Good afternoon, and thank you all for joining the ORIC Pharmaceuticals Business Update ESMO 2023 conference call. At this time, all participants are on the listen-only mode. As a reminder, today's conference call is being recorded. I would now like to turn the call over to ORIC's CFO, Dominic Piscitelli. Please go ahead. Good afternoon, and welcome to the ORIC Pharmaceuticals ESMO 2023 conference call. Earlier today, we issued a press release highlighting initial clinical data from our phase Ib trial of ORIC-114 in EGFR and HER2 mutated cancers. You may find the press release posted on the investor page of oricpharma.com. We have pre-recorded our prepared remarks, after which we will host a live Q&A session. Before we begin, starting on slide two, during this conference call, we will be making forward-looking statements, including forward-looking statements based on our current expectations and projections about future events and trends that may affect our business, utilizing data available to us as of September 26th, 2023. ORIC's actual results may differ materially from those expressed in or indicated by such forward-looking statements. For a description of risk factors associated with investing in ORIC, please refer to our recent filings with the SEC. ORIC specifically disclaims any obligation to update any forward-looking statements except as required by law. This presentation contains interim results based on initial data from the ORIC-114 clinical trial as of the database cutoff date of September 26, 2023. During this presentation, we will not be speaking to any data subsequent to such date. Now turning to slide three. During today's call, we'll discuss the target product profile we set out to achieve for ORIC-114, initial phase Ib trial results, next steps for the program, and finally, a broader market and competitive context, followed by Q&A. Joining me on the call today, we have Jacob Chacko, CEO, Lori Friedman, CSO, Pratik Multani, CMO, Matt Panuwat, CBO, and our guest speaker, KOL, Dr. Alex Spira. Now let me turn over the call to Jacob. Thank you, Dominic. Turning to slide four. Despite two accelerated approvals and numerous drugs in clinical development, a best-in-class profile has yet to emerge in EGFR exon 20 non-small cell lung cancer. Mobocertinib's recent failed confirmatory trial and subsequent withdrawal is a prime example of how the programs in the EGFR exon 20 space have underserved patients and missed on achieving an optimized TPP. The ideal best-in-class profile has 4 key components that are outlined on the right side of the page. The first goal is to be EGFR wild type sparing, to minimize the incidence of rash and diarrhea, while potently inhibiting a variety of exon 20 mutations. The second equally important part of the safety equation is to avoid off-target toxicities. Dirty kinome trees and other off-target liabilities lead to dirty safety profiles with a host of challenging toxicities like liver tox and QTc prolongation. Third, CNS activity. The high incidence of brain metastases and progression in the brain mean that if an exon 20 drug doesn't have CNS activity, then it doesn't have a best-in-class profile. It's that simple. And finally, compelling systemic activity, not just in exon 20 inhibitor-naive patients, but also in a post-Amivantamab setting. On slide five, you can see that it's not just Mobocertinib that has failed in hitting this TPP. Every exon 20 drug in clinical development is missing multiple aspects of the ideal TPP, with off-target toxicities and lack of CNS activity being the most universal shortcomings. This has created an opportunity for a best-in-class program to emerge, and you can see on the far right of the page the target product profile for ORIC-114. Slide 6 highlights that ORIC-114 has already generated data that suggests it is on the path to potentially becoming best in class in this space. The left side is a snapshot of one potential candidate, RP2D dose, 75 mg, dosed once daily. At this dose, ORIC-114 looks good from a safety perspective with respect to both EGFR and off-target toxicities. Consistent with the broader, heavily pretreated population that our study enrolled, this cohort included three post-Amivantamab patients, two of whom had brain metastases at baseline. Both had RECIST responses, one of which was a confirmed complete response. Within the small sample size of this cohort, ORIC has already achieved a number of firsts in the EGFR exon 20 space. First, CNS complete response ever reported in a patient with documented untreated brain metastases at baseline. Only development stage program to report a systemic complete response, and the only exon 20 inhibitor to report response after Amivantamab in a patient with active CNS disease. In fact, while the sample size is small, ORIC-114 in these post Amivantamab patients, has a response rate on par with or exceeding what competitors show in an exon 20 naive population. Turning to slide seven, what are the implications of the positive PAPILLON study? The obvious one is that Amivantamab will move to the frontline setting in EGFR exon 20. What's perhaps less obvious is that PAPILLON will likely complicate the path to approval for any drug that cannot demonstrate activity in post Amivantamab patients and in patients with active CNS disease, given that those patients were excluded from PAPILLON, since Amivantamab does not have CNS activity. ORIC-114 is the only EGFR exon 20 inhibitor to demonstrate activity in both of these settings, and that unlocks three distinct pathways to approval, which we can pursue in parallel for ORIC-114 across the first-line and second-line settings. Importantly, because of ORIC-114's activity post Amivantamab and in patients with active CNS metastases, it means that we can pursue approval pathways in which ORIC-114 would come after Ami, in combo with Ami, and instead of Ami. Furthermore, the data we've already generated begin to de-risk key proof-of-concept components relevant to these regulatory paths. Now, let me hand it over to Lori to remind you of the strong preclinical profile for ORIC-114 before Pratik covers the phase 1b trial results and next steps for the program. Thank you, Jacob. Slide nine highlights our key aims in identifying a clinical candidate that would support a best-in-class profile for EGFR and HER2 exon 20 insertion, insertion mutations. In the case of ORIC-114, chemists designed a molecule with multiple areas of differentiation. First, ORIC-114 is notable for its selective targeting of EGFR and HER2, while sparing inhibition of other kinases. Second, ORIC-114 has strong in vivo efficacy and excellent tolerability in preclinical models. Third, a key feature that was built into ORIC-114 is brain penetrance, which drives tumor regressions in xenografts grown in the brain of mice. Today, we're pleased to share that the preclinical data have translated well into clinic, where we see that ORIC-114 is well-tolerated, with antitumor activity, both systemically and against brain metastases. Taking each area of preclinical differentiation in turn, starting first with selectivity on Slide 10. Selectivity is one of the most important aspects for designing best-in-class compounds, as minimizing off-target toxicities is key in establishing a therapeutic index. Selectivity is one feature that differentiates ORIC-114 from other EGFR exon 20 inhibitors. In profiling across the kinome panel, ORIC-114 is exquisitely selective. In the table at the bottom of this slide, you can see the off-target data summary. ORIC-114 has zero off-target kinases inhibited, while other EGFR exon 20 compounds inhibited multiple off targets, which can lead to adverse events not related to EGFR, such as hematologic and liver toxicities. Moving to Slide 11, a second differentiation feature of ORIC-114 is strong potency against exon 20 mutations. You can see that ORIC-114 is highly efficacious in vivo, and once-daily oral dosing induced regressions in these three different models of EGFR exon 20 mutant lung cancer. Notably, these regressions were achieved without significant body weight loss, which further confirms the predicted therapeutic index for ORIC-114. Finally, turning to brain penetrance on Slide 12. Brain penetrance stands out as one of the most distinguishing features of ORIC-114, especially given the inability of approved and late-stage exon 20 agents to tackle brain metastases. On the left are drug property criteria enabling brain penetrance that are all met by ORIC-114: minimal P-gp engagement, suitable physicochemical properties, and high free unbound brain exposures across species. Shown on the right in head-to-head studies in rodents, ORIC-114 has high free unbound brain-to-plasma ratio compared to Osimertinib, and far higher than exon 20 competitors, competitors that have minimal free brain exposure. Shown on Slide 13 are results of an in vivo study measuring antitumor activity in the brain. This EGFR mutant lung cancer model was inoculated directly into the brain of mice, and