All right, testing. One, two, three. Jeff, are we good?
Yeah.
All right. Too many Jeffs. All right. 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. I think there's a tremendous role that this therapy can play. You'll hear about it throughout the evening. This slide contains our disclosures. During this event, management will be making certain forward-looking statements. You should reference our SEC filing, specifically the risk factors for additional uncertainties that may cause actual results to differ. Now that we've got that one out of the way, let's focus back on the program.
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. 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. Then Jeff and Dr. Nguyen will be discussing patient cases from our RESILIENT studies, as well as the broader treatment landscape for patients with EGFR exon 20 insertion mutations. 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. 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 CD19 x CD3 bispecific T-cell engager, which we're exploring currently and is in clinical development for three autoimmune diseases: systemic lupus erythematosus, rheumatoid arthritis, as well as Sjogren's disease. 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've 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 one study in relapsed refractory multiple myeloma.
CLN-049 is our FLT3 x CD3 T-cell engager, which is currently in two 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 x IL-12 fusion protein, which is currently in phase one dose escalation study. As you look at our portfolio, we have many clinical stage value creating opportunities, which we're clearly excited about. 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. We have the resources to continue to advance our pipeline, as well as generating multiple near-term and long-term catalysts. It is really important in today's environment, we have both cash and catalysts.
I think that's very important context. 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. Of course, this week in ASCO, we were really pleased to share the full data with the broader lung cancer community. 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've brought it forward from the initial phase one results to the REZILIENT1 pivotal study results in just four years.
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've been covering us for a while. 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 one to a 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. 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. As you think about the molecule, it's an EGFR tyrosine kinase inhibitor given orally for patient convenience.
It does have this novel pyrroloperimidine scaffold, which gives it, relative to other EGFR tyrosine kinase inhibitors, unique specificity for the exon 20 insertion mutation. 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. That is an unmet need and an underserved patient population. Now let me turn the program over to Dr. Jeff Jones, who'll 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 this 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. That's truly been the case of the people who executed this study. We're very, very grateful to them, to the investigators, and to the patients who participated. On to REZILIENT1. As many of you will remember, the REZILIENT1 study in its phase 2B enrolled two parallel patient populations.
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 two groups. The primary patient group, the largest, was after chemotherapy.
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. 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 two. If you look at the group of patients who were treated after Amivantamab, you can see that they had received a median of three 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 were treating these patients were looking to try to eke out as much efficacy as they could and often providing 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 a third 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%. What did we see? We saw clinically meaningful efficacy in the study population as a whole, but also both of these important subgroups. Overall, the confirmed overall response rate was 35%. In the patients who progressed after chemotherapy, we replicated the same response rate that we had seen in the phase one to a 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 response was similar across all groups, just under nine months.
What about those patients who were progressing after Amivantamab? 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. 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.
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 similar. 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. This is indicative of the clinical benefit rate that we showed earlier in the slides. 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. The waterfall plot really makes that clear that the majority of patients experienced regression of their tumor, even if it did not meet criteria for response.
As we were talking about, as Dr. Nguyen can certainly comment, even if tumors do not meet arbitrarily determined response criteria, alive with disease control is clinically meaningful. It is important to recognize that additional fraction of patients who achieve clinical benefit with zipalertinib treatment. Responses that are transiently obtained are not that clinically meaningful. It is important to understand the durability of response. We have 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. Here in the overall group, progression-free survival was just under 10 months. Perhaps to balance our efficacy findings with the safety profile of a drug, particularly for kinase inhibitors, it is important that the drug be tolerated since it has to be taken on an ongoing basis in order to remain effective.
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. 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. 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. 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.
This very important new finding that the drug is similarly active after prior treatment with the 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 and chemotherapy to standard of care chemotherapy plus placebo. That study is actively enrolling in global centers. For those of you who were 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. That is just the highlights of the clinical data. It is not meant to be exhaustive since the publication is available. We do have tonight, Danny Nguyen with us from City of Hope. Dr. Nguyen, maybe we can, why do not we pull up chairs, actually? Did not think of this beforehand. Can have a seat. Thank you. This is my able assistant, Lee. 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. You also treated the very first patient on the study way back in 2019.
Maybe we can start there. Just tell us about the initial experience of giving zipalertinib to that patient.
