Cullinan Therapeutics, Inc. (CGEM) Earnings Call Transcript & Summary

Good evening, everyone. Thanks for coming today. I'm Nadim Ahmed, CEO of Cullinan Therapeutics, and we're looking forward to discussing the results of the REZILIENT1 study that were presented today in an oral presentation this morning at the main ASCO session. At the same time, we're also looking forward to the promise of zipalertinib in patients with EGFR exon 20 mutations. And I think there's a tremendous role that this therapy can play, and you'll hear about it throughout the evening. This slide contains our disclosures. During this event, management will be making certain forward-looking statements. So you should reference our SEC filings, specifically the risk factor for additional uncertainties that may cause actual results to differ. And now that we've got that one out of the way, let's focus back on the program. So this evening, I'm pleased to be joined by Jeff Jones, our Chief Medical Officer; as well as Dr. Danny Nguyen, Assistant Clinical Professor from the City of Hope National Medical Center, who has a lot of experience and is a leading investigator on the REZILIENT1 study. So let me outline the agenda for this evening. I'll be making some introductory remarks. Jeff will recap the REZILIENT1 study results that were presented earlier today. And then Jeff and Dr. Newman will be discussing patient cases from our resilient studies as well as the broader treatment landscape for patients with EGFR exon 20 insertion mutations. And finally, I'll conclude by covering both the strategic and economic benefits of zipalertinib to Cullinan Therapeutics previewing some upcoming additional milestones for the program, and then we'll open up the session for Q&A. Before we dive into zipalertinib, I do want to talk about the tremendous and exciting progress we're making across the rest of our portfolio at Cullinan Therapeutics, starting with CLN-978. Many of you know, this is our CD19xCD3 bispecific T-cell engager, which we're exploring currently and is in clinical development for 3 autoimmune diseases, systemic lupus erythematosus, rheumatoid arthritis as well as Sjogren's disease, and we're looking forward to sharing the initial clinical data from the lupus study in Q4 of this year with this promising potential disease-modifying treatment regimen for autoimmune diseases. With CLN-619, our MICA/MICB antibody. We have narrowed the scope of that program to focus on our dose expansion cohorts in non-small cell lung cancer as well as our ongoing Phase I study in relapsed/refractory multiple myeloma. CLN-049 is our FLT3xCD3 T cell engager, which is currently in 2 hematology studies, the first one in relapsed/refractory AML and MDS and the second study in patients with minimal residual disease following induction therapy in the frontline setting, again, in the AML disease space. CLN-617 is our IL-2 by IL-12 fusion protein, which is currently in Phase I dose escalation study. So as you look at our portfolio, we have many clinical stage value-creating opportunities, which we're clearly excited about. At the same time, at the end of March this year, we reported approximately $570 million in cash, which gives us runway into 2028 based on our current operating plan. So we have the resources to continue to advance our pipeline as well as generating multiple near-term and long-term catalysts. And so really important in today's environment, we have both cash and catalysts. So I think that's very important context. And now let me get back to the focus for this evening, which is zipalertinib, our oral EGFR tyrosine kinase inhibitor, specifically targeting the exon 20 insertion mutations in non-small cell lung cancer. A couple of things I'll point out. As you're aware, in January of this year, we reported that we met the primary endpoint of overall response rate in the REZILIENT1 study. And of course, this week at ASCO, we were really pleased to share the full data with the broader lung cancer community. And before I have Jeff cover those results, I do want to spend a little bit of time recapping the important progress executionally that we've had with this program as we have brought it forward from the initial Phase I results to the REZILIENT1 pivotal study results in just 4 years. And the history of zipalertinib makes for a really interesting story and really drove the early growth of our company, actually, for many of you who have been covering us for a while. So back in 2019, we licensed this molecule in from Taiho. And it was at ASCO in 2021, where we first presented the promising results from the Phase I/IIa study which led to our partnership with our colleagues at Taiho, for which we received $275 million upfront in cash, additional economic benefits, which I'll go into a little bit later. And very importantly, we retained 50% of the rights for the molecule in the U.S., arguably the most important oncology market in the world. Now zipalertinib is a differentiated molecule. We believe it has potential best-in-class properties. And as you think about the molecule, it's an EGFR tyrosine kinase inhibitor given orally for patient convenience and it does have this novel pyrrolopyrimidine scaffold, which gives it relative to other EGFR tyrosine kinase inhibitors, unique specificity for the exon 20 insertion mutation, and it spares wild-type EGFR and also HER2, which portends for favorable tolerability. The other thing I'll point out is zipalertinib does have breakthrough therapy designation status by the FDA for relapsed patients with exon 20 lung cancer, those patients who have specifically received prior chemotherapy. And so that's an unmet need and an underserved patient population. And so now let me turn the program over to Dr. Jeff Jones, who will cover the REZILIENT1 study results. Thank you very much.