tumor shrinkage was measured by imaging. The log scale on the Y-axis shows ORIC-114 achieving orders of magnitude deeper regressions in tumors grown in the brain compared to the competitor compound. Thus, ORIC-114 preclinical data reveals the potential to treat patients with brain metastases. This is critical because 35% of lung cancer patients with EGFR exon 20 already have brain metastases at initial presentation. With exciting emerging data indicating ORIC-114 as a potentially best-in-class compound, we wanted to explore other mutations in EGFR that could be responsive. On Slide 14, we assessed a variety of atypical driver mutations in EGFR and found that ORIC-114 showed strong cell potency against both classes of atypical mutations, primary mutations and acquired resistance mutations, and a superior profile compared to competitors. On the right side of the slide are in vivo results in a model bearing the EGFR G719S mutation, which is the most commonly mutated site of atypical mutations in EGFR. ORIC-114 produces strong in vivo efficacy with complete regressions in five of 10 tumors. We are now eager to enroll these patients with atypical EGFR mutations into our clinical study. Next, I'll hand it over to Pratik, who will discuss the initial phase 1b results that show the preclinical best-in-class results of selectivity, potency, and brain penetrance are translating to patients. Thank you, Lori. Turning to Slide 15, we are conducting our phase 1b trial in patients with cancer with one of the following alterations of interest: EGFR or HER2 exon 20 insertion mutations, HER2 amplification or overexpression, and more recently, EGFR atypical mutations outside of exon 20. Notably, and I will come back to why this is important, patients with active asymptomatic CNS metastases are eligible, as are patients with prior EGFR exon 20 inhibitor therapy. ...The study has two parts. Part one is dose escalation, including exploring once and twice daily dosing. Through part one, we intend to determine candidate recommended phase II doses for subsequent part two dose optimization, where we select the final RP2D for potential phase II registrational cohorts seeking accelerated approvals. Now, before I get into the study data, slide 16 highlights some critical differences between the eligibility criteria for our study compared to those for competitor agents. First, because of our conviction in the CNS activity for ORIC-114, from the very beginning, patients with active, untreated brain metastases have been eligible for our study, in contrast to the studies of these other agents, either approved or in development, which excluded such patients. Instead, they required patients with CNS disease to be previously treated in order to be eligible. Similarly, these other studies excluded patients who had received prior EGFR exon 20 inhibitor therapy. We imposed no such restriction. As a result, in our study, we have an exceptionally high rate of CNS disease at baseline and prior exon 20 inhibitor therapy, both negative prognostic factors compared to the reported data sets for these other drugs. Slide 17 shows our progress in dose escalation as of our ESMO data cutoff. We have examined eight QD dose levels and three BID dose levels, with additional patients enrolled in cohorts to expand on safety, PK, and efficacy. We have not reached MTD and therefore continue to dose escalate, currently at 120 milligrams QD and just recently at 50 milligrams BID as well. Slide 18 depicts baseline characteristics. Of the 21 patients with EGFR exon 20 mutated lung cancer, 81% had received one or more EGFR exon 20 targeted agents, and almost 20% had received two such agents. Again, that's in marked contrast to the populations that have been enrolled by Amivantamab and late-stage investigational programs, which are largely exon 20 inhibitor naive. In our study, the most common prior EGFR exon 20 therapy was Amivantamab in 15 of 21 patients. Given its likely first-line approval based upon the PAPILLON data to be presented at this meeting, our experience post Amivantamab actually plays to our benefit, since many competitor compounds have not demonstrated activity in this setting, while we already have. Our study patients also had an exceptionally high rate of CNS involvement at baseline in 18 of 21 or 86% of patients. This contrasts significantly from competitor compounds, where typically 35% of patients had brain metastases at baseline and where patients with active brain metastases were excluded. Finally, in patients with HER2 exon 20 mutated non-small cell lung cancer, the rate of CNS involvement at baseline was 38%. Not as high as in the EGFR population, but still very much in keeping with the expected rate of involvement in advanced non-small cell lung cancer. Slide 19 summarizes our PK data for our QD cohorts. For simplicity, the PK curves for BID dosing are not shown here because exposures with BID dosing were consistent with the equivalent QD dose. You can see that ORIC-114 has a PK profile that supports once daily dosing with a half-life of approximately 10-15 hours and with low intra-cohort variability in exposure. Superimposed on the PK curves is a gray band representing the projected human exposure based upon multiple in vivo efficacy models of various EGFR exon 20 insertion mutations. From this, you can see that at the 45 mg dose, we begin to cover the majority of in vivo models tested, and by 75 mg and higher, we would predict consistent activity against the full spectrum of EGFR exon 20 insertion mutations, while also accounting for possible variability in exposure from patient to patient. Slide 20 shows the safety profile of ORIC-114. For purposes of this safety analysis, we subdivided our dose cohorts into three categories by total daily dose, based on whether the plasma exposure was below the range, approaching the range, or within the exposure range projected to be clinically active. Focusing on the middle and higher categories, ORIC-114 was well tolerated with minimal EGFR wild-type related adverse events and little evidence of off-target toxicities. The vast majority of adverse events were grade one or two in severity, with a low 6% rate of grade 3 diarrhea and no events of grade 3 or higher rash. There was a low rate of dose reductions and just 4% dose discontinuations due to safety. Overall, we compare favorably to competitors. Finally, it's worth pointing out that the 75 milligram and higher group has a safety profile that is quite comparable to the 45 to 60 milligram group. Paired with the anti-tumor activity I will review shortly, these data point to a wide therapeutic index for ORIC-114. Turning now to slide 21, we have the waterfall plot for the patients with EGFR exon 20 mutated lung cancer, who received a total daily dose of 45 mg or higher and were efficacy evaluable, meaning that they had at least one post-baseline scan. First, as you can see, across four different total daily doses, 11 of the 15 patients on this waterfall received prior Amivantamab, and the majority experienced tumor shrinkage, with RECIST responses consisting of multiple partial responses, including one patient at 45 mg who had two of three CNS lesions resolve on therapy. Most notably, one confirmed complete response with a complete response in the brain in a patient post-Amivantamab. Overall, this activity post Amivantamab is critical, given Amivantamab's likely shift to the first line, and the fact that no other competitor compound has reported activity both in the CNS and in the post Amivantamab setting. Slide 22 shows the corresponding swimmer plot of time on treatment. You can see the responses happen as early as four weeks, but may evolve and improve over time. It's too early to assess durability, but as of the data cutoff, our longest on-study patient with EGFR exon 20 mutated non-small cell lung cancer is at approximately 40 weeks and in response. Slide 23 provides case details for the complete response I called out earlier. This is a 55-year-old woman with EGFR exon 20 mutated non-small cell lung cancer, who previously received combination chemotherapy, then Amivantamab, on which she progressed. At study entry, she had four active CNS non-target lesions that had not been previously treated with either surgery or radiation. She received ORIC-114 at 75 milligrams once daily, which is a potential candidate RP2D dose under consideration. By the first cycle, she had a 60% reduction in all her systemic target lesions, which improved to a complete response at the next cycle, with 100% reduction of all target lesions and disappearance of all non-target lesions. This complete response was subsequently confirmed. She also had a complete response of all CNS disease after the first cycle, with complete resolution of all four of her CNS lesions, again, which was later confirmed. Her only adverse events of grade two or higher were grade two mucositis and paronychia. She remains ongoing on treatment and in complete response as of cycle nine. This patient demonstrates