All right, good evening, everyone. Pleasure to be here to talk about all of the exciting work going on at Cullinan Therapeutics. This is our disclaimer slide. I will be making forward-looking statements, so please bear that in mind as you listen to my presentation. So here's the agenda. So after my opening remarks, our Chief Medical Officer, Dr. Jeff Jones, who's sitting down behind me, will go through the ASCO data we had for CLN-619, our MICA/MICB antibody, as well as the data we released just today, hot off the press, of zipalertinib in prior amivantamab-treated patients. And then we're very fortunate to have Dr. Alexander Spira join us, who is the co-director of the VCS Research Institute and also is a director at Next Oncology Virginia, doing great things in community oncology. At Cullinan Therapeutics, we have what we believe is a very unique strategic approach to discovering and developing first-in-class and best-in-class molecules, what we refer to as modality-agnostic targeted research. What that means, essentially, is that our discovery efforts start by identifying the highest impact targets, and we then think about how is the best way to address these targets. So we are always target first, modality second, which is very different to many of our peers. And so that means we're not relying on a single platform or even a single product. So that's one thing. The other unique aspect of what we do is we set a very high bar for go, no-go criteria as we move molecules through research and development. So we front-load as much experimentation as possible early in the discovery process through what we call thriller or killer experimentation. And so when we get the killer result, as the name suggests, we kill the program and we reallocate our resources. When we get the thriller result, we think about: How can we increase our investment? How can we accelerate this program into the clinic? So by doing this, we bring forward only the most promising and highly differentiated molecules into the clinic. Recently, we were very pleased to announce our strategic expansion into immunology with CLN-978, our CD19 x CD3 T-cell engager, which we believe is an off-the-shelf potential disease-modifying regimen that can address unmet diseases across a range of autoimmune diseases. At the same time, our oncology pipeline remains on track, and you'll hear about that, especially given that we're here at ASCO. And so Jeff will talk about CLN-619, as well as our zipalertinib data. Throughout 2024, going into the first half of 2025, we have multiple clinical data readouts. As many of you are aware, we recently closed a financing of $280 million, which gives us cash runway into 2028, which allow us to both continue to progress the oncology pipeline and fully unlock the value of CLN-978, our CD19 x CD3 T-cell engager across autoimmune diseases, which will ultimately help us deliver on our mission to create new standards of care across oncology and immunology. So you can see the result of our unique R&D strategic approach. We now have a pipeline, clinical stage programs, first in class or best in class, highly differentiated, multiple targets, multiple modalities, giving us a very diversified pipeline across oncology and across immunology. As we've moved these programs into the clinic, we have a very exciting 2024 and beyond ahead of us. As I said, with multiple data catalysts in the form of clinical data readouts, starting with CLN-619, which is our first-in-class potential MICA/MICB antibody. We're gonna talk about the ASCO data, but in addition to the ASCO data, we have the expansion cohorts of endometrial and cervical cancer reporting out in the first half of 2025. CLN-978, as I mentioned, is our next generation CD19 x CD3 T-cell engager, and we've already declared our first indication will be systemic lupus erythematosus, or SLE, and we plan an IND in the third quarter of 2024. We released the zipalertinib data today, our best-in-class potential EGFR exon 20 inhibitor. And so we released the data today, you'll hear about, and we're still on track to complete the accrual of the relapse study by this year end. In addition, we have other clinical stage programs, so two programs for which we'll be reporting out data in the second half of 2024. CLN-049 is our FLT3 by CD3 T-cell engager, so another T-cell engager that we're exploring in phase one dose escalation in relapse refractory AML and high-risk MDS. Also, in the second half of 2024, we'll be reporting out on CLN-418, which is our B7H4 by 4-1BB bispecific immune activator, again, in phase one across a broad range of solid tumors. In earlier phase one, we also have CLN-619, which is our IL-2/IL-12 fusion protein, targeting a range of solid tumors again. As I mentioned, very pleased to have cash runway into 2028. Look, right now, this is a really exciting inflection point for Cullinan Therapeutics. As we continue to progress our oncology pipeline and fully unlock the potential value of CLN-978 in oncology and immunology. And as we think about our mission to create new standards of care for these patients, we believe we have the first-in-class and best-in-class molecules and pipeline to deliver on our promise. So now let me turn the program over to Dr. Jeff Jones, who'll talk about the exciting ASCO data. Thanks, Jeff. All right. Tonight we'll talk about what was new this year at ASCO, the combination cohort studying CLN-619 in combination with the checkpoint inhibitor pembrolizumab, and also provide an update on observations from the monotherapy arm of the trial, data that was initially presented at this meeting last year. Then I'll provide an overview of where we stand in the broader development program for CLN-619, and how the current data has informed those decisions. So maybe to start, just a reminder about what is still to some, a relatively unfamiliar mechanism of action. MICA and MICB are stress-induced ligands that are upregulated on the majority of cancer cells, and this allows them to be flagged for recognition by NK, NKG2D expressing cells of both the innate and adaptive immune system. But as in other clinical situations, cancer evolves mechanisms for immune evasion, in this case, proteolytic cleavage of MICA and MICB in the tumor microenvironment. This leads to immune evasion that can be restored to immune surveillance through the binding of CLN-619. It binds near the site of proteolytic cleavage and stabilizes MICA and MICB on the cell surface, and helps reestablish the immune synapse with NKG2D. But because the antibody is Fc competent, it also induces both ADCC and ADCP, effects that can be further enhanced in combination with checkpoint inhibitor. So to that end, we have been prosecuting a phase I study exploring CLN-619, both as monotherapy and in combination with pembrolizumab. And we have completed the dose escalation phase of the trial, and what I'll share with you tonight