Walking up, I'll start with a moment of gratitude for the clinical study team, many of whom are here tonight who were instrumental in the execution of the study. When I was still a university professor in practice, the one thing I told every clinical trainee was that if they conducted clinical research thinking of the patients as their own and providing the same level of care and attention as they did to the patients in their clinic, they would probably make good decisions, and that's truly been the case of the people who executed the study, and we're very, very grateful to them, to the investigators and to the patients who participated. So on to REZILIENT1. So as many of you will remember, the REZILIENT1 study in its Phase IIb enrolled 2 parallel patient populations. So there were the patients who had progressed after chemotherapy, but there was also this second group of patients who were enrolled in parallel who had received prior platinum-based chemotherapy, the prevailing standard of care in non-small cell lung cancer, including exon 20, but who had also received prior therapy with the now fully approved drug, amivantamab, as well as, in some cases, other exon 20 TKIs, mobocertinib had been approved and some patients had received that as well as additional investigational TKIs. At the time of the primary analysis, the data cut for which was in December of 2024, we had 175 patients in the primary analysis broken into the 2 groups. So the primary patient group, the largest was after chemotherapy. And then the second, the important subset progressing after amivantamab numbered 51 patients, which represents the largest series of patients receiving an investigational therapy after amivantamab treatment failure that's yet been presented. So if we were looking across at this group of patients, you can see that they were relatively heavily pretreated. In the overall patient population, the median number of prior therapies was 2. But if you look at the group of patients who were treated after amivantamab, you can see that they had received a median of 3 prior lines of therapy, which is more heavily pretreated than any other patient subgroup that's yet been reported for exon 20 if you look across the drugs that have been published. Owing to the high unmet need in this patient population, about 50% received anti-PD-1, PD-L1 therapy, which is distinctly ineffective in this patient population, which shows that doctors who are treating these patients were looking to try to eke out as much efficacy as they could and often providing less suboptimal -- less than optimal care. One final comment at the very bottom is this very important figure you can see that in the overall patient population, just under 40% of patients had evidence of brain metastases, but the minority of them, only about 1/3 of them had received prior brain irradiation. The others had stable untreated brain metastases, which is another unique feature of the REZILIENT1 data set. Again, looking at the amivantamab subgroup, which will be very important to remember, this group of patients, it was nearly 50% of the patients had CNS metastases. As many of you will know, as patients live longer with EGFR-mutated non-small cell lung cancer, the cumulative rate of CNS metastases sometimes rises to as high as 50%. So what did we see? So we saw clinically meaningful efficacy in the study population as a whole, but also both of these important subgroups. So overall, the confirmed overall response rate was 35%. But in the patients who progressed after chemotherapy, we replicated the same response rate that we had seen in the Phase I/IIa study in a post-chemotherapy treated group, the overall response rate, 40%. In a blended patient population of patients who had progressed after amivantamab plus in many instances, other EGFR TKIs, the response rate was still a clinically meaningful 24%. Here, the median duration of remission of response was similar across all groups, just under 9 months. So what about those patients who are progressing after amivantamab? So here, we double-click on that group and look now at the overall population as well as the group of patients who progressed after chemo and amivantamab alone as well as the more heavily pretreated group who had received other exon 20 TKIs as well. And there, you can see that the confirmed overall response rate after amivantamab alone was 30%, but fell to as low as 14% in the more heavily pretreated group, which is not entirely surprising. Also notable here, the really meaningful duration of response after amivantamab, the 14.7 months, which is really quite remarkable activity for zipalertinib. Mentioned at the beginning that nearly 40% of the overall patient population, nearly 50% in amivantamab had brain metastases, and it was very gratifying to see that the confirmed overall response rate in patients with brain metastases was 31%, very similar to the group without brain metastases, 35% and the duration of response was like similar. So the waterfall plot gives an indication of not only the patients who achieved objective response, but also patients who had regression of their tumor and achieved no better than stable disease. So this is indicative of the clinical benefit rate that we showed earlier in the slides. So patients overall achieved complete response, partial response or stable disease for at least 24 weeks and 64% of cases overall, 68% after chemo and 55% after amivantamab plus or minus another exon 20 directed therapy. And the waterfall plot really makes that clear that the majority of patients experienced regression of their tumor even if it didn't meet criteria for response. As we were talking about, as Dr. Yen can certainly comment, even if tumors don't meet arbitrarily determined response criteria, alive with disease control is clinically meaningful, and it's important to recognize that additional fraction of patients who achieved clinical benefit with zipalertinib treatment. Responses that are transiently obtained are not that clinically meaningful. So it is important to understand the durability of response. We've talked about duration of response, the other, which entrains that group of patients who have stable disease and durable clinical benefit is assessed by progression-free survival. And here in the overall group, progression-free survival was just under 10 months. We have to balance our efficacy findings with the safety profile of the drug, particularly for kinase inhibitors, it's important that the drug be tolerated since it has to be taken on an ongoing basis in order to remain effective. So it was very important to note that the safety profile in this larger cohort of patients is very similar to what we reported previously. The majority of adverse events were low grade. The most frequent adverse event was dermatologic adverse events, skin rash and related adverse events. And all of those were -- almost all of those were low grade. Higher-grade EGFR-associated adverse events like rash, diarrhea were in the single digits. And Dr. Helena Yu this morning reviewed the cases of pneumonitis, less than 5% and more than half of those patients had received prior treatments with an anti-PD-1 or PD-L1. So overall, very important to see that the clinical profile of zipalertinib continues to show efficacy at the forefront of what has been reported for exon 20 directed therapies after chemotherapy and -- now this very important new finding that the drug is similarly active after prior treatment with a fully approved drug amivantamab. This is not only clinically important, but also important for our regulatory ambitions. As we previously stated, we do plan regulatory interactions and a potential U.S. NDA filing in the second half of this year, which will be executed by our partners at Taiho Oncology. I'll also remind you that we do have the REZILIENT3 study ongoing, that is a randomized comparison of zipalertinib in chemotherapy to standard of care chemotherapy plus placebo. That study is actively enrolling in global centers. For those of you who are unable to join for the oral presentation this morning, bright and early at 9:00 a.m. on Sunday, those results were published simultaneously in JCO. The QR code is here, but the publication is online and contains additional detail about both the efficacy as well as more detailed tables for safety and adverse events. So that's just the highlights of the clinical data. It's not meant to be exhaustive since the publication is available. But we do have tonight Danny Nguyen with us from City of Hope. Dr. Yen, maybe we can -- why don't we pull up chairs actually. I didn't think of this beforehand. Have a seat. Thank you. And Danny is one of the leading physicians on the study. He recruited, I think we figured out yesterday, it was 37 patients of the total 244 that were enrolled as part of the safety set for the study. And you also treated the very first patient on the study way back in 2019. And maybe we could start there. Just tell us about the initial experience of giving zipalertinib to that patient.