three important properties of ORIC-114. First, potent systemic activity with a systemic confirmed complete response. Second, potent CNS activity with a confirmed intracranial response in active disease. And third, the therapeutic potential of ORIC-114 in the post Amivantamab setting. Now, we've spent a lot of airtime talking about EGFR, but I don't want to shortchange our potential in HER2 exon 20 mutated lung cancer, which represents a large unmet need and with less competition, and against which ORIC-114 is also highly potent. On slide 24, we have the waterfall plot for the patients with HER2 exon 20 mutated lung cancer. Across dose levels, we observed five responses. Of note, one of these confirmed partial responses consisted of a 100% decrease in all target lesions, with only persistent non-target lesions preventing a complete response determination. The corresponding swimmer plot on slide 25 demonstrates that as with the EGFR patients, we see onset of response as early as four weeks on treatment, although responses may develop over time as well. Here we also have patients on treatment at 40 weeks, one who progressed but is still deriving clinical benefit and another with stable disease. On slide 26, we have a second patient vignette, this time in a patient with HER2 exon 20 mutated lung cancer. This 67-year-old man was previously treated with three separate chemo or chemo immunotherapy regimens before coming on study. He received ORIC-114 at a dose of 30 milligrams twice daily and had a response after one cycle with 100% regression in all target lesions. This response was later confirmed, and the patient remains on treatment and in response in cycle three. The only grade two or higher drug-related toxicities were grade two rash and nausea. The response profile overall, and in this patient in particular, underscore the therapeutic potential of ORIC-114 in HER2 exon 20 disease. In summary, on slide 27, you can see that with the data we have generated to date, ORIC-114 has achieved many of the objectives we established for the first stage of this clinical program. We have demonstrated that ORIC-114 has good oral bioavailability, with pharmacokinetic properties that support once daily dosing. The safety profile shows a well-tolerated drug with minimal EGFR wild type related toxicities, minimal off-target toxicities, and a low rate of dose reductions and discontinuations. Furthermore, we have demonstrated systemic clinical activity, including in heavily pretreated patients in multiple patient populations of interest. In the EGFR exon 20 mutated setting, we have shown systemic as well as CNS activity in the face of active CNS disease and prior treatment with Amivantamab. In HER2 exon 20, we have also demonstrated a similar high degree of clinical activity. Overall, we are well positioned for further development with multiple opportunities ahead of us. Now let's look forward on slide 28 and review the steps we plan to take to determine the recommended phase II dose for future registrational studies. First, we need to identify the candidates for RP2D. Based on the data we've generated so far, 75 mg QD could be one of those candidates. Its PK profile provides good coverage. The safety profile is comparable to the 45-60 mg daily dose range with similarly low rates of rash and diarrhea, and we've seen no discontinuations due to toxicity. In terms of anti-tumor activity, in the three post-Amivantamab patients we treated at this dose, we saw tumor shrinkage in all three, with responses in two of those three, one of which was a confirmed complete response. In addition, of the two patients with CNS metastases, one had a confirmed CNS complete response, and one had stable disease in the brain. 75 milligrams may end up being one of our candidates for RP2D. Given the well-tolerated safety profile we've seen and the fact that we've not reached MTD, we continue to dose escalate and will seek to identify additional RP2D candidates, including determining whether there are any advantages to BID dosing, either in terms of safety or efficacy. So far, we have not observed a difference, but we'll continue to evaluate. Once we've selected our candidate RP2Ds, we will conduct dose optimization, enrolling a patient population that is more narrowly defined than what we have currently enrolled in phase 1b. Specifically, in the EGFR exon 20 setting, we will be enrolling patients who are either naive to prior EGFR exon 20 inhibitor therapy or who are only post-Amivantamab. Similar dose optimization will be performed in HER2 exon 20 mutated patients and in patients with atypical EGFR mutations. Based upon this collective experience, we then intend to select the final RP2D that we will take forward into phase II registrational cohorts for potential accelerated approval. Slide 29 presents a timeline view of what I just discussed. In the upper left are the patient populations I just mentioned that will be the focus of dose optimization. Once RP2D is determined, we will proceed with one or more registrational cohorts with a goal of accelerated approval. Specifically, we believe that there's an opportunity in EGFR exon 20 patients who are naive to exon 20 inhibitors for a drug that fulfills the complete target product profile that Jacob outlined at the beginning. In addition, as Amivantamab usage likely shifts to the first-line setting, given its lack of CNS activity, we believe there's a clear opportunity in patients who are post-Amivantamab. And finally, we believe we have opportunities in EGFR atypical mutations as well as HER2 exon 20 mutations, and we'll pursue them as the data dictate. Finally, let me close out this data review by stepping back and showing what we've accomplished to date in this clinical trial. On Slide 30, you'll see our phase 1b clinical trial of ORIC-114 and the important eligibility criteria I highlighted at the beginning against the array of phase I studies with other drugs, either approved or in development for EGFR exon 20 mutated lung cancer. Apart from BLU-451, all of these other studies have excluded patients with prior exon 20 therapy and patients with untreated CNS metastases. The result is that we have been treating a very different patient population from everyone else, one that is more refractory in having already experienced EGFR inhibitor therapy, and one that is sicker in terms of having potentially active CNS disease and just plain more CNS disease. In the face of this highly refractory patient population, ORIC-114 has already achieved a number of firsts against EGFR exon 20 mutated lung cancer. We are the only development stage program to report a complete systemic response. We are the first program to report a complete CNS response in active CNS disease, and we are the first program to show this in the setting of prior Amivantamab therapy, with a 33% confirmed response rate at the 75 milligram dose. These data position the ORIC-114 program well for further development and multiple paths to approval. I would now like to introduce our guest, Dr. Alex Spira, who has graciously agreed to join us to provide his own perspective on these data and on the therapeutic landscape in general. Dr. Spira is a medical oncologist and is the CEO and Clinical Director of Next Oncology Virginia. He's also Chair of the Research Executive Committee of US Oncology and Co-Chair of the Thoracic Committee. Dr. Spira, thank you for joining us today in Madrid at the ESMO conference. Thanks for having me. Now, you've worked on almost all the approved and clinical-stage EGFR exon 20 targeted agents, so perhaps we could spend a few minutes discussing the current therapeutic options for these patients. So the current therapeutic options are, as you know, Amivantamab in the second-line setting. Obviously, we've heard about PAPILLON data, and that may change things, but currently, that's all that we really have. I don't have to remind everybody of the recent withdrawal of from the market. Sure. And given, you know, this population versus other lung cancer populations, how significant is CNS disease or the potential to develop CNS disease in this specific population? So a majority of the patients that I've seen, and it's documented in the literature, have evidence of brain metastases, usually a presentation. We don't know what's unique about this patient population, but if you look, almost all of them have relatively asymptomatic but present brain metastases at baseline, and if not, they develop it rapidly early on. So it's important, as we'll get to with ongoing conversations today, how do you manage that? You know, currently, the only management we have is with radiation, and clearly that's something you'd like to try and avoid for obvious reasons. Sure. So you brought up mobocertinib's sort of recent removal from the market. Let's focus on Amivantamab as the currently available therapy. Can you give us your impression on its efficacy and safety profile? It's obviously effective. We've seen that by data, and there's no taking that away from