Good day, and thank you for standing by. Welcome to the ORIC Pharmaceuticals program update conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star one one on your telephone. You will then hear an automated message advising that your hand has been raised. To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker, Dominic Piscitelli, Chief Financial Officer. Please go ahead. Good morning from Singapore, and welcome to the ORIC Pharmaceuticals ORIC-114 program update conference call. Early this week, we issued multiple press releases highlighting updated data from our ongoing Phase 1b study of ORIC-114 in non-small cell lung cancer patients. You may find the press releases 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, during this call, we will be making forward-looking statements, including forward-looking statements based on our current expectations and projections about future events. Our actual results may differ materially from those indicated by such forward-looking statements. For a description of risk factors, please refer to our recent filings with the SEC. ORIC specifically disclaims any obligation to update any forward-looking statements. This presentation contains interim results based on data from ORIC-114 trials as of the cutoff date set forth on the applicable slide. During this presentation, we will not be speaking to any additional data subsequent to such date. Now, turning to slide three. During today's call, we'll discuss ORIC-114's preclinical differentiation, Phase 1b clinical highlights from ESMO Asia, new preliminary first-line data in EGFR PACC mutations, and next steps, 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 Keith Lui, Senior Vice President of Commercial and Medical Affairs. Now, let me turn the call over to Jacob. Thank you, Dominic. Turning to slide five, we've obviously been busy at ESMO Asia with two oral presentations and one poster presentation that collectively summarize an enormous amount of ORIC-114 data generated over the past year and a half in three different targeted therapy lung cancer populations. This slide is a summary of the key takeaways from our ORIC-114 experience, which we believe has established its potential best-in-class profile for patients with EGFR-mutated non-small cell lung cancer. First, we've observed highly competitive response rates in both pre-treated and front-line EGFR exon 20 and EGFR PACC mutations, the two populations that we have prioritized for ongoing development. Second, we've continued to demonstrate two key aspects that highlight ORIC-114's differentiation versus a crowded field of competitors, namely its profound CNS activity, which is critical because of the high prevalence of brain metastases in these populations, and its lack of significant off-target toxicities like cardiac, hepatic, and hematological liabilities that are found with competitor inhibitors. Finally, our substantial experience with ORIC-114 points us to 80 mg once daily as the preferred dose for future development. We will continue enrollment and long-term durability follow-up in the first-line EGFR exon 20 and first-line EGFR PACC populations, with the next planned update in mid-2026 ahead of the potential start of one or more Phase 3 registrational trials. Slide six highlights why we are so passionate about developing ORIC-114 as rapidly as possible for patients. EGFR exon 20 and EGFR PACC mutations collectively occur annually in approximately 9,000 patients in the U.S. alone. There is one FDA-approved therapy for first-line EGFR exon 20 and none for EGFR PACC mutations, and there is a complete lack of brain-penetrating compounds approved or in late-stage development to serve these patients. Either of these populations on its own represents a blockbuster opportunity in the U.S. alone, and both are among the largest, if not the largest, underserved targeted therapy populations that exist in lung cancer today. Slide seven summarizes the key aspects of an ideal target product profile that has yet to emerge to serve these populations, although we believe ORIC-114 is well on its way to doing so. While the next generation inhibitors, ORIC-114 included, have done a nice job of managing on-target toxicity, off-target toxicities continue to challenge the field. Additionally, the prevalence of brain metastases and the brain often being the site of first progression mean that robust CNS activity is an absolute must for a best-in-class inhibitor. Ultimately, strong efficacy both systemically and intracranially, combined with a manageable safety profile, should result in the differentiated long-term durability. Now, I've already mentioned the importance of brain penetrance in effectively treating this cancer, and slide eight helps explain the rationale. 