Yeah, sure. I do want to say I appreciate Cullinan trusting a young oncologist back in 2019 with this drug. You think I look young now. That was six years ago, I looked like a boy. I really appreciate it. It's a great collaboration. Yeah. In 2019, we treated patient number one in the world with Cullinan. At that time, the treatment landscape for EGFR exon 20, nothing was approved, only chemo. People would use off-label EGFR drugs that sometimes would work, but oftentimes would have significantly less benefit than their common EGFR counterparts. 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. Actually, eventually, it ended up getting fully approved and then withdrawn from the market. Cullinan came along. 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. I had a really fit male, non-smoker. He had been on chemo. He had been on immunotherapy. He had been on Poziotinib for about a year and a half or so, Mobocertinib for six months, clinical trial at MD Anderson with CAR T cells. Eventually, he came back to me because he lived locally. He was tired of going out of state and traveling everywhere. He came to me. Fortunately, we had Cullinan open, just open.
I think he enrolled right before Christmas at the very first dose level. I remember he said he probably started feeling better within like two or three days at the lowest level at the time. 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 was not getting foam in his mouth that he was coughing up all the time. He specifically said he was coughing up like cement. That fully resolved. That patient ended up miraculously just through all these clinical trials, including Cullinan, he was diagnosed with metastatic lung cancer from the get-go. He was alive for almost six years.
The zipalertinib, CLN-081 at the time, probably represented about two to three years of those six years for him. This was after he received all these other treatments. I knew the drug was going to work with patient number one. I am glad to see that we are here presenting a second publication with zipalertinib. The sad thing is since 2019, the treatment landscape has not changed that much. Poziotinib, which I talked about, was further in development, the data ended up not panning out. Mobocertinib, their phase three data did not pan out. 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 are apparently more effective, probably more durable responses, but way better tolerated, like extremely well tolerated.
I wanted to actually present some cases here that unfortunately I do not have that patient. I wish I could pull up his images, but I have some other patients that kind of represent the versatility of this drug. Here we have an 80-year-old Asian male. He actually did have a prior smoking history. That is why this is like a case where we highlight not all non-smokers get this cancer. Even some smokers do. It is best to check everybody. As you can see here, do we have a clicker? Wonder if it is at the top. This one. Okay, cool. Pretty obvious. I try to select cases where the big thing is you can see it. He presented with just a chronic cough, just cough, cough, cough. Everyone thought it was just sinusitis or pneumonia, whatever. He got worked up.
This was biopsied lung cancer. It turned out to be EGFR exon 20. This is the first set of scans right after treatment, the first interim scans when we scan patients on the trial. This area looked like it got completely better. In addition, his cough resolved by the time we followed up with it again at the, I think, the three-week mark. He also had other areas of disease too, but that kind of highlighted the benefit of this drug for him. He just symptomatically felt better too. 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." Hey, he got an extra 53 months of treatment with zipalertinib. Last time we checked, he was still alive because of this drug.
He had progressed after prior platinum-based chemotherapy. If you saw a patient like that today, standard of care would be,
yeah, Amivantamab has the approval for EGFR patients who had progressed on chemo. 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 REZILIENT1, how would you think about the choice between Amivantamab for a patient like this versus zipalertinib?
I would see, 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.
They have infusion-related reactions, skin toxicity, scalp rash. A lot of times there are dose holds, dose reductions. You have zipalertinib, which is oral, generally very well tolerated. They do have a side effect profile that's similar to an EGFR TKI. As the two drugs I mentioned prior, way better tolerated than the predecessors, poziotinib and mobocertinib. I think there's a very real chance 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 zipalertinib to follow. 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's certainly happened in other indications for lung cancers with other mutations as an oral option became available. That's my impression. I certainly have seen that with this patient population as well.
I think the next patient that you want to is actually one of those patients who would have received the PAPILLON regimen, a patient who received platinum-based chemotherapy in combination with Amivantamab, which was approved a little over a year ago now.
Similar, a 55-year-old white female, non-smoker, she got worked up as well. Unfortunately, the typical scenario for these patients who have really no major risk factors for lung cancer is it kind of gets delayed because no one expects these patients to get lung cancer and then ended up showing this mass. Sorry, this is after being treated with chemo and Amivantamab.
She had this leftover primary where all the cancer started off in the first place. After the first treatment, this thing nearly resolved. She felt a lot better too. The coughing and shortness of breath symptoms significantly improved.