it, and it is relatively safe. It is not a completely benign drug. One of the conversations that will always come up, especially if you look at the typical EGFR mutations, is that it still has real side effects ongoing. It is not a completely benign drug, but it's able to be administered. Very different than mobocertinib was, which really ran into a lot of toxicity trouble, which probably led to its demise. Sure. Now, you referenced CNS activity, so can you talk about that, or specifically, for Amivantamab? There is no known CNS activity. As you or just pointed out today, all the trials exclude CNS metastases. Based on the fact that it's a large molecule, it is unlikely to have any significant CNS activity. There's, of course, anecdotal reports, but for the most part, that has not been studied and is not felt to have any significant brain penetration. Stereotactic or whole brain is pretty much the only other option for- Correct. Got it. So then let's move to the other agents that are in clinical development. So there's CLN-081, Sunvozertinib, Furmonertinib, and most recently, the Blueprint compound, BLU-451. First, let's talk about your overall impression on the efficacy that's been published to date. So if you look, I did a couple things. So one is, and the slide's probably still on the screen for everybody. First off, almost none of them, aside from BLU-451, allowed untreated brain metastases. And many of the prior ones, if their publications, they tried to get away. Dizal is actually particularly known for that and say, has CNS activity, but all those patients had treated brain metastases, and they were really looking at secondary endpoints of new brain metastases, which is not really a valid endpoint, number one. Number two, as you can see, none of them have really been well-studied at all in the post-Amivantamab population. Pretty much they're all going for naive patients right now, and that's where they see most of their activity. So, you know, while they're active drugs, and you can't take that away from them, they all have those limitations right now. So then maybe we take a little detour. Can you comment on these restrictions on eligibility for patients with CNS disease? How does that play into your thinking about how to characterize a given drug? Well, I mean, that's super important for this patient population, right? I mean, one, is it makes the trials harder because so many of these patients have brain metastases, and you have to deal with them before going on. And, you know, for people with minimally, you know, minimally symptomatic disease, you hate to do that. So it makes the trials much harder. But more importantly, this is the hugest area of unmet need, right? We've got to find something that has that CNS penetration because it's such a big deal for these patients. Much like Osimertinib revolutionized the treatment of typical EGFR mutations. It was a better drug, but it's really changed how we think about brain metastases. The other example, of course, is alectinib, right? That was the first ALK inhibitor, and it really revolutionized the treatment of brain metastases, where we didn't have to radiate people, which is time, expense, but most importantly, side effects. So then would it be fair to say, given the sort of very, sort of stringent eligibility criteria with respect to CNS disease, it's hard to interpret the CNS activity of, of many of these agents? There is none. I mean, there, you can basically say there is none. Whether or not it's because they deliberately chose not to go forward or there is none, obviously, you have to go into the scientific data there, but there is no known CNS activity for any of these agents. All right. Well, so let's now then, with that context, talk about the ORIC-114 data that was presented here and that you played a part in helping us generate. So as you saw, you know, the patient population we enrolled is quite different, you know, from other compounds and their programs. 81% of patients had a prior exon 20 inhibitor therapy, 86% of patients with CNS mets at baseline, and we did include, as your patient, patients with active or untreated brain mets. So how would you characterize... I think you've already made a few comments, but perhaps a little more on this population versus the others that you- Well, first of all, you did a very well-designed clinical study because this is who the patients are right now. In the United States, especially, as well as many other countries, it's, you know, there, there's some active drugs out there, so it's hard to get those trials done. So kudos to you for that, number one. But most importantly, you looked at the most unmet need. Again, the most unmet need right now, especially with PAPILLON, presumably on its way to approval, it's gonna be in the post-Ami setting. There's still a role in the frontline setting, separate question, but you clearly have shown activity there, which is good, number one, and of course, the evidence of responses in the central nervous system are clearly differentiates this from everything else. So let's, let's then start with the efficacy for ORIC-114. So these patients, you know, as we said, are heavily weighted towards CNS involvement, already mostly have received some type of exon 20 inhibitor therapy. Can you put the antitumor activities into context with the other agents? So you can't really compare to one of them, because many of them in the study, EGFR TKI-naive. Obviously, you would expect any drug like that to have more activity, right? So it's really hard to compare apples to oranges. But the fact that you're seeing responses post-Amivantamab is, and post other TKIs, is great, number one. That really differentiates this molecule from some of the other ones. Now, one of the vignettes happened to be your patient. A star patient. Perhaps you can provide a bit more color on this patient's sort of treatment history and experience on... It's a very straightforward patient. She's a young Asian female who got platinum in the adjuvant setting, did not get immunotherapy because we knew she had an EGFR mutation. That and then recurred with systemic disease and brain metastases. We put her on Amivantamab because it was before your study was open, because I always put somebody in clinical trials, and she actually progressed right through Amivantamab, which is a little surprising, right? I mean, Ami is a pretty active drug. Right. And she progressed, and we put her on your drug, and you saw the slides, you saw the pictures, and, as a, you know, almost CR at first imaging and a CR at second imaging. I mean, this is about as good as it gets. You know, at the data cut-off, she's ongoing. Today, she's ongoing. She feels great. She has mild side effects, is able to take the drug and live a normal life. I know there was a delay in getting the confirmation 'cause she went on a vacation, as I understand. Yeah, I know you, you were probably yelling at me. Because you wanted that data as much as I did. But yeah, she got that, and she has went on vacation. She's been on another vacation since then. Got two young kids. Can you then speak to the safety profile that you've seen and experienced yourself? So you reminded me before I remembered she's on what, cycle 9, at least. That's the data cut-off, probably 10 or 11 right now. Actually, even another scan since the cut-off. Doing great. Honestly, she's able to live a normal life with very, very manageable side effects. How would you position the safety profile that you've seen versus other programs? Well, you know, I can compare you to the exact opposite extreme with Mobocertinib, which doesn't exist anymore, probably because of that. It is at least on par with the other drugs out there. I mean, I can't besmirch any of the other drugs. I mean, the data's out there. They're all, you know, much better tolerated than Mobo, which I think was unfortunately great first in class, but doomed after that. But it appears to be on par with any of the drugs. So me personally, and I also think based on the data, I have no safety concerns whatsoever. So, you know, we appreciate your compliment about the patient population we enrolled and sort of trying to stick to what, you know, where the medical need is. But, you know, as you saw from our discussion earlier, we are looking to now generate data in patients who are exon 20 inhibitor naive. Do you think with the data we've generated so far, that would be feasible for us? Oh, absolutely. I mean, you know, clearly you have an active drug there. I mean, the goal for patients and physicians with targeted therapies is to get that upfront, right? Nobody wants to do chemo anymore, right? And you can understand the patient's desire to do that. And it's very frustrating. And I have to say, obviously, you know, a little frustrating because of PAPILLON. We would love to have had a completely chemo naive, you know, just Ami versus, uh, chemo in that situation, but the trial was done with chemotherapy. But clearly, I think in the naive population, your