are data current as of the twenty-ninth of March. So let's look first at the group of patients who were enrolled to the combination therapy arm of the study. In the eligibility, patients could enter the study without regard to prior treatment with checkpoint inhibitor if they had an advanced solid tumor that had exhausted all existing opportunities for therapy, which could have differed depending on the geography, since this is a global trial. You'll see that we enrolled a relatively heterogeneous group of patients who were, in general, heavily pretreated with a median of three prior therapies, at 41% of the patients having received prior checkpoint inhibitor therapy as part of their prior therapy. This patient population is similarly heterogeneous to the monotherapy population you see on the right. We'll come back to that. But what you'll see is that the patients were in different proportion. Most notably in the combination cohort, we did not enroll any endometrial patients, whereas in the monotherapy arm of the trial, we did enroll three. So of the 22 patients that were treated in the combination arm of the trial, 18 were response-evaluable for response, and we did see confirmed responses in three patients. And all of the confirmed responses, just like in the monotherapy arm of the trial, occurred at doses of CLN-619, 3 milligrams and above. So it's worth double-clicking on these three responses because sometimes, it can be difficult to interpret data from a combination dose escalation. But in this case, while all three patients were checkpoint inhibitor naive, two of the three patients, both with oncogenic driver mutation-poziotinibtive non-small cell lung cancer, would not have been expected to respond to PD-1 therapy alone, making these responses very informative for the potential of 619 in non-small cell lung cancer. The responses were observed relatively promptly at 5 and 9 weeks, respectively, and the patient with EGFR mutated non-small cell lung cancer had a response that was durable for 6 months. Looking again at the monotherapy arm of the trial, last year, we presented data for 37 patients. This year, we present data for the full complement of 42 patients enrolled to the monotherapy arm of the study. Again, heavily pretreated, similar median of 3 prior lines of therapy. In this group, 50% had received prior treatment with checkpoint inhibitor. Among those 42 patients, 29 were response evaluable for response and treated at doses of 1 milligram per kilogram and above. One milligram per kilogram, you will recall from last year, was the dose level at which we began to see prolonged stable disease emerge. In this group of 29 evaluable patients, the clinical benefit rates, which we defined as objective response or stable disease sustained for at least 18 weeks, was 41%, which I continue to think is a remarkable finding in a phase I dose escalation study. I think it's again worth diving in a little bit further to discuss the responding patients, and these are the same responders that we presented last year: a mucoepidermoid parotid gland patient and two patients with endometrial cancer, one of whom had serous subtype, a particularly challenging subtype of endometrial cancer. Patients were heavily pretreated, as you can see here, and in the case of the mucoepidermoid parotid patients and the serous endometrial patients, both had received prior therapy with checkpoint inhibitors. Looking at the responses, all three patients experienced a better response during treatment with 619 than they had experienced with their immediate prior therapy, and all of the responses were durable beyond six months. Interestingly, in the group of patients who had stable disease, six of the nine patients had received prior treatments with checkpoint inhibitors. And in that group, there were some really remarkable cases. The cases of ovarian and breast cancer had each received seven prior lines of therapy, but both patients achieved stable disease that was durable for nearly a year. In the case of the pancreatic cancer patient, this patient had exhausted 3 prior lines of chemotherapy and continues with stable disease, now approaching 6 months. So takeaway messages here, durable objective responses are feasibly obtained with CLN-619 monotherapy, but the clinical benefit extends to a far larger and more diverse group of tumors, including cervical, endometrial, and ovarian, as we shared last year, but also non-small cell lung cancer. So of the 8 of the 11 patients with non-small cell lung cancer that were enrolled to both arms of the trial, 8 were RECIST evaluable for response, and of these, 6 had oncogenic driver mutations. So 3 of those 6 patients were the ones who experienced clinical benefits. Two partial responses in the combination arm of the study and a third patient with STK11 and APC mutations treated with monotherapy, who experienced stable disease for about 6 months. So I'll talk a little bit more about one of the responding patients. This is the EGFR mutated patient. This patient had experienced 6 prior lines of therapy before study entry, and his baseline image is shown on the right. There you can see, indicated by the green arrow, a 3.2-cm liver metastasis that had already regressed to meet criteria for partial response by cycle 4, day 1, which was subsequently confirmed at cycle 7, day 1. As in all areas of oncology, we're particularly in patients who are very heavily treatment experienced, we're concerned about the tolerability of treatment, and I think that is, again, an area where CLN-619 has really shown. So whether looking at the monotherapy arm of the trial or the pembrolizumab combination, the majority of treatment emergent adverse events are low grade. Treatment-related adverse events that are most commonly reported include fatigue and what we've characterized previously, infusion-related reactions, predominantly on the first dose. In all but one case, these were grade 1 or 2 severity, occurred primarily during the first infusion and could be mitigated with corticosteroid pre-medication. So to summarize key takeaways from our data presentation earlier this morning. First and foremost, objective responses were seen with CLN-619... CLN-619 and pembrolizumab, and these occurred in patients whose tumors would not typically be responsive to pembrolizumab, specifically non-small cell lung cancer with ALK and EGFR mutations. Fortunately, this combination is as well tolerated as monotherapy, where we have confirmed that these responses are durable and associated with a continuing favorable safety profile as the patients continued with treatment. We saw that the clinical benefit extended to a larger group of patients in multiple tumor types, including those whose disease had progressed after checkpoint inhibitor therapy. Based on these new observations, we have initiated expansion cohorts. Last year, you will recall that we