30% of patients have known brain metastases at initial presentation, and that number does not include the portion of patients who have brain metastases that are not yet detectable on conventional imaging. Over time, half of patients will develop brain metastases, and the brain is often the first site of progression, especially for drugs that are not brain penetrant. The bottom half of page eight explains why this is such a problem. You can see that non-brain penetrant drugs have dramatically different outcomes for patients with or without brain metastases. There are countless examples in the targeted therapy space of best-in-class drugs that are brain penetrant and thus address this discrepancy. Turning to slide nine, you can clearly see that not only is ORIC-114 demonstrating a response profile that is as good or better than competitor compounds, but you also see the preliminary evidence that for ORIC-114, the presence or absence of brain metastases does not make a difference. The drug delivers profound results for patients regardless of brain metastases. In fact, we felt so strongly about this aspect of our drug that, unlike every other competing drug in the space, from day one, we never excluded patients from the study if their brain metastases were untreated before study entry. As Pratik will cover shortly, we've enrolled numerous patients with active, untreated brain metastases and have achieved strong systemic and intracranial response rates. With that, let me hand it over to Lori to remind you of the strong preclinical profile for ORIC-114 before Pratik covers the Phase 1b clinical trial results and next steps for the program. Thank you, Jacob. Slide 11 highlights our key aims in identifying a clinical candidate that would support a best-in-class profile for EGFR exon 20 and atypical mutations. ORIC-114 was designed to have multiple areas of differentiation. First, ORIC-114 has strong cell potency against a wide variety of EGFR exon 20 and atypical mutations and demonstrates tumor regression in vivo. Second, ORIC-114 is notable for its selectivity towards EGFR while sparing all other kinases. Third, a crucial feature of ORIC-114 is brain penetrance. This high brain exposure drives regressions in xenograft tumors grown in the brains of mice. As shown on the right, these three areas of preclinical differentiation have all played out in the clinic, with potency translating into clinical responses across a breadth of EGFR mutations, selectivity translating into minimizing off-target tox liabilities, and brain penetrance resulting in robust intracranial responses in patients. Taking each area of preclinical differentiation in turn, starting first with potency on slide 12. A key differentiating feature of ORIC-114 is strong cell potency across a variety of EGFR exon 20 and atypical mutations. In this figure, potency is depicted on a color scale, with dark teal blue being the most potent and gold being the least potent. When ORIC-114 is compared to competitors in head-to-head in vitro studies, you can see that ORIC-114 stands out with excellent potency across the spectrum of mutations. Moving to slide 13, a second differentiating feature of ORIC-114 is selectivity. Off-target selectivity is one of the most important aspects for designing best-in-class compounds. In these data, profiling multiple compounds across the kinome, ORIC-114 is exquisitely selective, a key differentiation versus competitors. The table at the bottom of the slide summarizes the off-target data. ORIC-114 has zero off-target kinases inhibited, while other EGFR compounds inhibited multiple off-targets, which can lead to adverse events not related to EGFR, such as hematologic, cardiac, or liver toxicities. Finally, turning to brain penetrance on slide 14, brain penetrance stands out as one of the most distinguishing features of ORIC-114, especially given the inability of approved and late-stage EGFR exon 20 and PACC agents to tackle brain metastases. On the left, in head-to-head studies in rodents, ORIC-114 has a high free brain-to-plasma ratio comparable to osimertinib and far higher than competitors that have minimal exposure in the brain. Shown on the right are results of an in vivo study measuring anti-tumor activity in the brain. This EGFR mutant lung cancer model was inoculated 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. Next, I'll hand it over to Pratik, who will discuss the clinical dose optimization results that show that these preclinical best-in-class properties are translating to patients. Thank you, Lori. Before I get into the data, I'd like to provide an overview of the ORIC-114 development program. All the data presented here at the ESMO Asia Conference come from our global Phase 1b trial that is being conducted at 39 major academic centers in 10 countries in North America, Europe, and Asia Pacific. Over 300 patients have been enrolled across the dose finding, dose optimization, and dose expansion cohorts. Also, one key aspect of our program, which Jacob already raised, is that unlike every one of our competitors, we allowed enrollment of patients with active brain metastases from the very beginning of our trial, starting in dose escalation, because we feel so strongly that CNS activity is necessary for a best-in-class molecule in lung cancer. Now, turning to slide 16, we'll begin with our experience in non-small cell lung cancer with EGFR exon 20 insertion mutations. We enrolled two populations of patients harboring these mutations. The first cohort to start enrolling was second-line post-platinum-based chemotherapy, in which patients were randomized one-to-one to receive either of the two provisional recommended Phase 2 doses we selected for dose optimization, namely 80 mg or 120 mg of ORIC-114 once daily. The second cohort, which started later, consists of first-line treatment naive patients, and here we enrolled the two dose levels sequentially, one after the other. The first 15 patients received 120 mg of ORIC-114, after which the remaining 18 patients up to the data cutoff received 80 mg. This shift was based upon safety observations we made at the 120 mg dose in the