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 just chemo, toxicity-wise, adverse events, management?
Oh yeah. I remember this patient. She came to me, significant scalp rash, red pustules, bleeding, and just did not have a good time. When you only have that available and you are 55, you stick it out for your family and everything. Actually, as a side note, I just followed up with her. She is ongoing treatment. I think she is almost two years now.
We actually got her to the point where she just attended her son's wedding last month or something. Where she was getting treated, they were basically like, "You're in hospice at this point." The side effect profile, way better. She's so happy to—she's not side effect-frdee with zipalertinib. Don't get me wrong, she does have some rash and actually some residual scalp rash, but she has way better quality of life than the approved amivantamab right now. I'm happy for her. Actually, if you come to California, you might see her around town, actually. We have another—those two cases were more kind of like highlighting the data that we have so far with zipalertinib, post-chemo, and then post-chemo and ami.
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. Afterwards, when Amivantamab got approved, Amivantamab was given. I remember this patient. She travels from northern of the state to come to us. She was also recommended hospice before she started treatment. A 61-year-old Asian female, non-smoker. She had diffuse brain mets right before she came to see me. She got whole brain radiation just to control the amount of disease that she had in the brain. You can see here, she was also coughing. She was on continuous pain meds. She was having lots of abdominal pain, lack of appetite, and stuff like that.
Then again, first scans, this area got significantly better. Also, not highlighted here, these are like lymph nodes under her armpit, significantly improved. You just see specs there now. She is off of pain meds by the first cycle of treatment. She still follows palliative care, but off of pain meds, no pain like she was prior, really no other symptoms. She is just so happy. This is another patient we bring from the brink of hospice and actually participating in life now. The status of the disease in her brain was stable. Yeah. So far, because she has that history, we scan her head all the time. With every scan, everything has been stable ever since.
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. What we would always say is that preclinical studies are an imperfect predictor of subsequent intracranial response. While we have not specifically assessed intracranial response in the majority of patients in this study, it is very important that the response rate is relatively similar in that group. This is a really great example of that.
Yeah. 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. If you control the body well too, that also helps control the brain. Also, Amivantamab, for what it is worth, was not expected to help with the brain being such a big antibody molecule.
They've definitely shown benefit in the brain as well later on. I think this is a good representation, and I'm so happy for this patient.
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. 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. That's one of these cases.
Yeah. Same thing, 62-year-old female, non-smoker. She started off with this mass here. After first treatment, you can see it's still there, but significantly smaller. She definitely had less symptoms as well, shortness of breath, coughing, more activity. She's a nurse. She's a nurse.
It's not like for a lack of education that you could get chemo, you can get ami. If you got a really good response, maybe consider radiation and surgery. I think it's in her line of work. I remember her being an ICU nurse. I think she'd see the sickest of the sick, and she'd see the cancer patients show up in her ICU. I think she got really spooked from radiation and chemo side effects. That's why when I reached out to her, actually, her information was given to me by one of the advocate groups. I called her, and I think she was initially thinking of just not doing anything. I called her and then said, "Hey, we have this trial here. I think you'd be a great fit." She got encouraged and then travels to see me.
She's still on treatment right now.
Nearly four years at this point, right?
Yeah. Four years. 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.
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?
I definitely expect that patients would prefer an oral drug. I think Cullinan and Taiho are running first-line trials with combination with chemo. 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. I think, again, once an oral drug is on the market, I can see a huge uptake of that drug. Just actually talking with other providers at ASCO, because we know that Amivantamab is approved front line for common EGFR mutation, not the exon 20. There's a resistance to take that drug up. I'm an advocate for that drug upfront in that setting. A lot of the pushback is actually from the physicians.
They feel like the infusions with Amivantamab require a lot of logistics and planning and a lot of follow-up with the patients. With zipalertinib, you give it, you follow up with them in a few weeks. Most of the time, they're doing fine. 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 other cancers that are longer and frees up other resources, honestly. Again, I love giving Amivantamab and Lizurinib for the other. For this one in this situation, until we get something better than chemo ami, I think people are just begging for an oral drug to be available.
That's a very helpful perspective. 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 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 your 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 three 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. That is why we are 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. Within those mutations, exon 20 is approximately 12% of all of those mutations, which translates to a U.S. annual incidence of about 3,000-5,000 patients. It is 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. There still persists a significant unmet need for more effective and more tolerable therapies. That is important.