initiated endometrial and cervical disease-specific expansion cohorts with monotherapy, and have subsequently disclosed an ongoing combination of PD-1 and CLN-619 in endometrial as well. But based on these incremental observations, we are now enrolling patients in monotherapy and combination cohorts of non-small cell lung cancer, including patients who have oncogenic driver mutations. We are also quite interested in the potential of further combination of CLN-619, and do intend to initiate combination cohorts with chemotherapy, the first of which will be in platinum-resistant ovarian cancer. So just a few words about the hypothesis behind the chemotherapy combination. We understand that platinums and taxanes, in particular, can upregulate MICA and MICB expression, and chemotherapy can also promote the influx of relevant immune cell populations and promote their activation status. So we think that there is a very strong rationale to combine CLN-619 with chemotherapy to potentiate its activity by inducing cellular stress. And of course, there are numerous examples across antibodies in advanced in solid tumor oncology, where the combination of chemotherapy and immunotherapy has been an important part of the treatment armamentarium... So here now summarize the broader development program for CLN-619, and this is really trying to fully exploit the pan-cancer opportunity for the drug. So cervical, endometrial, and non-small cell lung cancer, we've talked about, and we do intend to initiate a platinum combination with chemotherapy and platinum-resistant ovarian cancer. Finally, I'll remind you that we do have interest to explore the potential of the drug in hematologic tumors, and here the scientific rationale is quite strong for multiple myeloma, and we will begin a Phase I dose-escalation study of monotherapy before the end of this year. Finally, a reminder that as the data continue to mature, including the translational data, we will potentially explore additional combination cohorts, either with PD-1 or chemotherapy, as well as a possibility of additional monotherapy cohorts. I'll turn now to an update on our small molecules of zipalertinib, and you know that this molecule is targeted for development in exon 20 insertion mutation EGFR non-small cell lung cancer, where exon 20 insertion mutations represent about 12% of EGFR mutated non-small cell lung cancer, but about 2% of non-small cell lung cancer overall. The largest remaining group of patients with EGFR mutated non-small cell lung cancer, for whom there are relatively few effective treatment options. So zipalertinib has a unique chemical scaffold that conveys high selectivity for mutant EGFR, and the drug is also HER2 sparing, which we think gives it a more favorable therapeutic index. In our Phase I/IIa study, the part of the REZILIENT-1 study, we treated 39 patients at the recommended Phase II dose of 100 milligrams BID and demonstrated an overall response rate of 41% with a PFS of 12 months, which is at the top end of what has been reported for other exon twenty-directed drugs. This also came with a relatively favorable safety profile, with no Grade 3 rash or diarrhea, common wild-type EGFR-associated adverse events, and a limited number of dose reductions and discontinuations. We began the REZILIENT-1 pivotal Phase IIb study in Q4 of 2022 and have been treating two parallel cohorts of patients. In the first cohort, patients have received prior chemotherapy, but no exon 20-directed drug. In the second, which is the focus of the data presentation tonight, patients have received prior treatment with exon 20, in this case, the focus being the currently approved drug, amivantamab. In this group of 31 patients enrolled to the prior exon 20 group, all patients had received prior amivantamab, and you can see here that 97% had also received prior platinum-based chemotherapy. As compared to the Phase I/IIa group, where the median number of prior therapies was two. In this group, the median number of prior therapies was three, so these patients are more heavily pretreated, and 50% of the patients, nearly 48, had prior brain metastases. The protocol allows patients with prior brain metastases if they are stable. So here in that group of, patients, 18 were evaluable for response at the time of the data cutoff in January, and here the overall response rate was 39%, and the disease control rate, inclusive of patients who had stable disease, was 94%. As you can see, this compares quite favorably with the results obtained in patients who had received only prior chemotherapy, where we reported out an overall response rate of 41% and disease control rate of 97%. At this point, both the duration of remission, or pardon me, duration of response and progression-free survival are immature to be estimated. I'll show here, though, the waterfall group for this, waterfall plot for this group of patients, and this displays 17 of the 18 patients, all of whom had some regression of their tumor. You'll note in the lighter blue bars, the patients who had received both prior amivantamab and another EGFR exon 20-directed drug, demonstrating that the clinical benefit of zipalertinib was broad across this patient population. Here, the swimmer plots. While I mentioned that the response, the follow-up for duration of response is still quite immature, you can see at the top that there are several patients who have had stable disease and objective response durable for longer than 6 months, and we are continuing, of course, to follow these patients, and we'll hopefully share an update in the near future. In terms of safety, I can share that the safety, the analysis demonstrated no new safety signals in this patient population. The safety profile is very similar to what we reported before, including treatment-related adverse events. There were no Grade 4 or higher adverse events. So our REZILIENT-1 study, including this group of patients who had been treated with prior exon 20 therapies, is only one part of a much broader development program, inclusive of the REZILIENT-2 and 3 studies, that are being executed by our partners at Taiho Oncology. The REZILIENT-3 study is a randomized Phase III study that we hope will make the drug available to patients in the front line, a study exploring the combination of zipalertinib with standard platinum doublet chemotherapy versus placebo... In the REZILIENT-2 study, I'll just note that there are several important cohorts there. In addition to studying monotherapy in the front line, this study is also exploring the drug to manage active brain metastases, and it's looking as well at patients with non-exon 20 uncommon mutations, including so-called PACC mutations, where there is great interest and persisting unmet need. So for zipalertinib, I think we're very gratified to see that there's promising anti-tumor activity, not only in patients who've received prior chemo, but