response rates are going to go up because they're going to. They won't be, have gotten ami, number one. It'd be really great to see if we can really push the envelope and get into patients even in lieu of chemo or of course, combined with chemo as well. Right. Certainly compared with ami, there's a lot of advantages. It's an oral drug, don't have to deal with any infusions like that, and obviously, it's very patient friendly. Now, you brought up the PAPILLON study. I mean, I think the expectation is that, you know, they will get first-line approval as with the Ami chemo combination. Given that, where do you see a need for a drug like 114? So clearly, I mean, those patients, the therapy will fail the patients, and they'll be in need of a second-line therapy. And at this point, there's nothing out there, right? I mean, you're basically looking at second-line chemotherapy in that situation, for the most part. So you clearly have a targeted therapy here. Again, not everybody's going to respond, but you already have evidence of post-Ami responses, as witnessed by my patient. And of course, if you can use that in lieu of, cargo pap Amivantamab, that would be great too. So then maybe you could just sort of give your opinion on, you know, the heavy competition in this space. Maybe Mobocertinib is no longer in the running, but there are a number of other drugs in development. Do you see a need for a drug with the profile of ORIC-114? Yeah, I mean, as I said, what do you—clearly right now, it just starts simple. What do you do with second line? It's a very wide-open thing, and there's going to be a huge desire with the data that you have to try and get this in second line. Of course, you're going to start to think about combinations, right? Right. Combining with other monoclonals out there and obviously Amivantamab or there are, there are other exon 20s in development, of course, as well, monoclonals, I should say, EGFR monoclonals as well. So there's clearly a role to either combine or look at single agents, de novo or second line. So there's still this an area of unmet need and will remain indefinitely. So you think a combination of 114 and Amivantamab is something that might be worth pursuing? Oh, absolutely. I mean, you know, you're hitting it from two aspects, right? You're hitting it from the intracellular aspect, which is the TKI domain, as well as the extracellular aspect with the monoclonal. So if you can combine those two, and it probably is combinable, right? I mean, if you look at the overall side effect profile, where there's obviously some overlapping toxicities, you should be able to combine these with reasonable doses. You guys have a relatively wide therapeutic window, so the concern there would obviously be rash or diarrhea, but based upon what you've seen and what I know from ami, and you guys know from ami, I think this should be where you could combine them with reasonable doses. Thank you. Well, why don't we shift gears a bit and talk now about HER2 exon 20. Less crowded, but there's still development activity, and HER2 has an indication in this patient population. Where do you assess the medical need for these patients? So a couple of things. So one is, Enhertu is currently approved in second line, and they're trying to still figure out their first-line strategy for that. So there's a need there. And Enhertu is not a perfect drug. It has real side effects. I mean, it is, as I like to say about antibody drug conjugates, it's chemo on a stick. So it's chemotherapy, and it carries with it, you all know, the instance of ILD. And in the lung cancer patient population, all the ADCs have an increased risk of ILD, probably because of their lung cancer or radiotherapy, smoking, although that's less and less over time. So regardless of that, they all have a real risk of ILD, and I've seen it myself in my own patient population. These are not completely benign drugs. So certainly two things, you could try and figure out a way to use it after, much like you've told the story versus ami. You could potentially use it in combination. Or you can use it in lieu of. So there's clearly an opportunity there for all three of those. And clearly, you have one thing that they don't have, is evidence of CNS penetration, which is, it's, you know, the chemo on a stick of T-DXd is still unlikely to have significant CNS activity based upon the science, and they're not looking for it either. Okay, and then finally, let's just close it out by talking about atypical mutations. So this is sort of a up-and-coming or newly identified subset that, you know, isn't well served by- Well, it's not newly identified. It's been out there for a while, and it's been for a lack of interest. Okay. All right. Yeah, we've known about this. Sorry to interrupt you, Pratik, but we've known about this for a while. It's a level of frustration because people either use off-label Osimertinib- Right or the dreaded drug, and I hope I'm not offending anybody, they call it afatinib, which is a horrible drug. It's similar to, mobocertinib. You know, the starting-- recommended starting dose of 45 milligrams is intolerable for most people. You have to start at 30, go back to 30, and even then, it's mostly intolerable. And I'm a little surprised that given the dollars behind AstraZeneca and Osimertinib, because there is some data that it works, that they haven't pushed the envelope right now. But I do think people have started to begin to think about like, "Hey, there's a market here," and that's a, a real percentage of patients. And you need a drug that works there. You need a better drug than the only approved drug. Right. afatinib and CNS penetration as well. Sure. Amgen doesn't have that. It sounds like there's opportunity there as well. Yeah, and I'm frustrated by that because I'm like, you know, I still can't figure out why AZ, who has so much money, couldn't do a small study to get approval. I mean, they have the resources, and, you know, we're stuck as clinicians, constantly explaining the differences between the two. And we see, you know, on average, you know, in our group, at least a patient a month with an atypical mutation. So perhaps we can get there first then. You can get there first. Thank you, Dr. Spira, for your time and valuable perspective that you've been able to provide. Let me now pass it over to Matt, who will now discuss the commercial landscape and potential for ORIC-114. Thanks, Pratik. On slide 34, we provide an overview of the current EGFR exon 20 competitive landscape. With the recent withdrawal of mobocertinib, Amivantamab is now the only approved therapy for patients with non-small cell lung cancer with EGFR exon 20 insertion mutations. But Amivantamab has numerous limitations, including high rates of rash and infusion site reactions requiring pre-medication, and most importantly, it does not have CNS activity. As such, patients with untreated or active brain metastases were excluded from clinical studies of Amivantamab, including the phase III confirmatory study in combination with chemotherapy. This leaves a wide opening for a best-in-class profile to emerge that can improve upon the many limitations of Amivantamab. Unfortunately, all agents in late-stage development for EGFR exon 20 have their own flaws, including that none of them have reported CNS activity in active brain metastases, and like Amivantamab, have excluded patients with active brain metastases from their studies. In contrast, ORIC-114 is the only exon 20 inhibitor with reported activity in patients with untreated or active brain metastases, including in the setting of prior treatment with Amivantamab and chemotherapy. ORIC-114's activity in the CNS and in patients previously treated with Amivantamab, positions it well as a potential best-in-class therapy to address a significant unmet medical need and commercial opportunity. Now, we acknowledge that the non-CNS competitors are further along in development than ORIC-114, but slides 35 and 36 highlight how vitally important CNS activity is to the long-term commercial prospects of a TKI, regardless of timing to market. Slide 35 provides a case study on a non-CNS active TKI, mobocertinib, which is obviously directly relevant in the context of EGFR exon 20. Consistent with other prevalent statistics, approximately 35% of patients in the mobocertinib phase I/II pivotal trial had CNS metastases at baseline. In these patients with baseline CNS metastases, 68% of them had the first site of progression in the brain. Additionally, even across all patients enrolled in the study, 38% had the brain as a first site of progression. This inability to treat brain metastases and to delay progression in the brain was associated with a lower ORR and significantly reduced median progression-free survival of only 3.7 months in patients with CNS metastases, compared to 8.1 months in patients without baseline brain metastases. These data highlight one of the critical flaws of drugs that lack CNS activity. They can have less durable