That is 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 front line setting. We have spoken about REZILIENT1 in quite some detail. That is our core relapsed refractory study. Our partners at Taiho are leading both the REZILIEN2 and the REZILIENT3 studies. REZILIENT2 is the phase 2 parallel cohort study. We are investigating zipalertinib monotherapy in a range of different patient types, including active brain mets. 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. This is becoming a larger and larger problem for patients with lung cancer.
We also have a cohort front line monotherapy for zipalertinib. Obviously, we have the ongoing REZILIENT3 study, which I'll talk about, which is a combination approach. This is a monotherapy approach. We're also investigating zipalertinib monotherapy in the so-called uncommon or PAC mutation patients. That is going to be important data for us as well. REZILIENT3 , as I mentioned, is also being led by our partners at Taiho. This is the front line study of zipalertinib plus combination platinum-based chemotherapy versus the standard of care, which is platinum-based chemotherapy. 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.
On the right-hand graph, on the right-hand of this slide, you can see the data from the original CRISALIS 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. 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 CRISALIS study. These data for us are very encouraging in a group of patients that have higher disease burden. Relative to Amivantamab, it looks like we have a more favorable safety profile with zipalertinib. You also heard about Dr. Nguyen's hands-on experience seeing some of these toxicities. Our belief is that zipalertinib is much more amenable to combination with chemotherapy. We believe that ultimately, zipalertinib plus chemotherapy could become a new potential best-in-class treatment regimen in the front line setting once we have those data. Now switching gears a little bit to our partnership with Taiho.
With zipalertinib, we have a source of future non-dilutive 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 front line EGFR exon 20 non-small cell lung cancer. We do have a co-development and a co-commercialization arrangement with our partners at Taiho in the U.S. We pay 50% of the development costs, but we also retain 50% of the profits in the U.S. Our partners at Taiho are leading the commercialization efforts. They have three 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 front line approval for zipalertinib. I just wanted to make that clear. We have plenty of time to make the decision of whether we opt in or not. It's not on the relapse setting. It's in the front line setting. 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 D, which is the patients with uncommon EGFR mutations or the PAC mutations. That is a series of dates 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. 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.
Any questions, Kaveri? Then we'll go to you, Sumit.
Good evening. This is Kaveri Pohlman from Clear Street. Thanks for all the information. Congrats on the progress. Just want to understand, maybe my questions are more directed towards the young oncologists here. 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? Is the prevalence of brain mets higher in late line versus front line patients? I have a second question.
Yeah, that's a very critical question to address. These EGFR exon 20 patients, a lot of them just de novo, in the beginning, will present with brain mets. A lot of times, it will progress with brain mets. The worst is when they progress with something called leptomeningeal disease, where it's deeper in, and the prognosis is three months or less after that. I will 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. I will say some of the preliminary data, as you saw so far, even if they had brain mets, they still respond, and there's good disease control, and they don't progress. I think that's very encouraging data.
Nadim just said, "I'm not sure we're able to actually present that data until a little bit later." 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 radiation, so they're okay, and then they start the drug. I would say a lot of patients don't tend to really progress in the brain as the first place when the drug stops working. That's just more anecdotal. Definitely, some patients do progress in the brain, unfortunately. Hopefully, we'll have more concrete data in the future at Congress.
That's right. In that module of the RESILIENT TWO trial, the intracranial response rate is being carefully characterized. That should be not too many months on, we'll have that data public. Right.
There is a lot of breakdown in terms of demographics, especially based on prior treatment in this presentation. What is the breakdown for those patients in real world when you see patients? How often are patients in second line chemo naive? How many are Amivantamab or other TKI experienced? I would say, in other words, what population really represents the majority of real-world setting in second line or later patients?
Yeah, good observation. I think also it depends on who you ask. At City of Hope, it is more of a tertiary referral center, so we definitely get heavily pretreated patients. Most of the patients initially get diagnosed in the community. Right now, a lot of the community oncologists, if they start them on treatment, are really tied by what is FDA approved and what insurance will approve. That will usually be chemotherapy plus or minus Amivantamab.
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 other options. These EGFR patients, a lot of them are younger, really savvy with technology. They do their research. Some of them may have been on other clinical trials even already. My experience is, yeah, a lot of them are heavily pretreated. 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 to UCLA for a trial. That guy still responded. I also think it also matters how you sequence treatment as well.