Yes, sure. And I do want to say I appreciate Cullinan trusting a young oncologist back in 2019 with this drug. You think I look young now as like 6 years ago, I looked like a boy. So I really appreciate it. It's a great collaboration. Yes, in 2019, yes, we treated patient #1 in the world with Cullinan. And at that time, the treatment landscape for EGFT exon 20, nothing was approved only chemo. People would use off-label EGFR drugs that sometimes work, but oftentimes would have significantly less benefit than their common EGFR counterparts. And actually, I was a little bit worried with Cullinan. I thought they were coming a little bit later because at that time, poziotinib was being clinically developed. They had good initial data. Mobocertinib was moving along and actually eventually, it ended up getting fully approved and then withdrawn from the market. So then Cullinan came along. And I was a little bit nervous in the beginning, but we had a patient that fit the study at that point, they allowed pretty much anybody. So I had a really fit male, nonsmoker, he had been on chemo, he had been on immunotherapy, he had been on poziotinib for about 1.5 years or so, mobocertinib for 6 months, clinical trial at MD Anderson with CAR T cells and then eventually came back to me because he lived locally. Like he was tired going out of states and traveling everywhere. And he came to me. And fortunately, we had Cullinan open, just open. And I think he enrolled right before Christmas and at the very first dose level -- and like almost -- I remember, he said he probably started feeling better within like 2 or 3 days at the lowest level at the time. So when I saw that this heavily pretreated patient just responded clinically. Before we got the scans, I knew that the drug was going to work because he was saying he was breathing better. He wasn't getting like foam in his mouth that he was coughing up all the time. He specifically said he was coughing up like cement and that fully resolved. And that patient ended up more miraculously just through all these clinical trials, including Cullinan, he was diagnosed with metastatic lung cancer from the get-go, and he was alive for almost 6 years. And the zipalertinib, CLN-081 at the time probably represented about 2 to 3 years of those 6 years for him. And this was after he received all these other treatments. So I knew the drug was going to work with patient #1. So I'm glad to see that we're here presenting a second publication with zipalertinib. And you know the sad thing is since 2019, the treatment landscape has not changed that much. Poziotinib, which I talked about was further in development. They -- the data ended up not panning out. Mobocertinib, their Phase III data didn't pan out. And I can tell you right now from my experience with zipalertinib, this drug beats both of those drugs out of the water. They not only be apparently more effective, probably more durable responses, but way better tolerated, like extremely well tolerated. So I wanted to actually present some cases here that, unfortunately, I don't have that patient. I wish I could pull up his images, but I have some other patients that kind of represents the versatility of this drug. So here, we have an 80-year-old male, Asian male. He actually did have a prior smoking history. So not -- that's why this is like a case where we highlight not all nonsmokers get this cancer, even some smokers do. So it's best to check everybody. And as you can see here, do we have a quicker. This one. Okay, cool. So pretty obvious. I tried to select cases where the big thing is you can see it. So he presented with just a chronic cough, just cough, cough, cough and everyone thought it was just like sinusitis or pneumonia, whatever, he got worked up. This was biopsy, lung cancer, and then it turned out to be EGFR exon 20. And then this is the first set of scans right after treatment. So the first interim scans when we scan patients on the trial, and this area looked like it got completely better. And in addition, his cough resolved by the time we followed up again at the, I think, the 3 week mark. So yes, also had other areas of disease, too, but that kind of like highlighted the benefit of this drug for him and just symptomatically felt better, too. And also 80 years old. I think a lot of people look at an 80-year-old lung cancer metastatic and you're like, well, it's over for you. So -- but hey, he got an extra 53 months of treatment with the zipalertinib. And last time we checked, he was still alive because of this drug.

So he had progressed after prior platinum-based chemotherapy. So if you saw a patient like that today, standard of care would be?

Yes. So amivantamab has approval for EGFR patients who had progressed on chemo. So right now, they would be getting amivantamab.

In a future state, say, hopefully this time next year, and zipalertinib is available, based on the clinical profile that we've demonstrated in REZ1, how would you think about the choice between amivantamab for a patient like this versus zipalertinib?

So I would see -- well, I think once the drug comes on the market and it's fully available to our patients and the prescribing doctors, and then we sit down and talk with the patient and we lay out, hey, these are the treatment options for your EGFR exon 20 patient. Amivantamab is IV, I think as we all know, and they have infusion-related reactions, Skin toxicity, Scalp rash. A lot of times, there's dose holds, dose reductions. And then you have zipalertinib, which is oral, generally very well tolerated. They do have side effect profile that's similar to like an EGFR TKI, but as the 2 drugs I mentioned prior, way better tolerated than the predecessors poziotinib and mobocertinib. So I think there's a very real chance like if you were to go just through whatever is FDA approved, I think a lot of patients would be getting chemo, plus or minus ami and then probably use zipalertinib to follow. But I think there's going to be a good population of patients that will refuse chemo because of all the chemo side effects, will refuse amivantamab because of their perceived toxicities and just jump straight to the oral regimen. That certainly happened in other indications for lung cancers with other mutations as an oral option became available. So that's my impression. And I certainly have seen that with this patient population as well.