second-line cohorts, which I'll discuss shortly. Turning to slide 17, here we have the demographics and baseline characteristics for the second-line cohort, totaling 45 patients randomized to the two doses of 80 and 120. Notably, across both dose levels, 38% had brain metastases at baseline, including patients with active CNS disease. Turning to slide 18, we have the safety profile for the second-line post-chemotherapy population by dose level. In general, treatment-related adverse events were predominantly grades 1 or 2, and grade 3 events occurred in roughly one-third of patients. Importantly, there were no significant off-target toxicities observed, for example, cardiac, hematologic, and hepatic toxicity, all of which have been seen with other investigational agents. And finally, there was a low rate of discontinuations due to treatment-related events. Dose reductions were significantly more frequent at the 120 mg dose level, with 57% of patients undergoing dose reduction down to 80 mg versus only a third of the patients who started at 80. Looking at the table on the right, the most common treatment-related adverse events occurring in at least 20% of patients were diarrhea followed by paronychia and stomatitis. These can all be attributed to on-target EGFR wild-type inhibition. Overall, the 120 mg dose level had a higher rate of grade 3 toxicity, particularly diarrhea, which explains the high rate of dose reduction. But that's not the full story. Besides more dose reductions at the 120 mg dose level, there was also a higher frequency and duration of dose interruptions, which affected dose intensity. Thus, most patients assigned to receive 120 mg never truly saw that dose intensity, and many fell well below even 80 mg. In contrast, the 80 mg cohort was able to maintain this dose, pointing towards 80 mg as our go-forward recommended Phase II dose. Slide 19 depicts the reduction of ctDNA from baseline after the first 28-day cycle of therapy. You can see that there was a high and very similar rate of clearance at both dose levels, with 69% clearance at 80 mg and 67% at 120. Thus, there seems to be little to no advantage to the higher 120 mg dose. On slide 20, we'll turn to efficacy. Given what I just noted above, that the 120 mg dose level compromised dose intensity, I'll focus my discussion on the 80 mg dose level. Here, we are looking at the efficacy evaluable population, which consists of patients who have received at least one dose of ORIC-114, have at least one measurable lesion at baseline, and have had the opportunity for at least three post-baseline scans. The best objective response rate was 45%, all confirmed partial responses, and from the waterfall on the right, you can see that many of the PRs are deep with more than 50%-60% regressions, and the disease control rate was 100%. For the 40% of patients with CNS disease at baseline, looking at the table and the bars labeled with asterisks on the waterfall, you can see that there is no appreciable difference in response in these patients, which is the hallmark of a CNS active drug. Thus, ORIC-114, 80 mg once daily, appears to achieve a balance between an acceptable safety profile while providing strong clinical activity. The next slide depicts the swimmer plot for the 80 mg dose level in the second-line patient population. You can see that responses on ORIC-114 generally occurred by four weeks, which is the first on-study scan time point, but there are multiple examples of later responses occurring up to four or more months on treatment, demonstrating continued tumor regression with time. While progression-free survival and duration of response data are still immature, we can say that with a median follow-up of about 30 weeks, two-thirds of the responders remain on treatment. On slide 22, we'll now turn to the treatment-naive or first-line EGFR exon 20 cohort, which is one of our main opportunities for future development. As I stated earlier, we initially dosed these patients at 120 mg, but then shifted to 80 mg. Turning to slide 23, our first-line experience to date consists of 15 patients who received 120 mg of ORIC-114, followed by 18 patients who received 80 mg. In aggregate, 39% of patients had brain metastases at baseline, similar to our second-line population and higher than the literature average of 30%. On slide 24, we have the safety profile for the first-line cohort broken out by dose level. As we saw with the second-line data, here, there was also a higher rate of grade 3 or greater adverse events at the 120 mg dose level, with 80% of patients undergoing a dose reduction, whereas there was only a 22% rate of grade 3 or greater events at 80 mg, with 17% of patients undergoing dose reduction. Again, there were no significant off-target toxicities and a low rate of discontinuations, and as with the second-line cohort, the most common treatment-related adverse events were diarrhea, paronychia, and stomatitis. Note that of the dose reductions at 120 mg, approximately 60% of them occurred within the first couple of cycles, so these patients were more quickly dose reduced than in the second-line cohort, and therefore almost all were receiving an average 80 mg dose for their time on treatment. It was this observation that prompted us to shift from 120 mg dose and start a new cohort of first-line patients at the 80 mg dose level. On slide 25, we have the available ctDNA results, which again show a high rate of clearance after