I think, as you saw in the data, in a patient who was chemo, amivantamab, and EGFR pretreated, and then get this drug, the response rates are lower. That's why a lot of times what I'll do is if I saw someone 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 the study or something. I've had a little bit better responses. In my heavily pretreated patients, when I did that, I don't think the response rates were that low. I think it depends on who you ask. Yeah, a lot of my patients were unfortunately heavily pretreated. You get occasional newly diagnosed patients to come see you as well.
That one, they knew that chemo was an option, and they just flat out refused, so.
No more questions, I think. There was Sumit and Andy, and we were Mark here as well. Lee's going to make you run around a bit.
Yeah. Andrew Berens with Leerink Partners. One maybe science question and 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 zipalertinib, is there any data to suggest the role of MET amplification in exon 20? The housekeeping question is, I think you guys are responsible for co-promoting too.
If you're not going to make a decision until the front line, are you thinking about building a salesforce and then not continuing that? Is that how it would work out?
Let me start with the last one. Yeah. I think as we think about what we want to do in the future, the important point is that it wouldn't be opted in until the front line indication. 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. For us, I think we would really want to strategically think about how the rest of the portfolio is moving. It obviously becomes much more attractive if you have other products that your reps could carry.
It's going to be the choice of, at that time, do I have other products, or is it focused in on zipalertinib? As I said, we got plenty of time to make that decision. Hopefully, I addressed your question, Andy.
Yep.
You had the other question, the big mechanism of resistance question.
Yeah. First off, I appreciate your question. Coming from, it sounds like, non-medical person, you guys really understand the data quite well at a medical conference. That's a high-level question, I think. Mets. In my opinion, the EGFR, whether it's common mutation like the exon 19 and 21, and then the exon 20, and then these atypicals are the catch-all others, they all activate the EGFR receptor. It's just the mutation is a little bit different.
What distinguishes the exon 20 from the common is that this one main drug, this Tagrisso drug that has an 80% plus response rate in the common mutation, does not fit into that EGFR exon 20 space as well. For all intents and purposes, the EGFR receptor is still activated and turned on the cancer. A lot of these EGFR exon 20 patients, in my observation, have progressed very similarly than if they were a common EGFR. I have seen patients develop a T790M mutation, which Tagrisso is good for, C797S, and then other resistance mutations. Amivantamab is already approved for EGFR exon 20, which is EGFR and MET bispecific antibody. I would presume that it is another bypass pathway for exon 20.
Yeah, I mean, I'm not the only doctor who has thought about combining zipalertinib with a CMET agent as well to maybe augment that effect, much like the Mariposa study for amivantamab and lazertinib, like another EGFR TKI. I think we're all kind of on the same page.
Pullman, you this morning mentioned we have collected plasma on the patients enrolled in the study. We have circulating tumor DNA. We will be able to look ultimately at some of the characteristics, molecular characteristics at the time of relapse. Lee, can we go to Sumit next? Oh, did you have enough to follow up, Andy?
I was just going to say, when may we see some of the breakdown of the resistance?
No specific timeline. I'd say right now, we're focused on actually making the drug available to patients is mission number one. Lee, we have to do Sumit next. He's been waiting. All right, Mark, you're going to drop the mic on me, I think.
Mark Frahm from TD Cowen. Maybe on this idea of, while the approval would be in the second line setting, that patients may opt to refuse other therapies to try to get to zipalertinib. I mean, even here, you had a case study of a patient who's already refusing approved available therapies. Just do you have a sense of how many patients are already refusing just because of the burden of the side effects of amivantamab, are already refusing that therapy even when there isn't a good option available for them commercially?
Yeah, 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. I've not seen anybody who got zipalertinib, and then who also got ami, did not have a major ami side effect. They would report that they did not like it. A lot of those patients, like you saw, are young, fit, otherwise, and they're motivated to live. If Amivantamab is the only thing that's keeping them alive, they will tough it out.
Could I just ask another question related to what Mark is asking? Obviously, a lot of the newly diagnosed patients are in the community. The ones that you do see, how do you decide between giving them chemotherapy alone or Amivantamab plus chemotherapy? What's that proportion? I think you're kind of getting at that, Mark, right?
