort? And how might this become a value-generating program?

Yes. That's a great question. So when I think about glioma, I divide it into a pie about 50-50 low grade on 1 side and about 50% high grade on the other side. But within those subsets, you can divide them again. So each side, both the lower and high grade have a low-risk and high-risk features. Currently, vorasidenib is only approved in 1 of those pieces of that pie. It's only approved in low grade, low risk. That means what remains for an opportunity is high risk, low grade, low risk; high grade and high risk high grade. So the Phase III study that we're doing targets 3 of those parts -- 3 pieces of that pie. Instead of the vorasidenib 1 piece, our Phase III trial targets 3 of those pieces. So we think that's a very significant unmet need for patients. It's clearly a much larger commercial opportunity. And so we -- to get that drug approved in those 3 pieces of that pie, we have to do an overall -- we have to do a progression-free survival study, which is why -- we just need to enroll a certain number of patients. We have to follow them for a certain amount of time, and that's why the readout is 2029. Now that said, we also think that it's important for us to get this drug out to patients as quickly as possible. And there is yet another piece of that pie that isn't currently being adequately addressed, which is -- if you look at all grade 3 oligodendroglioma patients, these patients are a little bit different because unlike the Phase III study patients, which I talked about, those patients have completed surgery and radiotherapy and somewhere between 6 and 12 cycles of temozolomide. So as a result, they don't tend to have measurable disease. When you don't have measurable disease, you have to use PFS. You can't use response rate. Well, clearly, response rates are much faster readout than PFS. So the grade 3 oligodendroglioma study is important because those patients have measurable disease. These are patients who have not had a resection or not a recent one, have, in general, significant measurable disease, and they just can't take because these patients can live 15-plus years, they just can't take chemotherapy or radiotherapy every day for the next 15 years. I mean it would just be impossible to tolerate that. So we think it's a huge unmet need. But because now these patients have measurable disease, we can use overall response rate, unlike the SIGMA Phase III study, which is a PFS readout -- this will be an ORR, an overall response rate readout by RANO 2.0 criteria. So we think that if we can see a significant response rate in that study, and we've guided to reading that study out by 2027. Clearly, that's a much earlier readout. We know there are examples of all the glioma drugs being approved on a very small data set with response rate, we know that day 1 glioma drug was approved on less than 80 patients with an overall response rate. So clearly, we see a really robust response rate. We think that would -- that would justify a discussion with FDA as to what would it take to get this drug approved to get it to patients a lot sooner than a readout in 2029 for the Phase III study. So we think that it's important to do the study because, number one, it's a really important unmet need. These patients just cannot take chemo and radiation for 15 years. That's just not tenable. They need something that's much better tolerated, much more convenient. And secondly, it gives us an opportunity to see the activity of this drug in an area where nothing else works. Vorasidenib has no responses in this highway population. The response was literally 0%. So we think that it will give us an opportunity to look at the response rate of this drug and potentially initiate a discussion with FDA to just figure out how to get this drug to patients even earlier. We also think that generating data in this subset were nothing works and even vorasidenib has a 0% response rate will compel physicians and patients, who think, hey, this is a drug that has activity where nothing else does, should -- is this a better drug. Is this a more powerful drug. Is it to do things that other drugs can't do. And we think that could potentially influence the glioma market and the practice of what position the patients decide to use or attempt for treating a disease that has relatively few treatment options that is still, at the end of the day, an invariably lethal disease. So we think that the second study is a very important study for all of those reasons.

The next question comes from the line of Mayank Mamtani with B. Riley Securities.

Congrats on the progress. I appreciate the level of detail on IBTROZI launch. Just maybe on the metric should we expect for you to provide the new patient start numbers in the coming quarters, like you have and expect to see this 200-patient quarterly run rate to sort of continue in the coming quarters, including perhaps when there's a competitor entrant later in the year? And also, what's the real world discontinuation you're seeing in earlier line? I know you gave the 75% discontinuation rate in later line. But I was just curious if you had something in frontline, I understand the sample size will be small there? Then I have a follow-up.