also in patients who have received prior therapy with additional exon 20-directed therapies, where the objective response rate thus far looks quite similar to patients who are exon 20 therapy naive. The safety profile remains favorable when administered after prior amivantamab, and we think that this bodes well for the future of the drug as a potential therapy for patients with relapsed exon 20 mutation non-small cell lung cancer. We remain on track to complete the pivotal Phase IIb study enrollment by the end of this year and do look forward to continuing to advance this program with our partners at Taiho Oncology. I will complete my remarks now and turn it over to Dr. Spira, who will talk a little bit about the treatment landscape for metastatic EGFR mutated non-small cell. Thanks. Hey, everybody. Late evening in ASCO. Very tired. I'm gonna talk... I will talk today, kind of reiterating if you were at any of the sessions, kind of where the landscape is, probably reiterating a lot of the comments by the discussants as well, really pointing to where are we going in what's become a complicated landscape. So slide, everybody's here has probably seen in multiple different ways how we break everything down in terms of EGFR mutated patients. We all know that there's a lot of different mutations in the non-small cell lung cancer pathway. We break it down into either the exon 21, L858R, the exon 19 deletion, what we call the typical mutations. Jeff alluded to before the incidence of exon 20 insertions, to which there were no treatments but till a few years ago. And obviously, there's been a lot of interest, including zipalertinib, as you've heard today. We'll talk a little bit about the atypical EGFR mutations. This is kind of the stepchild of EGFR. Not much work has been done, much interest of late. We have approved drugs, we have off-label use of drugs, and it's been a renewed area of interest. It's really came about with excitement about the exon 20 drugs and reinvigorating the field. You can see on the bottom all the different mutations. That's a science question. I'll pass on that right now, but it's become a complicated area where even financial analysts have to look at molecular biology to know what we're talking about. The treatment landscape for non-small cell lung cancer with EGFR mutations, as you can see, has gotten rather complicated, with a lot of different options here. These are the NCCN guidelines. These will be probably rapidly changing. Osimertinib remains the top as category one for the typical EGFR mutations, really because of its well tolerability. That being said, there's a lot more under these optional ones, and again, this will be changing, soon as well as we learn about the availability of new drugs and new treatments. Some of this, of course, is related to the Flora data. We have MARIPOSA. We'll allude a lot to that over the next few minutes. You know, I think clinically, we get very excited. You know, Mr. and Mrs. Smith comes in, metastatic lung cancer, obviously a devastating diagnosis. We see a ton of these. This is the lung cancer of non-smokers. When patients walk in, you know, it's very exciting to tell patients, "Well, you have metastatic lung cancer, but the good news," we'll talk about the current standard, there's a pill. We all, you know, most people in the United States, not so much ex-U.S., but virtually everybody in the United States is treated with osimertinib. And it's worth looking back at the original FLAURA data from a few years ago. Yes, it's a great drug, but if you look, the median survival curves are good, but they're not great. And if you really look back at progression-free survival, you're hovering around, you know, 18 months for osimertinib on these curves. Remember, this is what led to the approval of osimertinib in the frontline setting. Brain metastases, of course, did worse. I always like to look at the overall survival curve on the right, and that's a really good curve by any stretch. You see people do well. osimertinib did better than the standard of care at that point, which was either gefitinib or erlotinib. But I still challenge everybody to look and say that a median follow-up of 1-2 years, the probability of overall survival is only about 60%. It's really sobering to remember that, you know, these are still patients, majority of which are young, the majority of which never smoke. They're, you know, very often with young families. When you're looking and saying that the median overall survival is still only a couple of years, and five-year survival is probably single- digits, maybe 10%, depending on the analysis, we clearly need to do better. So take-home message is, it's good, but there's clearly room for improvements. One of the things we break it down in the typical mutations, again, sorry to remind you of freshman biology, if you don't want to go... Freshman biochemistry, if you don't want to go that far back. The difference between exon 19 deletion and L858R, the two most common typical mutations, or we call the typical mutations. Exon 19 deletion does better. L858R does significantly worse, even on osimertinib, with a median progression-free survival of somewhere around 12-15 months. A little bit better in the exon 21, but clearly need to do better. So one of the questions right now is: how do you improve on the standard of care? And where that goes in, in the typical paradigm that we've heard in oncology since before I was a fellow a very long time ago, is if you get... You give your best treatments first. That's always been the paradigm. Whereas, as a baseball fan, you don't want to save your pitcher for tomorrow because it might rain.... And that's been questioned if you've kind of sat in on all these sessions, right? I mean, we've made a lot of improvement over the last couple of months, with the advent of the FLAURA-2 data, carboplatin plus osimertinib, versus osimertinib. So the addition of chemo to osimertinib and MARIPOSA, which was presented at ESMO and is impending publication in a major journal coming up soon. MARIPOSA is the use of amivantamab and lazertinib, compared with osimertinib. So 1, adding chemotherapy or 2, adding the bispecific EGFR antibody to frontline newly diagnosed patients. There's obviously implications for PALOMA-3, which I'll get to in a few seconds. So here we have the FLAURA2 data that shows that platinum-based therapy with osimertinib is better than osimertinib alone. Nobody was really surprised by this data. It's probably additive more than anything else. But as you can see, the progression-free survival, both upon investigator assessment and, blind, and independent central review, were both improved. We're still waiting for the OS curves to kind of be, you know, bear out there, but again, clear improvement there with progression-free survival. Again, as expected. This is the ESMO data. This has not been published