So I think the next patient that you want to -- is actually one of those patients who would have received the PANTHEON regimen, a patient who received platinum-based chemotherapy in combination with amivantamab, which was approved a little over a year ago now.

Yes. So similar, a 55-year-old white female, nonsmoker, she got worked up as well. And unfortunately, it's a typical scenario for these patients who have really no major risk factors for lung cancer as it kind of gets delayed because no one expects these patients to get lung cancer and then they're showing this mass. This actually -- I'm sorry, this is after being treated with chemo and amivantamab. So she had this leftover primary where all the cancer started off in the first place. And then after the first treatment, this thing nearly resolved and she felt a lot better, too. Again, like the coughing and short of breath symptoms significantly improved.

So given your experience now she had received prior treatment with amivantamab, was there anything different about giving zipalertinib in that setting as compared to, say, a patient who was progressing after prior treatment with this chemo, like toxicity-wise, adverse events, management?

Oh, yes. I remember this patient. She came to me significant scalp rash. Red, partial bleeding, and just didn't have a good time, but when you only have that available and you're 55, you stick it out for your family and everything. And actually, as I know, I'd just follow up with her. So she's ongoing treatment. I think she's almost 2 years now. We actually got her to the point where she just attended her son's wedding like last month or something. So with -- and where she is getting treated, they're basically like you're in hospice at this point. So the side effect profile way better. She's so happy to -- she's not side effect free with zipalertinib. Don't get me wrong. She does have some rash and actually some residual scalp rash, but she's way better quality of life than the approved amivantamab right now. So I'm happy for her. And actually, if you come to California, you might actually see her around town actually. And so we have the -- so those were -- those 2 cases were more kind of like highlighting the data that we have so far with zipalertinib post chemo and then post chemo and ami. So these are kind of just like other situations where this patient had chemo, the standard chemo, but some facilities still give immunotherapy when we know it's probably not the best thing to do because a lot of times, they don't have any other options. And then afterwards, when amivantamab got approved, amivantamab was given. And then I remember this patient, she travels from northern of the state to come to us. And she's also recommended hospice before she started treatment. So a 61-year-old Asian female, nonsmoker, she had diffuse brain mets right before she came to see me and she got a whole brand radiation just to control the amount of disease that she had in the brain. And then so you can see here, like she was also coughing, she was on continuous pain meds. She's having lots of abdominal pain, lack of appetite and stuff like that. And then again, first scans, this area got significantly better. And then also not highlighted here, these are like lymph nodes under her arm pit, significantly improved. You just see specs there now. So she's off of pain meds by the first like cycle of treatment. She still follows palliative care, but off of pain meds, no pain like that she was prior, really no other symptoms. And her -- she's just so happy. And this is another patient we bring from the brink of hospice and actually participating in life now.

And the status of the disease that in her brain?

Stable. Yes. So so far, because she has that history, we scan her head all the time with every scan, everything has been stable ever since.

Yes, this is a really great example of the activity in patients who have documented brain metastases. Preclinically, many of you will have remembered or queried us about the predicted CNS activity of the drug. And what we would always say is that preclinical studies are an imperfect predictor of subsequent intracranial response. And while we haven't specifically assessed intracranial response in the majority of patients in this study, it's very important that the response rate is relatively similar in that group, and this is a really great example of that.

Yes. And I think sometimes with whole brain radiation, if you can completely control the brain disease, my experience is if the drug is so strong systemically, hopefully, it controls the systemic disease from seeding further the brain. So if you control the body well, too, that also helps control the brain. And also amivantamab for what it's worth was not expected to help with the brain being such a big antibody molecule. But they've definitely shown benefit in the brain as well later on. So I think this is a good representation, and I'm so happy for this patient.

And so this last patient, just as a reminder, the trial would allow recruitment. We presented a primary analysis of patients who had progressed after chemo plus or minus amivantamab. But the eligibility criteria for the larger patient population included patients who would have declined chemotherapy or other standard of care agents after discussion with their doctors, they were still potentially eligible for study. And that's one of these cases.

Yes. So yes, same thing, 62-year-old female, non-smoker, and she started off with this mass here. And then after first treatment, you can see it's still there, but significantly smaller, and she definitely had less symptoms as well, short of breath, coughing, more activity. And she's a nurse. So it's not like for a lack of education that you could get chemo, you can get ami. And if you got a really good response, maybe consider radiation and surgery. And I think it's in her line of work. I remember her being an ICU nurse. I think she sees the sickest of the sick and she sees the cancer patients show up in her ICU. I think she got really spooked from radiation and chemo side effects. So that's why when I reached out to her, actually, she was -- her information was given to me by one of the advocate groups, and I called her, and I think she was initially thinking of just not doing anything. So I called her and then said like, hey, we have this trial here. I think it'd be a great fit. And then she got encouraged and traveled to see me. And then she's still on treatment right now.

Nearly 4 years at this point, right?