clinical benefit, certainly in patients with baseline brain metastases, but potentially across the entire patient population. Slide 36 shows a contrasting case study that we believe is potentially analogous to the broader market context facing ORIC-114. In this case, the development of alectinib. alectinib was the third ALK inhibitor approved, which occurred 4 years after the first ALK inhibitor was introduced to the market. However, alectinib was the first ALK inhibitor with CNS activity included in its FDA label. In its confirmatory phase III study, alectinib demonstrated a PFS of 26 months, compared to only 10 months with non-CNS active crizotinib. Thus, despite being third to market, alectinib, with its best-in-class CNS activity, today commands over 70% share of the ALK inhibitor market by sales. Now, as we think about the commercial potential of ORIC-114 on slide 37, we see three potential market opportunities within non-small cell lung cancer, all of which we've touched upon during today's presentation. We showed you earlier today the impressive activity of ORIC-114 in EGFR and HER2 exon 20 lung cancer, and our preclinical profiling of ORIC-114's activity in EGFR atypical mutations suggests the potential of seeing equally impressive activity in that population once patients have been enrolled. Any one of these opportunities exceeds the size of the RET inhibitor market, which is on pace to generate over $500 million in sales over the coming years. Collectively, these three opportunities represent approximately 6.5% of non-small cell lung cancer, or up to 12,500 patients in the U.S. annually, which exceeds the addressable population of the RET and ALK inhibitor markets combined, which is a multibillion-dollar total addressable market. Most importantly, none of these opportunities being pursued by ORIC-114 currently has an approved agent with an FDA label that includes CNS activity, which leaves the door wide open for a best-in-class CNS active agent to garner significant share, even if not first to market. Now I'll turn the call over to Jacob to provide a summary of today's call and a quick review of ORIC's pipeline. Thank you, Matt. Turning to slide 39. You've heard today from the ORIC team and from Dr. Spira why we are so enthusiastic about the initial results from the phase 1b trial, and why ORIC-114's activity in both post-Amivantamab patients and in patients with active brain metastases position us well to pursue multiple accelerated paths to approval in parallel. Any one of those target populations for ORIC-114 would address large unmet medical needs and open up significant commercial markets. Now, just for a moment, I want to abstract back from talk of markets and TPPs. If you can put yourself in the shoes of the patient with EGFR exon 20 lung cancer, whose vignette Pratik covered earlier. You've taken chemo for your lung cancer and progressed. You've taken what is now the only marketed agent, Amivantamab, and progressed. Even worse, you now have 4 metastases that have spread to your brain. You've done your research and spoken to your physicians, so you're painfully aware that almost none of the investigational agents can handle your brain metastases. And worse yet, because of your untreated brain metastases and prior exon 20 therapy, you don't even qualify for nearly all those clinical trials. But there's a drug, ORIC-114, whose developers believe can help you. You take that drug, and for the first time in your treatment history, you find yourself completely free of cancer lesions in your lung and in your brain. This patient and so many others like her, who are underserved by current therapies, is why the development of ORIC-114 is so crucially important. It's why, despite the competitive landscape, we believe this drug has the opportunity to become best in class. It's what will drive this team to pursue one or more approvals for ORIC-114 as rapidly as possible. Now, shifting gears briefly from ORIC-114, our pipeline is one of the most robust in small cap biotech. Like ORIC-114, ORIC-533 and ORIC-944 are in phase 1b dose escalation studies. Both are targeting large market opportunities in multiple myeloma and prostate cancer. Slide 40 is a reminder of the key differentiating features of ORIC-533, our small molecule, orally available inhibitor of CD73, that is focused on multiple myeloma. We expect to report initial phase 1b data later this quarter. Slide 41 is a reminder of the key differentiating features of ORIC-944, our small molecule allosteric inhibitor of PRC2, that is focused on prostate cancer. We expect to report initial phase 1b data for this program in Q1 of 2024. We'll wrap up our prepared remarks on slide 42. We're very proud of the team and pipeline that we've assembled here at ORIC, and we're looking forward to providing additional updates on our robust pipeline over the coming quarters. Before we open it up to Q&A, I'd like to thank Dr. Spira and our other investigators, as well as the entire ORIC team, who've worked diligently to tackle our mission on behalf of patients. And most importantly, I'd like to thank our patients and their families, whom we hope to help overcome resistance in cancer. With that, let's open it up for Q&A. Thank you, sir. As a reminder, to ask a question, you would need to press star one one on your telephone. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster. And I show our first question comes from the line of Anupam Rama from J.P. Morgan. Please go ahead. Hey, guys. Congrats on the update, and thanks so much for taking our questions. I actually have two for Dr. Spira. The first one is, how do you benchmark these results for ORIC-114 versus kind of the competitive landscape for EGFR exon 20? You talked a lot about [ava], Amivantamab, but maybe also the other development agents in the context, particularly of the population enrolled. And the second question, also for Dr. Spira. You talked about the importance of CNS activity in patients with active and untreated brain mets, but maybe you could put some metrics around it. So what portion presented with active brain mets at baseline and ultimately, brain mets being the site of progression? Thanks so much. So number one is, you can't really compare to any of the other drugs because they didn't. Number one is almost all those patients enrolled in the studies are naive, right? So they're all naive to TKI inhibitors, CLN, Dizal, all of them are naive. Blue obviously is a little different there, but the rest, so, you know, and again, you can't really compare them head-to-head. Almost all patients develop brain metastases over time, or at least at the beginning. I would say at least walking in the door, you know, those patients presented with metastatic disease, at least 50% of patients will have evidence of brain metastases. And over time, almost 100% of patients will develop brain metastases. And that's expected to continue. As you know, I mean, as we do get more treatments that work, and again, you can't belittle the efficacy of Amivantamab, if you look at patients who get that, patients will relapse in these atypical places and live longer, so they have more of a time to develop that. So it's pretty much going to be everybody that develops it over time. Similar to other EGFR mutations and ALK, where they have a strong predilection for the brain for reasons we don't quite understand. Thanks so much for taking our questions. Thank you. And I show our next question comes from the line of Maury Raycroft from Jefferies. Please go ahead. Hi, congrats on the update, and, thanks for taking my questions as well. How do you compare the overall safety profile for ORIC-114 to competitor compounds with regards to both EGFR-related toxicities and equally important off-target toxicities? I was also wondering, do you need regulatory feedback prior to starting the dose expansions and getting into naive patients? Lastly, when could we expect the next data update from this program? Let me take the first two questions, and then take a third. So, in terms of the overall safety profile versus competitors. So we feel, and I think some of that came out in our discussion with Dr. Spira earlier, that we have as good or better in terms of safety compared to the other agents in development, especially considering we had a more heavily pretreated patient population than the other competitor compounds. But let's break the safety down into two parts. So first is the EGFR-related toxicities, which most people are focused on. We've seen only grade 1-2 rash, and we've used a very inclusive definition of rash. It can get reported under various different types of events or terms. What we did to be most conservative was lump anything that could be considered a rash into one term called rash, and even with that, we still only see grade one, two, and, and no grade three or higher events. But you'd have to take a look at other competitor safety tables, where rash can be sort of sprinkled across a lot of other different terms and, and gets