Oh, yeah, yeah. Those patients that I see, I offer them chemotherapy and Amivantamab upfront. I mean, the PAPILLON study demonstrated the overall benefit. Yeah, it's really the best that we have right now. Until an oral agent gets on the market, those are what the patients are going to get. Yeah. Okay.
Hi, Shomit from Johns. Great data. Trying to understand, fast forward a year from now, if everything goes right, the treatment landscape in the front line setting. We have Sunvo, could get approved. Pharmo could get approved. We have two exon 20 oral drugs, monotherapy in the front line setting versus REZILIENT3 is coming up as a chemo comp. How are physicians going to make the decision? Then again, we saw the data this morning, zipalertinib after TKI is not as effective. How are you going to position this?
Yeah. Yeah, that's definitely a valid point. I would say a lot of right now, I think 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 a discussion board with another oncologist who sent his patient over to China to get the sunvozertinib and bring it back. They already had to dose reduce it by half because of the side effects of it. That is what patients are willing to do to be alive, to go over there and bring the drug back. I will tell you, I do not have personal experience with sunvozertinib. I do see the data.
Yeah, their efficacy data is definitely up there for sure. I do see nuances in terms of tolerability, side effect, and dose reduction. 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. 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 all the data in the U.S. I feel like a lot of providers, where I'm from, especially in California, everyone's heard about zipalertinib now. There's definitely a good reputation with that drug. They've also done a lot of outreach to patient advocacy. There's an EGFR exon 20 support group, Marsha Horn, who she knows.
She's actually referred me a lot of these patients. She knows that the drugs are very well tolerated too. At the end of the day, a lot of those patients get directed to treatment by that group. I think locally, a lot of the data was U.S.-driven, which is good. I think a lot more U.S. providers are familiar with zipalertinib. Definitely, Sunvozertinib and furmonertinib are going to be competitors for sure.
Maybe a question for Jeff. Do we have any idea what percent patients could have active brain mets? You have 14% patients with radiation treatment, 33% untreated. Is it fair to think most of those untreated had active mets? Do we know any CNSOR?
CNS response rate, so the CNS-specific response rate, we can't calculate it because we don't really know the—we're not always sure of the denominator because all of the patients aren't being systematically assessed in the CNS. If we even gave, and if they don't have target lesions in the CNS, then they're not being systematically followed over time. We'll have an answer to that question when the module C of REZILIENT2 is presented later this year. 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. As a group, the cumulative rate as survival improves is roughly 50% in very heavily pretreated later-line patients.
If you live long enough, it happens. 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. It is a very important clinical problem.
The interim data did not really show a statistically significant OS benefit. We do not really know what the mature—I just wanted to know, what do you think? Do you think it will be able to show a statistically significant OS benefit? Does it really matter given that the hazard ratio is already 0.67? How do you see the potential of zipalertinib in first line, whether amivantamab shows a significant or does not show a significant benefit? Thank you. Yeah.
I think the reality is, 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 PAPILLON first line?
Yeah. Could they be treated with Amivantamab at progression? Like a crossover in that study?
Yeah. Yeah. If they progressed on chemo, they can get Ami second line. And we know Amivantamab monotherapy second line is effective or has activity. 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. I think you throw zipalertinib in there. I think it'll definitely make these patients live longer.
This patient, taking it by itself first, it's kind of interesting to see 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. Maybe it makes it resistant to a lot of other targeted treatments. It is possible that you hit them with the TKI first. They do not really develop this crazy cancer afterwards. You can still use chemo and amivantamab in later lines. 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.
I've seen other cancers where a drug was only approved third line, and you have to have chemo, and you have to have another agent. What they'll do is they get one dose of chemo, they get one dose of that agent, they'll just say they don't tolerate it. All of a sudden, in their third line, and then the insurance approves the drug. 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. I think,
and receives the best therapy for their particular condition, whether or not it's gone through the regulatory review process for that specific setting. To your first question, the overall survival data that's reported is probably the best that will ever show up for the PAPILLON study.
I mean, because of crossover, because 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. 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. The experiments are never pure, which is in all of our collective and our patients' best interest.
All right. Thanks very much. Dr. Owen, thanks very much. Jeff, thank you very much. Appreciate it.
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. 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. Thanks again for coming tonight, and we'll keep you updated in the future. Thanks for your attention.