Yes, 4 years. So this is why I'm saying if the drug is available, you weigh all your options, no matter what the approval is, I think there's going to be a large preference for an easy-to-take oral regimen for this type of cancer and plenty of patients like her.

So this morning, during the oral session during the discussion, there was some discussion about sequencing. It sort of picks up on this point that you make about if an oral medicine gets approved, if it's available for prescribing, if ultimately it's approved in the front line that it presents a compelling option for patients as compared to the existing treatment with amivantamab for the reasons that you suggested. Is that what you expect to happen?

So I definitely expect that patients would prefer an oral drug. I think Cullinan and Taiho are running first-line trials in combination with chemo. So we'll see the results of that. I would say that the landscape right now, I think, is still for approval, FDA. Patients are still getting chemo ami, plus or minus ami first and then ami second if they didn't get it first line. But I think, again, once an oral drug is on the market, I can see a huge uptake of that drug. And just actually talking with other providers at ASCO because we know that amivantamab is approved frontline for common EGFR mutation, not the exon 20. And there's a resistance to take that drug up. And I'm -- I'm an advocate for that drug upfront in that setting. And a lot of the pushback is actually from the physicians. They feel like the infusions with amivantamab requires a lot of its logistics and planning and a lot of follow-up with the patients. With zipalertinib, you get it, you follow up with them in a few weeks. Most of the time, they're doing fine. So I think an oral drug that's well tolerated not only improves patients' quality of life, but the treating physicians and their staff's quality of life, it frees up the infusion chairs for other indications for like other cancers that are longer and frees up other resources, honestly. Again, I love giving amivantamab and lazertinib for the other. But for this one, in this situation until we get something better than chemo ami, I think people are just like bagging for an oral drug to be available.

That's a very helpful perspective. So hopefully, this has given a bit of color to the statistics. I think it's often very helpful to get greater insight into the cases that we encounter in the clinic and how any drug provides a unique set of attributes that uniquely solves that clinical problem. Drugs are designed to solve a need, and that's -- it's important for us at Cullinan and important for people who are consuming this data to get a little more insight into really some remarkable experiences that you've had as part of the trial. I was telling some of our colleagues between you and Dr. Yu, there's no one in the world that knows more about giving zipalertinib for the treatment of non-small cell lung cancer than you. So we really do appreciate you sharing your perspective with us tonight. I think, Nadim, you want to make some additional remarks, and then we'll open it up for questions to the 3 of us. Great. Thank you.

All right. Thanks, Jeff. Thanks, Dr. Nguyen. One thing I will say is the remarkable outcomes in those patient case studies really demonstrate the versatility of zipalertinib across multiple patient segments. And that's why we're so excited about the promise of this molecule. Now in terms of the U.S. opportunity for zipalertinib, EGFR-mutated non-small cell lung cancer makes up 16% of all non-small cell lung cancer. And within those mutations, exon 20 is approximately 12% of all of those mutations, which translates to a U.S. annual incidence of about 3,000 to 5,000 patients. So it's an important market opportunity. The other thing we heard from Jeff and Dr. Nguyen also is that patients with exon 20 tend to have a poorer prognosis compared to many of the other EGFR mutations. And so there still persists a significant unmet need for more effective and more tolerable therapies. And so that's important. And that's one of the reasons why with our partners at Taiho, we have this broad development program for the molecule across multiple patient segments from relapsed/refractory disease all the way up to the frontline setting. So we've spoken about REZILIENT1 in quite some detail. So that's our core relapsed/refractory study. Our partners at Taiho are leading both the REZILIENT2 and the REZILIENT3 studies. REZILIENT2 is the Phase II parallel cohort study, where we're investigating zipalertinib monotherapy in a range of different patient types. So active brain mets. So as you heard from Jeff, in our REZILIENT1 study, we showed systemic response in patients who had brain mets at baseline. This study will answer the question around intracranial responses in patients with active brain mets. So this is becoming a larger and larger problem for patients with lung cancer. We also have a cohort frontline monotherapy for zipalertinib. So obviously, we have the ongoing REZILIENT3 study, which I'll talk about, which is a combination approach. This is a monotherapy approach. And we're also investigating zipalertinib monotherapy in the so-called uncommon or PAC mutation patients. And so that's going to be important data for us as well. REZILIENT3, as I mentioned, is also being led by our partners at Taiho. So this is the frontline study of zipalertinib plus combination platinum-based chemotherapy versus the standard of care, which is platinum-based chemotherapy. So an expansive program and lots of data to read out over the coming months and years. Now as you heard from Dr. Nguyen, at the moment, we still only have one drug approved for exon 20 mutation patients. And so on the right-hand graph, on the right hand of this slide, you can see the data from the original CHRYSALIS study that led to the initial approval of amivantamab in that relapse setting of patients who received prior chemotherapy. Overall response rate of 40%, median duration of response of approximately 11 months and a median progression-free survival of approximately 8 months. Now it's difficult to compare studies, but in REZILIENT1, we did have a cohort of chemo-only patients that we presented earlier this morning, and you heard from Jeff as well. So we saw efficacy response rate of around 40%, median duration of response approximately 9 months and importantly, a median progression-free survival of 9.5 months. The important thing to point out here is that in REZILIENT1, we had a higher proportion of patients with brain mets at baseline compared to the 22% in the CHRYSALIS study. And so these data for us are very encouraging in a group of patients that have high disease burden. And relative to amivantamab, it looks like we have a more favorable safety profile with zipalertinib. And you also heard about Dr. Nguyen's hands-on experience seeing some of these toxicities. And so our belief is that zipalertinib is much more amenable to combination with chemotherapy. And so we believe that ultimately, zipalertinib plus chemotherapy could become a new potential best-in-class treatment regimen in the frontline setting once we have those data. And now switching gears a little bit to our partnership with Taiho. So with zipalertinib, we have a source of future nondilutive capital, which is especially important in the current market context, in addition to the $275 million we received upfront when we closed the transaction. We're also eligible to receive a total of $130 million for the U.S. approvals of both second-line and frontline EGFR exon 20 non-small cell lung cancer. And we do have a co-development and a co-commercialization arrangement with our partners at Taiho in the U.S. so we pay 50% of the development costs, but we also retain 50% of the profit. In the U.S., our partners at Taiho are leading the commercialization efforts. They have 3 approved products already in the U.S. and have a commercial infrastructure, deep expertise in the commercialization of targeted therapies. Now we do have a co-promotion option, and we get to opt in or not with the frontline approval for zipalertinib. So I just wanted to make that clear. So we have plenty of time to make the decision of where we opt in or not. It's not on the relapse setting, it's in the frontline setting. So I just wanted to make that clear also. Now look, we've spent a lot of time talking about the executional progress to date, but I also want to spend a few minutes talking about upcoming near-term milestones, some of which we're announcing for the first time this evening with the permission of our partners at Taiho. Specifically, for the REZILIENT2 study, I'm pleased to announce that we're going to have data in the second half of this year, specifically for cohort C, which is the patients with active brain mets as well as cohort B, which is the patient with uncommon EGFR mutations or the PAC mutations. So that's a series of data for the second half of this year. You heard also earlier from Jeff with the REZILIENT1 study, our partners at Taiho are the IND holders, and they are planning a potential NDA submission for the relapsed/refractory EGFR exon 20 patients. I'm also pleased to announce that the frontline study, REZILIENT3, we are expecting to complete enrollment in the first half of 2026. And so with that, let me close the formal part of the presentation and invite Jeff and Dr. Nguyen also up for a Q&A session. Thanks again.