in manuscript form. Again, coming up shortly. This is the addition of amivantamab and lazertinib, in or versus osimertinib. And again, improvement in progression-free survival, both at the 12- and 24-month landmarks, 73% versus 65%, 48% versus 34%, hazard ratio 0.7. The initial data presented at overall survival, almost there. You can almost see it. We expect that at the next iteration. So again, two very good options right now, but as everybody says, what do you do? And if you heard, if you heard a lot of the discussions at ESMO or any ASCO meetings, there's a lot of concern about switching to these new, better regimens. We're still waiting for overall survival. We'll talk about the benefits. We're still waiting for overall survival. It's a sobering reminder that only 75% of patients make it to second-line therapy. So do you want to use your best treatment up first, or do you want to wait? And that's a lot of the discussion. You know, while many people are young, many people are older, many people progress with brain metastases. And in that scenario, we know that real-world data says you may not even get to that second line of therapy, so don't save your horse because you want to use it upfront. And of course, the idea is if you can delay or prevent resistance, you might do better for the long term. I don't think anybody thinks there's going to be long-term cures or by intensification, but it's where we are right now. What are the downsides? You increase toxicity in 100% of patients. You increase the time in the clinic. Some of that is the use of having to come in for IV chemotherapy or IV amivantamab. The PALOMA-3 data, which I'm sure everybody has looked at, was very enticing in a few ways. You decrease the immune-related reactions when you're in the clinic. It's a much quicker, it's five minutes versus many hours. Clearly, more convenient for patients than moving towards either a Q2, Q3, or Q4-week amivantamab infusion, but you still have to come in versus taking a pill at home. Obviously, a very different world when doing that. We always say, you know, it's an increase in cost. In the United States, we don't pay attention for cost, but, you know, obviously, the addition of amivantamab in the newly diagnosed, and everybody is a huge financial burden and financial toxicity that you really can't forget. So there's been a lot of debate, and I think if you ask 100 oncologists, depending if you're at a Janssen ad board, an AstraZeneca ad board, or a generic ad board, the uptick in the newly diagnosed patients is still probably gonna be the majority getting osimertinib. That's really because of the convenience of an oral regimen that has very limited side effects. I tell my patients it's one of the easiest drugs to give. There's been some data. You look at biomarkers. There's abstracts being presented at this meeting, looking at the people that might really benefit, what are the biomarkers that can do it? And I think if you look at that, it's people that visibly have worse disease, higher burden of disease, multiple other mutations. But again, there's a lot of debate as to which is the right patient. Use the example of that 35-year-old mother of two, what do you want to do? On one hand, you want them to get the best possible therapy, but also, on the other hand, there's a 35-year-old mother of two that wants to spend time with their kids and not going into the clinic and not dealing with side effects. So it's unclear where we're gonna end up, but it's gonna be a very divided market. What do you do with second-line post osimertinib? So let's suppose the patients just get osimertinib currently before the addition of these medicines, or even after, these new regimens have become available, but you're gonna leave them on osimertinib. MARIPOSA two, carboplatin, pemetrexed, + or -, osimertinib, is the standard of care right now. MARIPOSA two, which is chemo + amivantamab. Datopotamab, the TROP2, antibody drug conjugate. I still am placing bets as to whether or not it's going to be approved or not. I'm sure you guys have some thoughts. I have some thoughts. I don't know where that's gonna end up. Patritumab is the HER3 drug, clearly a very active drug, not insignificant toxicity as well. So there's a lot of things going on, but remember, this is a very young population, often to go through multiple lines of therapy. It's not uncommon. I've seen patients for a clinical study that are on four different lines, docetaxel, gemcitabine, throwing osimertinib back again, and there's still clearly an unmet need in that second line in advanced therapy. To remind everybody here, the question always asked, you know, especially since you've heard, about CLN-619, where does immunotherapy stand? We know that immunotherapy does not work in these patients by and large, and is essentially always inferior to cytotoxic chemotherapy. Here, mostly docetaxel. Addition of PD-L1 to chemotherapy does not improve outcomes in metastatic EGFR mutant patients post-TKI. Again, more data here, as well. This is the MARIPOSA Two data, just to remind everybody what I mentioned before, really looking at combining the red and the blue lines, although there's a little separation, not to significance. So we're really talking about amivantamab chemo versus chemotherapy, after osimertinib, and clearly improvement in MARIPOSA Two. So if you get osimertinib and you want to give chemotherapy, this will be a major standard of care. It is toxic. Remember, you're giving people amivantamab, which has its EGFR-related side effects, as well as chemotherapy as well. But this is an emerging standard of care, published in The New England Journal last year. I mentioned before, datopotamab. Datopotamab is the TROP-2 ADC. You know, obviously, everybody here has probably been thinking about the Tropion study compared to docetaxel. We all know the squamous versus non-squamous breakdown, but really fascinated here by the AGAs, the actionable genomic alterations cohort. And if you look, I mean, that's a great waterfall plot with a lot of good responses there. Most of the patients, although this is any actionable genomic alteration, almost all of them were EGFR. It's clearly a very active drug. Where this plays out is obviously unclear, especially as, you know, we're looking for the label coming up soon. And this kind of came out of nowhere because, you know, in the EGFR world, when we think about EGFR, why do you think about TROP2? And I think what we know from this is probably a lot of TROP2 expression on EGFR mutating non-small cell lung cancer cells. We've talked about pertuzumab. There's a lot of other ADCs coming down the pipe. And of course, docetaxel is still the tried and true, and it seems no matter what oncology clinical trials to do, it always does better and nobody can beat it. We'll talk briefly now about the exon twenty insertions. It's a small number, depending on where