one cycle, occurring in 10 of 14 patients. On slide 26, we have the systemic objective response rate in the waterfall plot. We're looking at the efficacy evaluable population, those patients with the opportunity of at least three post-baseline scans. Since in this cohort, we initially enrolled patients at 120 mg, followed by a second cohort at 80. As of the data cutoff, only the first group of patients were on long enough to read out for efficacy. Follow-up is still in progress for the 80 mg dose group. Now, based on my earlier comments on dose intensity, these patients, although they were assigned to 120 mg because of the early and rapid dose reductions, effectively received an 80 mg dose, and so these data actually read more on the 80 mg dose level. The best objective response rate here was 67%, with a confirmed ORR of 60% and a disease control rate of 93%. On the right, you can see in the waterfall plot multiple responses occurring in patients with brain metastases at baseline. The next slide has the swimmer plot for the same 15 patients, and again, although many of the responses to ORIC-114 occurred as early as four weeks, as in the second-line setting, we also see tumor regression over time with multiple late responses. At a median follow-up of 33 weeks, 80% of responders are still on treatment. On slide 28, we have the CNS-specific intracranial objective response rate using an independent radiological review employing the RANO criteria. On the right, you can see the responses in the waterfall. Seven patients had brain metastases at study entry. Three of these patients had measurable lesions, meaning the masses were one centimeter or larger, and all three had confirmed partial responses for an intracranial ORR of 100% for patients with measurable disease. Four patients had what is termed non-measurable disease, meaning that the metastases in their brains were smaller than one centimeter. With non-measurable disease in the brain, anything short of 100% regression is termed non-CR, non-PD. So it's notable that two patients had total clearance of all their lesions, thus achieving intracranial complete responses. And finally, three of these five responders, including the two complete responses, had active CNS disease, which means they received no prior treatment for their brain metastases. With this CNS ORR based on an independent third-party assessment using current CNS response criteria, we can confirm the CNS potency of ORIC-114. It is able to achieve responses in the brain at the same rate as it does systemically, including in patients with untreated disease, which is a hallmark of a CNS active drug. Turning to slide 29, we have a vignette of one of the patients who had a complete CNS response. This is a 60-year-old woman with EGFR exon 20 mutated non-small cell lung cancer and no prior therapy, who presented with five non-target lesions in the brain. These lesions had not been previously treated and therefore would be considered active disease. She received 120 mg of ORIC-114, and by cycle 1, she achieved a systemic partial response and an intracranial complete response, which were later both confirmed. You can see the adverse events that she experienced with a grade 3 event leading to a dose reduction. As of the data cutoff, she remains on treatment in response at cycle 6. We highlight this case as another demonstration of ORIC-114's brain-penetrating properties because these smaller non-target lesions represent a setting where the blood-brain barrier would be largely intact. On the other hand, larger brain metastases can lead to a breakdown of the blood-brain barrier, in which case even non-CNS-penetrating agents can achieve some tumor regression. This distinction is important because one of the key properties of a brain-penetrating compound is not only causing regression of visible disease, but also preventing the progression of currently clinically undetectable CNS disease. It's this property of decreasing the rate of relapse in the CNS that translates to the potential for longer progression-free survival. We saw evidence of this potent CNS activity during dose escalation and now have multiple examples here with our expanded EGFR exon 20 experience, and as I'll discuss later, we saw intracranial CRs in our EGFR atypical population as well. Turning to slide 31, we'll shift to a discussion of the EGFR atypical patient data. Here, we enroll patients with non-small cell lung cancer, including those with active brain metastases that harbored an EGFR atypical mutation, which includes PACC or PACC mutations, classical-like mutations, and deletion 19 non-PACC mutations, all as either singleton or complex. In general, we were very permissive in terms of the range of EGFR atypical mutations we allowed into this dose optimization cohort, although for future development, based upon the efficacy signals we've seen, we would focus on the first-line PACC population. These patients were also allowed to have any prior therapy, including chemotherapy and EGFR tyrosine kinase inhibitors such as osimertinib and afatinib. As a result, the median number of prior therapies for this patient population is two, meaning that on average, these patients were receiving their third line of therapy. A total of 47 patients were enrolled and randomized to receive either 80 mg or 120 mg of ORIC-114 once daily, and because this is a later-line population, there was a higher rate of CNS involvement at baseline, with 