So any questions? Kaveri? Then we'll go to you.

This is Kaveri Pohlman from Clear Street. Congrats on the progress. I just want to understand -- maybe my questions are more directed towards the young oncologist here. So regarding the efficacy in brain mets with the data so far, and I believe the drug is going to get approved in case it gets approved based on the data here. How do you think about zipalertinib's activity and its use in different types of brain mets patients, whether it's asymptomatic or symptomatic versus untreated? And what -- is the prevalence of brain mets, is it higher in late line versus frontline patients? And then I have a question -- a second question.

Well, sure. Yes, that's a very critical question to address like, these EGFR exon 20 patients, a lot of them just de novo like in the beginning, will present with brain mets. A lot of times, they will progress with brain mets and then the worst is when they progress with something called leptomeningeal disease, where it's like deeper in and the prognosis is 3 months or less after that. I would tell you my experience is that I don't have much experience with the actual active brain mets with this drug. When I had patients enrolled, we had to treat them. So I will say like some of the preliminary data, as you saw so far, like even if they had brain mets, they still respond and there's good disease control and they don't progress. So I think that's very encouraging data. And then Nadim just said, like I'm not sure if we're able to actually present that data until a little bit later. But my experience is I've seen a lot of patients who had come into the study with brain mets, we treat the brain mets with like radiation, so they're okay and then they start the drug. And I would say a lot of patients don't tend to really progress in the brain as of like the first place when the drug stops working. That's just more anecdotal. Definitely, some patients do progress in the brain, unfortunately. But hopefully, we'll have more concrete data in the future at congress.

That's right. In that module of the REZILIENT2 trial, the intracranial response rate is being carefully characterized. So that should be not too many months on, we'll have that data public.

And there's a lot of breakdown in terms of demographics, especially based on prior treatment in this presentation. What's the breakdown for those patients in real world when you see patients? And how often patients in second line are chemo-naive -- and how many are amivantamab or other TKI experience? Or I would say, in other words, what population really represents the majority of real-world setting in second line or later patients?

Yes, good observation. And I think also it depends on who you ask, like at City of Hope, it's more of a tertiary referral center. So we definitely get heavily pretreated patients. Most of the patients initially get diagnosed in the community. And right now, a lot of the community oncologists if they start them on treatment are really tied by what's FDA approved and what insurance will approve. So that will usually be chemotherapy plus or minus amivantamab. So a lot of patients will have already come to me already have seen that therapy and then they're progressing and they're looking for like other options. And these EGFR patients, a lot of them are younger, really savvy with technology. They do their research. So some of them may have been on other clinical trials even already. And my experience is like, yes, a lot of them are heavily pretreated. And I've seen -- I started off with that first patient because he was one of my most heavily pretreated patients. He traveled all the way to MD Anderson for a trial and traveled UCLA for a trial, and that guy still responded. So I think it also matters how you sequence treatment as well. I think as you saw in the data, in a patient who was chemo, and EGFR pretreated and they get this drug, the response rates are lower. So that's why like a lot of times, what I would do is if I saw someone who was on an EGFR TKI and then they come see me, I try to squeeze in a little bit of a different mechanism drug like chemo or something in and then get them on like the study or something. So I've had a little bit better responses like in my heavily pretreated patients, when I did that, I don't think the response rates were that low. So I think it depends on who you ask. But yes, a lot of my patients were unfortunately heavily pretreated. But you get occasional newly diagnosed patients to come see you as well. And like that one, they knew that chemo was an option, and they just flat out refused.