So we have said since our very -- since the first quarter that we reported sales that we would continue to look at new patient starts. I think that's an important metric. It's particularly important in the first year where depending on the mix of patients and the duration of response or the rate of discontinuation, your revenues will not necessarily track with your new patient starts, especially as an example of your a third-line patient you just continue in a month or 2, you're not going to have the kind of revenues that you would expect in the first line setting. So we think it's important, and we said this since June 11, when we got approved, that we would focus on new patient starts at least for the first year because I think that's the best metric is our patients using this drug do physicians who want to prescribe it. And over time, what you'll see is that we've said there's only about 1,000 or so TKI-experienced patients. So if you see -- if you continue to see 200 patients per quarter, and we know that at some point, we're going to have captured the majority of that 1,000 patients. That means any growth at all in that 200 number has to be in first-line patients. And while that revenue may not appear immediately because it takes you a year to get stacking. When you start to see that growth in first line, you will see over time revenue stacking. And you will also see a significant increase in revenue. It's just not going to happen immediately because those third-line patients are going to come off, some of them discontinue within a month. And we think those first-line patients will be on for 5 months. So I think that for the next few couple of quarters, we still think NPS is important. But a year into our launch, so by third quarter of this year, we'll have been doing this for a year, and we continue to get 200-plus patients per quarter, and the majority of those are TKI experienced. That means we will have captured the majority of the TKI experience market. So any growth at all in that NPS number has to, by definition, be in first line. So I think that's what you should be looking for. I think the revenues will catch up to NPS with a few more quarters. It's just not going to do it right away, but that's what you would expect.

On the discontinuation on the earlier line.

Oh, yes, sorry. So 75% of our discontinuations came from late-line patients. So -- so very late.

For the patients that we know, as David said, it's a subset of patients, the one that we're going through the hub or patients going through the hub and discontinuing 75% of them were late line, which gives a lot of confidence to us about the fact that, yes, the main patients will discontinue are clearly late line patients. If you go back to our clinical trial, the rate of discontinuation was very low, as you know, 6.5%, right? So this is really what we're going to see. We're going to see some of those late-line patients, unfortunately, as is expected in oncology, not responding very well to a third or fourth line of therapy. That's true in oncology. And what we've seen in our subset going through the hub is that those are the most discontinuation we see by far.

Understood. And then on the nonpivotal cohort SIGMA study that David, you just touched on, is there a threshold on ORR that you may have quantified or have in mind that would warrant that accelerated approval discussion? Sorry if I missed that.

I think that we've seen OR anywhere north of 20%. I mean this is a population, as you said, the biggest glioma drug in the world, vorasidenib has a 0% response rate in that population. So couldn't be lower, maybe, but certainly at 20% or higher, I think that would be extremely interesting.

The next question comes from the line of Greg Renza with Truist.

Congrats on the progress. David, just maybe on your current resource position. As you've commented on the current financial structure and also the path with the IBTROZI launch, maybe providing that path to potential profitability. Just wondering if you could provide a finer point on maybe what that horizon looks like. And related to this, as you've spoken about business development, you've mentioned the complementarity that IBTROZI and safusidenib provide for the pipeline. How are you thinking about adding to that mix especially in light of that focus or that mention of profitability?

So you might recall that last year before we announced the Sagard Healthcare deal, we had said that at that point, we had enough cash to reach profitability. Well, since we made that statement, we raised $150 million with Sagard with another $50 million in debt. And then since then we've done a deal with Eisai, where we got another $60 million, and we'll have yet another $30 million upon European approval submission or approval next year. So we stand by that statement. We -- we have certainly far more cash than we need to get to profitability. Now if we do a significant business development deal that would certainly take some cash. But -- we're aware of the importance of getting to profitability without having to need additional financing. These are still difficult markets. I think that we, in general, we've been relatively conservative on that front. So we'll carefully weigh the upside of a deal. And certainly, any deal we do would have to be what we consider a good deal as we consider AnHeart, we think that was a great deal for us. So any further business would have to be a great deal for us. So we have to be -- we have to weigh the benefits and cons of using our cash and cutting into our runway to profitability. But we feel very, very confident that we'll get to profitability right now easily with what we have on hand. And we do believe that given what we have, we think that further business development is an important -- it's always been an important part of our company growth historically. And we think we will continue to look for opportunities that we think are particularly compelling for us, especially if they can capture some of the synergies that we already have within our company.

That's great. I appreciate that color. And maybe just one last one. If you could just comment on the DDC platform. I think I heard you mention maybe some updates into the year. Just maybe just remind us of your conviction on the platform as you invest at that area of the business?

So we are absolutely convinced that, that platform is real and has real potential. We -- that was a first-in-class compound. It's a first in history compound actually. So we learned a lot with 1511. And it wasn't that we didn't see any responses at all. We did see responses with 1511. It just weren't consistent enough for us to invest $100 million also in a Phase III study. We look at all our all our drug candidates as would this be worth spending $100 million on or should we make it better? And it's something you always have to balance in early-stage programs. So the answer for 1511 was probably not. And we learned enough to figure out how to make it better or to make a DDC better, and we are hard at work doing that. But we feel very confident that our DDC program will yield molecules that will go to the clinic and that we probably will take forward in development and we'll update you all hopefully by year-end this year.

The next question comes from the line of Yaron Werber with TD Securities.