fragmented. So I think that's a distinction that we still come out ahead. In terms of diarrhea, again, mostly grade one, two, and only 6% grade three. So overall, in terms of EGFR-related adverse events, I think we compare very favorably, with respect to the competitor numbers. Now, let's talk about off-target toxicity. Here, I think we look even better than the competitors, and this type of toxicity often gets glossed over because most people are focused on the EGFR-related events or adverse events of interest. But these other safety liabilities can be equally problematic. And so if you look at drugs like Furmonertinib, Sunvozertinib, CLN-081, you will see, depending on the drug, things like rates of hepatic toxicity, QTc prolongation, myelosuppression in the frame of anemia, and CPK increase. We don't see any evidence of that with our drug, and so we feel like we have a very clean off-target safety profile, which was basically predicted from the very clean kinome panel that we showed at the beginning of the presentation. And then finally, just what's in our favor is we have a wide therapeutic window. As you saw from the presentation, we've seen responses as low as at 45 milligrams, actually even below that at 20 milligrams BID. And we're currently testing 120 milligrams. And so clinicians have ample room to dose reduce in a given patient while still maintaining therapeutic potential. So that, I think, also gives us an advantage in terms of safety. Maury, before we go to your, your questions, your questions two and three, let's ask Dr. Spira also to weigh in on what Pratik just commented. Little to add. I mean, it's, you know, the EGFR toxicity is clearly on par with the other drugs, the same, if not a little bit better. And the off-target effect, the non-EGFR toxicity, is minimal. I mean, I don't even think about it, right? So, you know, has never been an issue in all the patients that I've treated, as echoed by the data. So I have no safety concerns there whatsoever. And then your question about regulatory feedback, if we shift to enrolling a naive population. We don't need any specific regulatory feedback. And then, Maury, on your final question, we plan to update on the phase 1b data in the first half of 2025. Got it. Okay, thanks for taking my questions. Thank you. Thank you. I show our next question comes from the line of Colleen Kusy from Baird. Please go ahead. Colleen, if you have your phone on mute, please unmute your line. Hello, Colleen, your line is open? Okay, I show- Colleen, you're there, we can't hear you. Keep speaking. I'm going to- Let's go to the next one. Okay, I show our next question comes from the line of Matthew Biegler from OpCo. Please go ahead. Hey, guys, can you hear me? Yeah, we can, Matt. Oh, hey. Congrats from us as well. It's a very exciting case study, that complete responder. I had two questions, one for Dr. Spira. You know, as we think about accelerated approval as a single agent, what do you think the bar is for chemo and/or radiation if there's CNS lesions present? Are we talking, you know, single digits here? And I guess, how does that look- ... relative to what ORIC-114 has shown before? And then my second question is for the team. You know, it's, it's intriguing, the idea of a combination, I mean, especially up front, but maybe, you know, more near term as you think about a combination strategy, what do you think you'll pair it with? Would it be Amivantamab, or would it be with a form of chemotherapy? Thanks. Well, I, I guess the first question is, I didn't quite understand the question. So basically, you know, there's a lot of discussion, and I think investors usually use, like, a 30% overall response rate and a 6-month DOR as kind of excluding the lower bound in the salvage setting of chemotherapy, which, depending on the tumor type, you know, tends to get low single digits. Is, I guess my question is, you know, is that consistent kind of with your experience in the exon twenty space? Do you think that this drug needs to be somewhere, you know, in that 20%-30% OR range with duration over 6 months? Yeah. That's, you know, a typical thing that we think about. You know, the CNS activity is actually, you know, if you're looking at simply physician use, is actually even lower. You know, most studies, when they describe CNS activity of drugs, it's not even necessarily on label. It's usually anecdotal stuff that people talk about as well in the context of everything else, because it's so, you know, devastating, number one, and number two, those studies have notoriously, you know, this disease has a lot more brain metastases than other diseases, so it makes it easier to look at, but it's a very low bar. I mean, you start to show from a clinical standpoint that you have any CNS activity, that's a real differentiator of everything. I can give you the example of KRAS. You know, adagrasib has published CNS activity. Amgen, I'm sure I don't have to tell you, but the sotorasib story and probably mismanaged by Amgen a little bit, they decided not to look at CNS activity, for sotorasib for a while, for reasons that are unclear, and it rapidly, among KOLs, ended up being the biggest differentiator, although they probably both work the same. It is a big differentiator there. So it's a very low bar, and if you have any evidence of CNS activity, physicians will use it. Yeah, Matt, and I'll just add in there that, obviously, given the activity we've already seen in a heavily pretreated, in fact, almost exclusively pretreated population, as we think about the single agent accelerated approval strategy here, it would be a exon 20 naive population with and without brain mets. So given the signal we've already seen, we are encouraged by what we should see in that exon 20 naive population. And on your question about Ami combos and how we think about it, I'll ask Pratik to weigh in there. Sure. So, I mean, I think the, you know, the standard combo that you know, Amivantamab did and CLN is doing is with chemotherapy, and, you know, that certainly would be sort of on the table for us. But, as was brought out, I think, during our discussion earlier, you know, combination with Amivantamab, I think is very compelling, because it would represent a chemotherapy-free combination regimen. And you know, in this case, ORIC-114 would fill a gap that Amivantamab has, which is it lacks CNS activity. And ORIC-114 is relatively unique in its ability to fill that gap versus the other exon 20 inhibitors that are in development. So I think, also on the table for us is an Amivantamab combination to essentially create a novel combination that could address CNS up front. Got it. Appreciate it, guys. Thanks, Matt. Thank you. I show our next question comes from the line of Colleen Kusy from Baird. Please go ahead. Your line is open, Colleen. All right, it seems like Colleen's having audio issues, let's move on. Thank you. And I show our next question comes from the line of Yigal Nochomovitz from Citi. Please go ahead. Hi, team, this is Ashiq Mubarack. I'm Yigal. Thanks for taking my questions, and congrats on all the updates. I had two or three questions. I guess the first is that you showed some nice exposure data and relatively low rates of discontinuations and dose reductions. I guess my question is, how confident are you that you're getting sufficient CNS penetration and target saturation, specifically in the CNS at a 75 mg dose or similar? Is there room to really push the CNS activity by pushing the dose, given the safety profile? How are you thinking about that? So, you know, I think the, the target saturation really is sort of, evidenced by the fact that we saw a CNS complete response, in a patient with active brain disease. So, certainly at, at 75, we have a, a solid example. And, you know, at least systemically, we're seeing good dose proportionality. As we increase the dose, we're getting increased exposure. So, you know, we have every reason to expect that that will translate into higher CNS exposure. And, you know, we saw a CNS response at 75, and we're dosing at 120. So we're quite confident that at this point, we are getting very good, CNS, exposure and target inhibition. Okay, got it. I also wanted to ask about HER2 exon 20, because I think that's maybe, maybe a little as a dose of significant interest. So I guess I'm just wondering how how the data you shared specifically in HER2 exon 20 maybe compares to data sets previously presented in the same setting with the, with HER2 exon 20 inhibitors. Is there any color you can share context-wise? ... Sure. No, so we're very happy that, you know, again, we're still all talking about a phase 1 dose-escalation study. But in that context, we did see substantial activity in the HER2 exon 20 population, and with, you know, the good safety profile. The only sort of approved benchmark right now is in HER2, so their response rate is 49%, with a DOR over 12 months at the low dose. But as Dr. Spira mentioned earlier, it comes with a price of a substantial rate of grade 3 or