So more questions, I think there were Soumit, Andy, and we got Marc here as well. So actually going to make you run around a bit.

Yes. Andy Berens, Leerink Partners. Two. One maybe science question and a question for the doc and then a housekeeping one. We saw some good data today from HUTCHMED and AstraZeneca with an oral MET inhibitor on top of Tagrisso that had some pretty impressive efficacy. Just wondering in the context of amivantamab and maybe future plans for developing zipelertinib, is there any data to suggest the role of MET amplification in exon 20? And then the housekeeping question is, I think you guys are responsible for co-promoting too. So if you're not going to make a decision until the front line, are you thinking about building a sales force and then not continuing that? Is that how it would work out?

Let me start with the last one. And so yes, so I think as we think about what we want to do in the future, so the important point is that it wouldn't be opted in until the frontline indication. And the way the commercialization profit arrangement works, whether or not we have our own reps or we use Taiho's reps, we still pay for that commercialization. And for us, I think we would really want to strategically think about how is the rest of the portfolio moving. It obviously becomes much more attractive if you have other products that your reps could carry. So it's going to be the choice of at that time, do I have other products? Or is it focused in on zipalertinib? And as I said, we've got plenty of time to make that decision. So hopefully, I address your question, Andy. Yes. Okay. And then you had the other question.

The big mechanism of resistance question. So...

Yes. I would -- well, first off, I appreciate your question. And coming from like it sounds like nonmedical person, you guys really understand the data quite well like at a medical conference. So that's a high-level question, I think. So MET. So in my opinion, the EGFR, whether it's common mutations like the exon 19 and 21 and then the exon 20 and then these atypicals are like the catch all others. They all activate the EGFR receptor. It's just like the mutation is a little bit different. So what distinguished the exon 20 from like the common is that this one main drug, this Tagrisso drug that has like an 80-plus response rate in the common mutation doesn't fit into that EGFR exon 20 space as well. But for all intents and purposes, the EGFR receptor is still activated in terms of the cancer. So a lot of these EGFR exon 20 patients in my observation, have progressed very similarly than if they were a common EGFR. So I've seen patients develop a T790M mutation, which Tagrisso is good for, C797S and then other resistance mutations. So amivantamab is already approved for EGFR exon 20, which is EGFR and MET bispecific antibody. So I would presume that it is another bypass pathway for exon 20. And yes, I mean, I'm not the only doctor who has thought about combining zipalertinib with a c-MET agent as well to maybe augment that effect, much like the MARIPOSA study for amivantamab and osimertinib like another EGFR TKI. So I think we're all kind of like on the same page.

And Helen Yu this morning mentioned we have collected plasma on the patients enrolled in the study. So we have circulating tumor DNA. We will be able to look ultimately at some of the characteristics of molecular characteristics at the time of relapse.

Do you have another follow-up...

When do we see some of the breakdown of the resistance?

No specific time line. So I'd say right now, we're focused on actually making the drug available to patients is mission #1.

We have to do something next. He's been waiting.

Marc Frahm from TD Cowen. Maybe on this idea of mutation -- while the approval would be in the second-line setting that patients may opt to refuse other therapies to try to get to zipalertinib. Just I mean, even here, you had a case study of a patient who's already refusing approved available therapies. Do you have a sense of how many patients are already refusing just because of the zipalertinib side effects of amivantamab -- are already refusing that therapy even when there isn't a good option available for them commercially?

Yes, that's definitely a good question. And the amivantamab, a lot of these patients -- well, we had enrolled a lot of patients who are post ami. And I've not seen anybody on zipalertinib and then who also got ami did not have a major ami side effect, and they would report that they did not like it. A lot of those patients that you saw are young, fit, otherwise, and they're motivated to live. So if amivantamab is the only thing that's keeping them alive, they will tough it out.

So could I just ask another question related to what Marc is asking. So obviously, a lot of the newly diagnosed patients are in the community. But the ones that you do see, how do you decide between giving them chemotherapy alone or amivantamab plus chemotherapy? And what's that proportion? I think you're kind of getting at that mark, right?

Yes, yes. I mean those patients that I see, I offer them chemotherapy and amivantamab upfront. I mean the PANTHEON study demonstrated the overall benefit. So yes, it's really the best that we have right now. And until an oral agent gets on the market, those are what the patients are going to get.

Soumit Roy from Jones. Great data. Trying to understand fast forward a year from now, if everything goes right, the treatment landscape in the frontline setting. So we have Sunvo, could get approved, Furmo could get approved. So we have 2 exon 20 oral drugs monotherapy in the frontline setting versus REZILIENT3 is coming up as a chemo combo. So how physicians are going to make the decision? And then again, we saw the data this morning, zipalertinib after TKI is not as effective. So how are you going to position this?