you look, between 2%-9% of patients. I think I heard before, 2-4. I quote people, 4-10. This slide has a 9%. Small number of patients, but it's a huge unmet need for patients in this subset. It's evolved very quickly over the last couple of years. Mobocertinib was the drug that was until it wasn't withdrawn from the market because they got a little bit unlucky in that frontline clinical study, and it was clearly a toxic drug. Amivantamab, first approved, as you all know, in the second line, and then rapidly moved to the frontline with chemotherapy. Here are some of the waterfall plots. I mean, what a, you know, great drugs here, great waterfall plots, which you love to see. And there's obviously new TKIs in development as well. I listed Blue. The Blue program is shut down. But, you know, it's an evolving area, but clearly an area of unmet need. Here's the outcomes on the PAPILLON study, looking at amivantamab-chemo versus chemo. A lot of numbers on this slide, but we know that amivantamab-chemo does better than chemotherapy. Would love to have seen an amivantamab-only arm. I think the concern was that you were not gonna beat chemotherapy because chemotherapy still works here. But it would have been great to offer people a single targeted, EGFR therapy versus chemotherapy. Remember, these patients have a targetable mutation, so no matter how much you want to do it, chemotherapy still got a bad name. Safety profile here. You've probably seen this a million times in a million different ways at the ASCO meeting this year. Depending on which, MARIPOSA, MARIPOSA Two, PALOMA Two, PALOMA Three, you know, these drugs do have real side effects and is one of the reasons, of course, that nobody's enthused in the front line. It's really getting back to the EGFR related side effects from my... I call it the cetuximab days, which is paronychia rash, as well as the MET-related. Remember, it's a bispecific, so you get a lot of edema with this drug, as well as hypoalbuminemia. And these side effects are real. You know, people blow off the fact that you have swelling ankles, but when you've been on this drug, you're a little bit older, it can be a significant life-changing event, especially in real-world patient populations. The real question is, you know, we're now giving our all, our horses up front. Everybody's gonna get chemotherapy and amivantamab, by and large. When do you do second line? There currently is no standard of care. It's really docetaxel or docetaxel/ram, and it's really wide open for a new horse in this aspect because we don't know what to do in these patient populations. Finally, I'll talk a little bit about the stepchild, the atypical mutations, G719X, exon 18, a smattering of others. This is a world I'm not sure it can be replicated right now. There is one approved drug, the drug we as oncologists hate to give, and it's probably overdosed, afatinib. I've been sat on a billion ad boards, and I did not know this until somebody told me. Afatinib was approved based upon a bunch of retrospective studies where they put together, and they said, "Look, we had a whole bunch of patients that got afatinib, and they kinda did okay." It got FDA approved a long time. I'm not sure that would ever happen again. Afatinib was approved for other reasons, and it was probably, it was a second labeling, but it was really a, a leap forward that I don't think anybody... I actually would never thought actually happened. There's still a lot of off-label osimertinib abuse. I guess the market was too small for AstraZeneca. As I like to say, and they never pursued it. It's-- in the real world, it's used about 50% of the time. But given this, it's a very tough situation. You know, we tell patients, "Well, we have an off-label use of osimertinib that does work. It's not approved. Likely, we'll get it from insurance. It's out there." Or you have the drug that's approved that we all hate to give. It's a very, very toxic drug. It's very similar in toxicity to mobocertinib, and if that means anything to you. So that's kind of where we are in the EGFR mutated landscape right now. It's rapidly evolving. I mean, I think if I did this presentation a year ago, it would be drastically different. It'll all be, "I don't know what's going to happen here, where the possibilities are," and it's gonna be changing even more rapidly over the next 6-12 months. So it's a fun time to be an oncologist. I'll leave it there and say thank you. Yeah, thanks, thanks, Alex. I think we'll turn it over now to Q&A, and, as we're gearing up for that, you've had experience giving zipalertinib. You've seen the data we presented before, and then, you know, tonight after amivantamab. But- ...How do you, how do you think about the place for a drug like zipalertinib, and is what you say is a rapidly evolving, treatment landscape for exon 20? So I think there's clearly, there's clearly a place for it. Number one is I've had the pleasure of giving every exon 20 drug that's been out there. I don't know how that happened, but I've had experience with everyone, and it is clearly the best. It's at the top of the list, or one of the few at the top or at the top in terms of tolerability. I know obviously you guys are here, but I'm not just saying that it is an incredibly well-tolerated in this field. And I still, I think, very clearly looking at post-ami or even in frontline settings, there's clearly a role for such a well-tolerated drug. You heard my slide, it's obviously crowded out there, but there's still a niche for many of these drugs for patients. I think there's a clear way to make it, to get it to approval and help our patients. Great. I think, Lee, you're gonna... Hello, good evening. Kaveri Pohlman here from BTIG. Thanks for taking my question. Dr. Spira, I just wanna kind of... Can you just tell us about your experience with amivantamab? If you still—if you're still planning to use or you still use chemotherapy as a single agent because of amivantamab's toxicity profile, and how much benefit subcutaneous you think could provide? And maybe if I can just kind of ask a follow-up on that, do you expect amivantamab + chemo from the PAPILLON trial to show OS benefit? Okay, so lots of questions there, and I don't want to... I also want to make sure I'm talking about which exon, which mutations we're talking about. I'm specifically talking about exon 20 insertion mutations. Okay. All PAPILLON. Got it. So one is, there's going to be overall survival advantage. I think there's no doubt. I mean, you look at those PFS curves, and anybody would be shocked if it wasn't there. Subcu ami is a deal changer. Sorry, it's been a long day. Everybody's going to get it for multiple reasons: time in the clinic, convenience to patients, tolerability. So everybody's going to get it. You know, in the exon 20 space, it's easy. I mean, there is no competitors. In the frontline setting, it's the best