Thank you very much, team, for the question. This is Steven on for Yaron. On the IBTROZI launch, in terms of trying to get more penetration in the first-line setting, where it seems like crizotinib might still be entrenched, what else can you do in terms of increasing the potential for first line? Have you engaged regulators to try to perhaps get a preference in the 1L setting in the NCCN guidelines? And if so, how is that going? And secondly, any update or perhaps any news on the BET inhibitor NUV-868? And then thirdly, on the approval in Europe, I seem to remember that there was in a head-to-head trial versus XALKORI that was thought to be necessary for approval. It seems like that's no longer the case. Can you maybe update on the thinking there?

Sure. Let me take the first couple of questions, then I'll hand to Colleen. So -- so crizotinib is -- you still use a significant amount because it is pretty well tolerated. But as you know, crizotinib does not cross the blood-brain barrier. And when there were no options other than crizotinib, that would have been appropriate. Today, I would consider it about practice to use crizotinib in the first-line setting for -- when you don't really know which patient is going to go on to develop the CNS that way. First of all, 36% of them present with a brain met. But even if they don't -- we know that 50% of them will go on to get a brain met. I can't tell which the 1 of 2 is going to do that. And to give a drug that doesn't have any CNS coverage, in my opinion, as an oncologist is malpractice. I think that is inappropriate for patients. So I can't comment on how long crizotinib will be entrenched. I think that KOLs and patients appreciate the importance of CNS coverage. And I think that's part of our job and Colleen's team is -- that's one of our main messages. I think we have to continue to do that. So I can't tell you that crizotinib will go away. But I do think that over time, it is the absolutely wrong drug to use for this disease. In terms of engaging regulators to get preference in the first line setting, we do actually believe that our drug is differentiated. And we are looking at strategies to have that captured within the NCCN guidance. So on that, I would say stay tuned on that. But we are well aware of the difference in performance metrics of our drug against other drugs. So we think that IBTROZI is an extremely compelling choice for patients and physicians. And we think that should be adequately reflected in all the sources that are available for patients and so -- and so and physicians. And so -- that is not lost on us. Colleen?

Steven, I just want to elaborate a little bit more, so David spoke about -- the patients that we're receiving that have been pretreated, and obviously, progression toxicity that you just spoke to, brain-penetrant. So in addition to those patients, we're also looking to expand the market and you ask what else can we do? So I will tell you that it's our personal mission that we take it very personally that these patients that have ROS1-positive non-small cell lung cancer are going through their patient journey in the appropriate way. And 1 of those ways is to ensure that they're being tested before a treatment decision is made. So when we look at educational opportunities, we have several of them in this idea that patients are not only getting tissue, but liquid biopsies and I spoke about also earlier DNA testing being very, very important to understand the actionable mutations before a treatment decision is made. So in addition to us getting patients that are being switched off other TKIs, we are definitely growing the market and helping to educate more on the importance of understanding the entire picture before treatment decision is made.

Okay. And then on 868 and then the European approval?

So on the European side, we don't believe that any additional clinical trials will be needed, and we'll give you more details once the MA is submitted. On 868, there's been some interesting -- some interest in that compound. So I think we're looking at all our options.

The next question comes from the line of Silvan Tuerkcan with Citizens.

I just wanted to ask is the gross to net for the pricing stabilize at this point? And can you share where that's coming out? And if you have any idea where that will end up?

Yes. Thanks for your question, Silvan. So I mentioned during my presentation that we were a little bit above 25% for Q4 and that we were still expecting this to grow a little bit beyond that, to say exactly when it's going to stabilize is always a very difficult question because it all depends upon negotiations with payers, obviously. But yes, we think that we are in a very good place in terms of access, which is what we wanted. We really wanted to make sure that all patients that needed that access reported that's what we were. And we think that doing all of that will take us probably a little bit further up, but not so high. I give you much more detail than that. But yes, we're still going to increase that a little bit in the coming quarters.

There are no further questions waiting at this time. That will conclude today's call. I would now like to pass the conference back over to management team for closing.

Thanks so much. We want to thank you for all your support. Launches can be anxious. I think everyone has been looking at our numbers. We've gotten some feedback that some people might have been disappointed with the gap they perceived between the new patient starts and the revenue number. This is to be expected. As you know, in launches, especially in oncology and as an oncologist, I can tell you that late-line patients get started first. They're the ones that are out of options. The pool is already identified. This is a prevalent population. It's hard to find the new patients. So when you get those late-line patients, they're going to discontinue faster. I would say just be patient. It's all going to happen. We're very confident in this launch. We like the way things are going, and we think that we will get the first-line patients as long as those NPS numbers continue anywhere remotely in that ballpark. We know that we are running out of TKI experienced patients. The growth will be in first line. So I want to thank all of you for your continued support, and we look forward to updating you further on our next call.

That concludes today's call. Thank you for your participation, and enjoy the rest of your day.