Yes. Yes, that's definitely a valid point. So I would say a lot of -- right now, I think that one of the main points of showing the post-AMI data is that right now, until that happens, those patients are still coming to us after ami and that zipalertinib is showing great benefit in that respect. I think there might be a little bit of a side effect profile with Sunvozertinib, for instance. I just came from like a discussion board with another oncologist who sent his patient over to China to get the Sunvozertinib and bring it back. And they already had to dose reduce it by half because of the side effects of it. But that's what patients are willing to do to be alive, to go over there and bring the drug back. So I will tell you, I don't have personal experience with Sunvozertinib. I do see the data. And yes, their efficacy data is definitely up there for sure. But I do see nuances in terms of tolerability side effect and dose reduction. And I think it's going to -- at the end of the day, if you have a multiple choice, it's going to be whatever the provider is really used to giving. And I think I appreciate the zipalertinib. I think many of the sites were open in the U.S. I think Sunvo got a lot of data initially overseas and then they had to get it, all the data in the U.S. So I feel like a lot of providers, where I'm from, especially in California, everyone's heard about zipalertinib now, and there's definitely a good reputation with that drug. And they've also done a lot of outreach to patient advocacy. There's an EGFR exon 20 support group, Marcia Horn, who she knows -- she's actually referred to me a lot of these patients. And she knows that the drug is very well tolerated, too. And at the end of the day, a lot of those patients get redirected to treatment by that group. So I think locally, I think a lot of the data was U.S. driven, which is good. And I think a lot of more U.S. providers are familiar with zipalertinib. But definitely, Sunvozertinib and furmonertinib is going to be competitors for sure.

Maybe a question for Jeff. Do we have any idea what percent patients could have active brain mets? So you have 14% patients with radiation treatment, 33% untreated. Is it fair to think most of those untreated had active mets? And do we know any CNS ORR?

CNS response rates and the CNS-specific response rate, we can't calculate it because we don't really know that -- we're not always sure of the denominator. Because all of the patients aren't being systematically assessed in the CNS. So if we even gave -- and if they don't have target lesions in the CNS, then they're not being systematically followed over time. So we'll have an answer to that question when the module C of REZILIENT2 is presented later this year. So that's going to be the best opportunity. In terms of the frequency of CNS metastases in exon 20, it is a cumulative risk in EGFR patients. I think you're suggesting that it may be numerically higher in patients with exon 20, perhaps in some other EGFR mutations. But as a group, the cumulative rate as survival improves is roughly 50% in very heavily pretreated later-line patients. So if you live long enough, that happens. Like I can remember, when I started training in oncology, CNS metastases from breast cancer were uncommon because patients would die before they lived long enough for that to happen. The same thing is happening. As you prolong survival, you start seeing emergence of later CNS progression. So it is a very important clinical problem.

The interim data didn't really show a statistically significant OS benefit, and we don't really know what to mature. I just wanted to know, what do you think? Do you think it will be able to show a statistically significant OS benefit? And does it really matter given that the hazard ratio was already 0.67. And how do you see the potential of zipalertinib in first line, whether amivantamab shows a significant or does not show a significant benefit?

Yes. I think the reality is like a lot of times outside the context of a trial, those patients may see other treatment options that are effective as well. Actually, I'm not sure if on the -- are you talking about the path beyond first line?

Could they be treated with amivantamab at progression -- in that study?

[indiscernible].

Yes. So if they progress on chemo, they can get ami second line. And we know amivantamab monotherapy second line is effective or has activity. So the question is whether just if you do it all together or you do it in sequence, if it doesn't matter, they still live as long or longer than at least if you only had chemo. And I think you throw zipalertinib in there. I think it will definitely make these patients live longer. And this -- patient taking it by itself first, it's kind of interesting to see -- I mean, do those patients benefit even better if you use zipalertinib first. I have a suspicion maybe because after you give chemo, you give amivantamab, the cancer mutates, it becomes a little bit more resistant and maybe it makes it resistant to a lot of other targeted treatments. And it is possible that you hit them with the TKI first. They don't really develop this crazy cancer afterwards, and then you can still use chemo and amivantamab in later lines. So I think a lot of these patients, even though you have the chemo ami on the market approved, once you get the zipalertinib approved at whatever indication, I think people will become kind of creative to get those medications in their hands. So I've seen people -- I've seen other cancers where like a drug was only approved third line and you have to have chemo and you have to have another agent. And then what they'll do is they'll be like they get one dose of chemo, they get one dose of that agent, they'll just say they don't tolerate it and then all of a sudden in the third line and then they get -- the insurance approves the drug. So that's unfortunately, just in the real world, that's how we make it so that a patient can get these things approved by insurance. So...

And receives the best therapy for their particular condition, whether or not it's gone through the regulatory review process for that specific setting. But to your first question, it's -- the overall survival data that's reported is probably the best that will ever show up for the PANTHEON study. I mean because of crossover, because of those patients are being treated at investigational sites where they likely have access to other investigational therapies like zipalertinib or another EGFR TKI, that's going to dilute any potential survival benefit. It's one of the challenges, we've all heard about the importance of overall survival in oncology studies. It's quite the hot topic of the moment. But that implies that patients exist in some sort of vacuum and that we continue to follow them until they fail rather than trying to give them the best available therapy. So the experiments are never pure, which is in all of our collective and our patients' best interest.

All right. Thanks very much. Dr. Nguyen, thanks very much. Jeff, thank you very much. I appreciate it. So let me just close out by saying the progress of zipalertinib is just one example of, I would say, Cullinan's unique ability to match the right target with the right modality and also our ability to rapidly execute. Going back to 2019, we licensed in zipalertinib for $2.5 million from Taiho, entered into an agreement with very favorable economics for Cullinan, and we still retain the economic upside of the potential for the molecule in the U.S. So that's really important for us. Secondly, together with our partners at Taiho, we are really looking forward to address the significant unmet need in exon 20 non-small cell lung cancer patients by offering zipalertinib as a potential new oral treatment option for patients that need safer and more effective therapies. So thanks again for coming tonight, and we'll keep you updated in the future. Thanks for your attention.