therapy. Everybody's going to be giving it. We're all intrigued by PALOMA. Why? You know, they presented data that they weren't expecting of this overall survival advantage. and I've sat at about five different ad boards from Janssen, and I've heard all their scientists, and you've probably heard this as well, and nobody can really explain why. There's a lot of this hand-waving, but the curves are what the curves are. I mean, it wasn't expected, but it's going to be used 100% in the frontline setting, and the subcu is going to be used almost uniformly everywhere in the world. There'll probably be one or two places where you can't, just because of the regulatory approval, but it is going to be used that way. Did I get all your questions? I wanted to know, like, do you still do chemotherapy alone just because of the toxicity profile? You know, it's interesting. There is one doctor, I actually sat at a lecture, and he's a crotchety, old oncologist from the West Coast, and I'll leave it at that. And he actually said, "I wouldn't give it, but every other oncologist is going to." I mean, you'd be hard-pressed to not give a targeted therapy for a patient with a targetable mutation. I'm much more likely to give amivantamab off-label without chemotherapy rather than chemotherapy alone. Hi, Andrew Berens, Leerink Partners. Thanks for hosting this. It's great. Just a couple, I guess, on CLN-619. Do you guys have any of the biomarker data of the three patients in the combo, like PD-L1 level, STK11? And then, maybe a bigger picture on that program. Is the goal to develop this yourself, or are you gonna contingent, you know, consider strategic options? And then maybe, just on zipalertinib, would you guys have had any data on the atypical mutations to expand the opportunity? Yeah. So, I'll take the first one because it's the most—the last one first, 'cause it's the most straightforward. So from a preclinical standpoint, TPC did generate data suggesting activity against rare, EGFR mutations, and for that reason, that cohort is included in the REZILIENT-2 study, but, there's no data yet from that, publicly available. But it is, you know, another opportunity for the drug for sure, and a patient population in total that's around the same size as exon 20. In terms of your second question, I didn't, Paul, let you take that one. Sure. So I think the program that Jeff outlined, gets us into expansion cohorts, Andy, and I think we'd want to see the data for that first, as with potential partners. And so I think... Look, one thing I would say is, you know, post-financing, we're very well capitalized now, and so we want to do as much work to prove proof of concept across our pipeline, but especially CLN-619, which is our most important molecule in oncology, as well as CLN-978 now, which is our most important molecule in immunology. So I think we want to see a bit more declarative data and then assess what the strategic, strategic optionality is. And then you had one other question. Yeah, the three patients that responded in the combo arm, do you have any of the biomarker data, like PD-L1 status, STK11? Yeah. So for the patients that responded, so for the gastric cancer patient, that patient was a PD-L1 expresser. That patient might have been expected anyway to respond to PD-1, just based on what we know on gastric cancer, but didn't receive it because they reside in a country where it was not yet reimbursed. In terms of the other two patients, I don't believe we have, you know, additional molecular information on those patients. I don't believe we had obtained biopsies from those. Hi, Soumit Roy here from Jones Research. One question on the 619, the expansion cohort. Are you going to, in the endometrial cancer, are you going to include patients with prior IO therapies, or it's going to be excluded this time? Yes. I mean, I think, we have enrolled patients who are both, IO exposed and IO naive, but we are most interested in the patients who are progressing after prior PD-1 therapy. All right. Probably one question for Dr. Spira. When you look across the current presentations at ASCO, there are multiple, either TCE approach or small molecule approach, spanning different mutations of EGFR with one drug, drug. In case of Cullinan, do you think the modality will win or taking this rifle shot approach, the safety profile would be working in advantage for Cullinan? I think it's a little bit of both. I mean, we're very limited on some of these drugs by toxicity. So I think it's a little bit of both that's going to lead towards, you know, next generation approaches and looking at things. And again, I don't know if they're gonna take my advice or not, but I think there's also a role looking at combinations. You know, I think one of the things that we need to look at is, you know, can you combine some TKIs with monoclonals and increase durability of responses, get them a little bit deeper as well? And for that, you need a very well-tolerated drug to make up for some of the other toxicities as well. Maybe if I could ask one follow-up question, since you mentioned the PAPILLON study. We obviously have our own frontline study ongoing, so let's just assume success there, you get approval there. So kind of what's the clinical situation when you have both of those options available to you? The use of an oral medicine is always preferable for patients. So anything you can put an oral component in, that's certainly easier. And I'm an amivantamab lover. I mean, I am. I was involved in, you know... my name has been across the platform numerous ways. It's still got real toxicity. And, you know, I practice in a, you know, I'm not a real academic, I'm a pseudo-academic, so all my patients come from, real-world situations. There's a lot of them. That's where we do our programs and we do our trials. And I will say the toxicity that I see is always higher. You know, patients are a little bit older, patients a little more comorbidities. I call it the anti-MD Anderson effect, where, you know, when you're 34 years old and you can fly from Dubai to MD Anderson, you do great. Remember, that's the entire story of, I'm blanking the other exon 20 drug that failed. Obinutuzumab. Not Obinutuzumab, the- poziotinib. poziotinib. The whole poziotinib study, right? If you remember that, there was a 75% response rate initially reported, but in an MD Anderson study. It went down to 17% thereafter. So amivantamab has a real tox-- I love it, but it has a real toxicity. So anything that can mitigate that rash toxicity. Again, if you look at all the criticisms about giving MARIPOSA in the frontline setting, it's based upon one thing, especially with the advent of the subcutaneous formulation, rash and diarrhea. And anything that can be used to mitigate that is going to help. Thank you. Matt Phipps, William Blair. Thanks for the event and all the information. Why not evaluate CLN-619 in an EGFR