55% of patients having brain metastases at study entry. On the next slide, we have the safety for these patients. As with the exon 20 experience, the most common related adverse events were diarrhea, paronychia, and stomatitis. Treatment-related adverse events were predominantly grade 1 or 2, with no grade 4 or 5 events and no significant off-target toxicities. There were no discontinuations due to treatment-related adverse events. However, as with the EGFR exon 20 experience, there was a high rate of dose reductions at 120 mg, with 68% of patients dose reducing, and 80% of those reductions occurred early in the first eight weeks on treatment. This cohort was the last of the dose optimization cohorts to start enrolling, so by this time, investigators were quick to dose reduce patients from the 120 mg dose down to 80 mg, leading to a dose intensity in these patients of approximately 80 mg once daily. For this reason, they were analyzed by combining them with the 80 mg assigned dose group. Turning to slide 33, we have the response data for the efficacy evaluable patient population, those patients with at least three post-baseline scans. In addition, this analysis is focused on those patients with PACC mutations, which is where we saw the strongest signal. As I stated earlier, we're combining all patients who were either assigned the 80 mg dose or, if they were assigned to 120, they actually received dose intensity of 80 mg. Of the 22 patients represented here, 12 patients started at 80, while 10 patients started at 120 but had an early dose reduction. Focusing on these 22 patients, you'll see that the best ORR is 36%, all confirmed with partial responses, with a disease control rate of 91%. And in the 59% of patients with CNS disease at baseline, looking at the table and waterfall plot, again, there's no meaningful difference in response. Overall, these results are all the more impressive given that this is a median third-line patient population, and they compare very favorably against efficacy benchmarks with other agents being developed in this same patient population. Slide 34 shows the swimmer plot for these patients, and as before, we see many responses to ORIC-114 occurring at the four-week mark, with additional examples of late responders. With a median follow-up of approximately 33 weeks, 75% of responders remain on treatment. Now, before starting the next section, given that our initial treatment experience in the PACC population was so heavily skewed to later-line patients, effectively median third-line patients, we felt it was important to provide a brief update here of our early experience in treatment-naive first-line PACC patients. Turning to slide 36, these are preliminary data from our ongoing first-line EGFR PACC cohort, who are all receiving the 80 mg dose. These data were not available at the time of the abstract deadline for ESMO Asia, but we are providing an early look here because it confirms our conclusion that 80 mg of ORIC-114 once daily is a well-tolerated dose able to achieve significant clinical activity, including in the CNS. Here we have an early look at the first 10 patients with EGFR PACC mutations who have had at least one post-baseline scan on study. The safety profile we've seen in this cohort is in line with what we've seen to date at the 80 mg dose level in other cohorts. Turning to efficacy of these 10 patients, eight have had a partial response, giving an ORR of 80%. So far, three responses are confirmed, and five are as yet unconfirmed but still ongoing on treatment and pending confirmation. You can see the tumor regressions in the waterfall to the right. Many of these patients also had CNS disease at baseline, indicated by the asterisks over the bars. We, of course, were interested to see if there was also evidence of intracranial response, and I'm happy to say there clearly was. Turning to slide 37, we have the CNS-specific intracranial response rate here based upon investigator assessment using RECIST criteria. In this early look at our first-line EGFR PACC population, we had six patients with baseline CNS metastases at study entry, of which five had a post-baseline scan. All these patients had active disease at baseline, meaning no prior treatment of their CNS mets. On the right, you can see the responses in the waterfall. Of these five evaluable patients who had brain metastases at study entry, four had measurable lesions and all responded, with three partial response and one complete response, resulting in an intracranial ORR of 100% for patients with measurable disease. The other patients had non-measurable disease, which right now is non-CR, non-PD. While still early, we are very encouraged by these data and the potential of ORIC-114 to be a best-in-class molecule in both the EGFR exon 20 and EGFR PACC mutated patient populations. Finally, let me close with one more case vignette, this time of a 67-year-old man with non-small cell lung cancer and a PACC mutation. The patient had systemic disease as well as a target lesion in the frontal lobe of the brain. He received ORIC-114 at 80 mg once daily and achieved a partial response in his systemic disease as well as a partial response in the brain, both confirmed. He's only experienced grade 1 skin toxicity and remains on study in response in cycle five as of the data cutoff. Hot off the press, we learned from the patient's physician that the week before this conference, that after the fourth