higher adverse events, 40%, and a 13% rate of interstitial lung disease. They are doing a phase 3 confirmatory study, but untreated brain mets aren't allowed. So here, as with EGFR exon 20, I think we do have the potential for both standalone clinical activity as well as the ability to address CNS disease. There are some small molecules that are in development, the Bayer molecule and the BI molecule, they're at early stages, with responses in the 40+% range. But untreated brain mets aren't allowed in these studies. And so I think, again, it's hard to compare dataset to dataset. But we are continuing to push in this patient population, and as you saw earlier, we're gonna take that forward into our dose expansion, and we'll see how our data compares to others. Okay, got it. That's, that's very helpful. And then, one last one for me. I guess, how are you thinking about sizing of the dose optimization cohorts and, and when you could get those up and running? And, and similarly, you sort of alluded to the idea of combining with Amivantamab. I'm, I'm just wondering if that's part of the, the dose optimization plan or maybe accelerated cohorts plan, or is that something for more maybe down the road? Thanks. So, for the combining with Amivantamab, that would be its own separate development because, you know, we would need to identify a combination dose and then take that forward. But the dose optimization, we have dedicated cohorts to look at EGFR exon 20 naive, post Amivantamab, HER2, and atypicals, and they are sort of conventionally sized as to what others have done in terms of of dose optimization comparing 2 dose levels. Great. Congrats again. Thank you. Our next question comes from the line of Michael Schmidt from Guggenheim. Please go ahead. Hey, guys, congrats on the update, and thanks for taking my questions. I had a couple follow-ups just on the EGFR exon 20 cohort. I think there were 13 patients with CNS mets. I may have missed it earlier, but how many of those were untreated? And you did highlight, obviously, the CR, but how many of the others had a CNS response? Given this, a phase 1 study, we don't have a detailed CNS treatment history in all the patients. We did confirm the active CNS disease in the patient who had the CR, because that was critical to understanding that treatment response in that patient, as you can imagine. As we move into the efficacy studies, though, we will have a sort of dedicated capture of that treatment information, but unfortunately, we don't have it for all the other patients. Okay, understood. And were there any other CNS responses in some of those patients? Well, you did see from the waterfall that in the exon 20, we did have a patient who had 2 of 3 brain lesions disappear on treatment, and in the HER2, a patient with multiple lesions that decreased in size on treatment. Great, thanks. Then just regarding the prior Amivantamab, did the majority of patients receive Amivantamab in the second-line setting as per the approved label, or did some patients had it in first line coming off of the [TOPAZ-Mon study]? Yeah, I don't know the answer to that offhand. We did have patients. All patients had to have prior chemotherapy. So in one way or another, they either got Ami and chemo together or sequentially. Great, thanks. And then lastly, you know, I know you're still going higher in dose and safety looks great, obviously, but you did see two PRs already at the 40 milligrams once a day dose cohort. Yeah, how do you interpret that, and you know, how much room to increase response rate at higher doses do you think there is? No, I mean, that's, you know, I think that points to what I was mentioning earlier in terms of the therapeutic window. You know, there, you know, all EGFR exon 20 insertion mutations aren't the same. And so drugs, all drugs, including ours, will have different potencies against different ones. That's why we have that band in the PK figure of sort of a range of potencies for ORIC-114 and in vivo models. So, you know, we want to be at a dose level that is above that range and accounting for any potential interpatient variability and exposure. We feel like we're now within that range, but, you know, you will see patients who will respond at lower dose levels, which, you know, plays to our advantage because, you know, there is room for dose reduction, if necessary. Whereas other drugs that may have a narrow therapeutic window, if you have to dose reduce, you might as well just come off the drug. We don't feel that's true for ORIC-114. Right. Okay, great. Well, thank you, and congrats on the, on the data today. Thanks, Michael. Thank you. And I show our last question comes from the line of David Nierengarten from Wedbush Securities. Please go ahead. ... Hey, thanks for taking the question. Nice to see the brain activity, nice to see drugs do what they're designed to do. I had a question on the future development pathways, especially in the frontline setting. When you think about, you know, I mean, I think it's a little bit clear how you could pursue approval in the post Amivantamab study setting, but looking maybe on a finer point on the other routes to approval. First, on the, you know, single agent plus or minus brain mets, and maybe Dr. Spira can comment on this too. I mean, it would seem, assuming Amivantamab gets approval, that you would have a study that's weighted anyway towards patients who present with brain mets. So is that, is it really, you know, the best route to look at, you know, plus or minus brain mets, I mean, if the advantage of the drug is in CNS activity? And then looking at the combination study with Amivantamab or potential combinations, frontline look, do you have any preclinical safety combination data? I'm just curious, like, some of the gating factors for going into a combo study. Thanks. So with respect to your first question, I think, your question is, you know, do we have an opportunity in the frontline setting if Ami chemo has a label there? I think, you know, the opportunity we see is that, you know, we have, Ami chemo, we don't think will have any mention of CNS activity within their label. And so that represents still an unmet need within that patient population. And so we feel, if we can develop our dataset more fully, to demonstrate, systemic but also compelling CNS activity, there still remains the opportunity for a treatment-naive, you know, post-chemotherapy treatment-naive, indication, for ORIC-114. So I mean, I think, you know... But your point is taken, and you know, since we have treated so many patients and seen such good activity post Amivantamab, it's not an either/or for us. We're gonna develop both indications, and you know, make decisions as that data develop. Maybe- In terms of the- For Dr. Spira. Yeah. Maybe for Dr. Spira, if he is presented with a patient who shows up with brain mets, and he has these options, I mean, would you prefer to treat the patient with a combo of, assuming the safety supports it, but treating the patient with a combination of Amivantamab and one fourteen? Or would you, you know, likely reach for a monotherapy with one fourteen? I'm just kind of curious what your, you know, gut instinct is on combo versus single agents. It's a great question. I think it's a little premature. I think that's gonna a lot- Yeah ... depend on the efficacy and the staring at it. At the end of the day, it'll depend on, A, the label, and then, B, the subtleties, and C, you know as well as I, when this comes about, and if they were both approved, and you ask 50 KOLs, you'll get 75 different answers. So great question. I mean, I think the key thing is if it's approved with brain mets, we would use one fourteen in one way or another, and it really just depends upon the other subtleties of the data. And then, David, if you're asking specifically on the either/or question in the setting of a, you know, a registrational study that we'd be running, we don't look at it- Yeah ... as either/or. We'd actually look at both, at running both of those studies. And the good news is, as we can see, even from our phase 1 experience, there's plenty of these EGFR exon 20 patients that we could easily enroll both of those studies. Okay. Yeah, it's a little bit of a curiosity, you know, if you would see one arm excel, you know, recruiting patients faster than the other one, you know, kind of how you saw that development factor, but that makes sense. So, yeah, kind of trying to, you know, feel you out on the timing involved with, you know, those studies, you know, potentially. I know it's far out, far in the future, but thanks for the details. Yeah, great question. Actually, just given the nature of the trials in this space, David, I'd say it's actually not that far out in the future. No, yeah. We are actively planning and thinking through the considerations right now. It's a great question. Thanks. Thank you. Thank you. That concludes our Q&A session and today's conference call. Thank you all for participating. You may all disconnect at this time.