cohort with some other kind of standard of care or something that has activity in the setting as opposed to Keytruda, whether it be nivolumab, chemo, a TKI, or maybe even docetaxel/ram, which I think maybe at least has some versus Keytruda? Matt, is that a question for us or Dr. Spira? I guess it's for you guys, since you're in that trial, but maybe- Sure. Look, as Jeff showed you, we've started to explore other combinations, and Jeff mentioned how chemotherapy is well described in the literature for up-regulating MICA/MICB expression. And so for us, the platinum-resistant ovarian cancer cohort in combination chemotherapy is just the start of the story, not the end of the story. And so obviously, we're thinking about other tumor types in that context, including lung cancer. And can you comment on the design of those targeted mutation cohorts? Is it any kind of a Simon two-stage or some kind of gated enrollment, and make sure you have some kind of efficacy bar to continue to expand? Yeah, it's a good question. And so, we tried to keep the trial design schema here, pretty, pretty clear. But we do enroll an initial group of patients, evaluate the response, which is gating for enrollment of the full cohort of patients. Yes. The specific numbers differ by cohort. Thank you. This is Kaveri from BTIG again. Is there any specific known biology that makes non-small cell lung cancer patients with oncogenic driver mutations more prone to respond to this treatment for CLN-619 and pembro combination? Yeah, it's a very good question, and it's one that we've asked ourselves, of course. I think there's no definitive answer there, but I think there are some characteristics of those patients' tumors that make them unlikely to respond to PD-1, most particularly downregulation of antigen presentation machinery and MHC-1. And so that may actually has no impact on the mechanism of action of CLN-619, but may actually make it more likely to work since MHC-1 does have some negative regulation of NK cell function. Got it, and maybe a quick one. Sorry if I missed it. What was the median duration of follow-up for the updated zipalertinib data for amivantamab pretreated patients? We don't have a median duration of follow-up calculated at this point. It's immature for durability. Got it. Thank you. ... Bijan Mekoba, CFOL Research. Congrats on the data, and thanks for the event. Just two questions. How are you thinking about exploring development in lung cancer? And then also, what's the rationale for opening the monotherapy cohort? I'm wondering, what are you looking to achieve with that expansion cohort? And then, one additional question for ovarian cancer. Now, what are some of the early signals that you'll be looking for with this expansion to continue development? Mm-hmm. No, it's a good question—both are good questions. So, in the first case, you know, when it's very challenging in a single-arm study to elucidate the relative contribution of the two drugs. So I think while we feel reasonably confident that these patients are unlikely to respond to PD-1, we do want to further understand the relative contribution of 619 versus the combination therapy. So for that reason, we're at least going to generate some initial data with monotherapy to better tease that out. I think the future path for an effective immunotherapy in EGFR mutated patients could take a number of forms. So I think as Alex was stating, you know, there are changes in the field. Chemotherapy is what the majority of patients receive after TKI failure. There's opportunities to combine with that standard of care, as well as perhaps evolving standards of care. An immunotherapy with a favorable safety profile has that potential, but I think we take the first step by simply characterizing its activity in the current study. And then, on ovarian cancer, is there a potential for a biomarker? Just as you were speaking, I thought of that. Is there- I'm having trouble hearing you. Oh, sure. For ovarian cancer, A potential for a biomarker? That's correct. Yeah. Ovarian cancer. In ovarian cancer, right. I think there are potentials for biomarkers across tumor types. In our biomarker and translational program, we're looking at a whole panel of things. Thus far, we haven't identified a predicted biomarker for response. In the case of the ovarian cancer combination, I mean, first and foremost, we're looking for evidence of safety of 619 in combination with chemotherapy. That's the primary aim of the first part, and then, of course, we're looking for relative efficacy against historical control to understand where we think the antibody is providing additional clinical benefit. Mm-hmm. I, I would add, I think the other opportunity in ovarian cancer is if you look across the spectrum of gynecologic malignancies, endometrial cancer seems to be the most sensitive to checkpoint inhibition. Then you get cervical cancer, and then ovarian cancer has been very, very challenging for checkpoint inhibition. And today, most of the time, platinum-resistant ovarian cancer, you're treated with straight-up paclitaxel. So I think it's an experiment worth doing, and if the theory of upregulation MICA, MICB expression holds, you know, that gets us excited about that opportunity because the unmet need has still lingered for a very long time. Thanks. Robert Driscoll from Wedbush. Maybe just quickly go over the regulatory strategy for zipalertinib, just kind of with the frontline study running and then this, over the REZILIENT-1 or REZILIENT-2 with the different cohorts. To go over the- The regulatory strategy. Registration strategy. Right. So I think what we've said before is that for REZILIENT-1, the study we're running, we believe there's still an accelerated approval pathway open. We do understand that the unmet need population is evolving. That's the driver behind enrolling the patients post amivantamab, a decision that we took, now almost 2 years ago, understanding that amivantamab would likely receive approval in the frontline. But we think that the unmet need population is going to evolve to include patients who are relapsing post chemo, as well as patients who have had prior exon 20 directed therapy, and we think that data set really supports approval there. In the frontline, this is a place where, as the PAPILLON study showed, chemotherapy still has an important role in combination with exon 20 directed therapy. We think that the strategy that we've taken in combining zipalertinib with chemotherapy is the right one. I think the PAPILLON experience suggests that. We you know, we think that it does provide a favorable alternative for patients to receive oral medication for all of the reasons that I think Alex has just outlined. We think that you know, we're working with Taiho to very quickly expedite that study, understanding that it needs to be substantially completed at the time of filing in the relapse setting.