cycle of treatment, the patient now has a complete response in the brain. How about that? This concludes the data I wanted to review today. I'll now pass it back to Jacob to put our results into perspective, but I think you'll agree that through this major update to the ORIC-114 program, we have laid a strong foundation to support its best-in-class potential. Jacob? Thanks, Pratik. Well, Pratik obviously covered an enormous amount of data. The most relevant of which is summarized on slide 40. You can clearly see that not only is ORIC-114 demonstrating a response profile that is as good or better than competitor compounds, but you are already seeing the preliminary evidence that for ORIC-114, the presence or absence of brain metastases does not make a difference. The drug delivers profound results for patients regardless of their status of brain metastases. And while the data are too immature to comment definitively on durability, we obviously like what we've seen thus far and are looking forward to providing longer-term follow-up in future updates. Turning to slide 41, we have previously mentioned that our potential registrational development priorities for ORIC-114 are focused on frontline populations in both EGFR exon 20 and EGFR PACC mutations. We believe today's substantial update establishes ORIC-114's potential best-in-class profile for patients with EGFR mutated non-small cell lung cancer. We've observed highly competitive response rates in both pretreated and frontline EGFR exon 20 and EGFR PACC mutations, our two populations of interest. We have continued to demonstrate ORIC-114's two key differentiators: profound CNS activity and a lack of significant off-target toxicities, two factors that we believe will be key to eventually establishing long-term differentiated durability. Finally, we've selected a preferred dose of 80 mg once daily for future development, and we will continue enrollment and long-term durability follow-up in these two frontline populations with the next planned update in mid-2026 ahead of the potential start of one or more Phase 3 registrational trials. 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 for both ORIC-114 and ORIC-944 over the coming quarters. Before we open it up to Q&A, I'd like to thank our 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. The question-and-answer session. As a reminder, to ask a question, you will need to press star one one on your telephone and wait for your name and company name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster, and our first question comes from the line of Anupam Rama from JPMorgan. Your line is now open. Hey, guys. Thanks so much for taking the question. Congrats on the data, and go Buckeyes. So within the second-line EGFR exon 20 dataset, you guys talked about how your response rate was lower at the 120 mg than at the 80 mg. You alluded to this being driven by some safety. Can you dig into what exactly you're seeing in terms of the AEs impacting dose intensity? And then a second question, just what gives you confidence in the 80 mg moving as your Phase 3 dose, and when do you think you might have FDA sign-off to move forward with the dose? Thanks so much. Hey, Anupam, thanks for the question. Go Trojans, and I'll ask Pratik to address your questions. I think I'd have to take the Buckeyes side of things. Thanks for the questions. I'll take them in order. Yeah, you're right. We did see a lower response rate in the second-line EGFR exon 20 cohort at the 120 versus the 80. There was a higher rate of grade 3 diarrhea at the 120 mg dose level, which largely explains the higher rate of dose reductions as well as some of the skin tox we saw again at the 120, but beyond the higher rate of dose interruption, there were also more dose holds, and the issue with those holds is you have periods where you're not going to have enough drug on board, and so the patient may progress in this window or actually never have a chance to respond, so we saw this when we looked at the average daily dose of the patients in the 120 mg dose group. With the dose reductions and interruptions, although they were assigned 120 mg, they actually had an average daily dose of 65, and some patients went below 50 as their average daily dose. So they just weren't getting continuous target coverage necessary to either achieve or maintain response. That's in contrast to what we saw at the 80 mg dose, where patients had a lower rate of dose reductions and dose holds. And so most of those patients actually saw the effective dose of 80, which allows for continuous target coverage and the full efficacy of the drug. So that's kind of how the safety played off into efficacy in that second-line cohort. Now, in terms of confidence that 80 mg are dosed moving forward to Phase 3 and our sort of feeling about FDA's, what their read will be as well. I think at this point, we've generated a robust dataset with ORIC-114 at both the 120 and the 80 mg dose levels across all the cohorts. We have over 170 patients treated. And so I think within any given cohort and across all the cohorts, they collectively support 80 mg being the go-forward dose. But let me go into a little more detail. First, the second-line cohort data, which EGFR cohort data, which I just mentioned, the 80 mg dose level, we saw 45% confirmed ORR, which compared to other benchmarks were as good or better in that same patient population. Second, in our first-line EGFR exon 20 cohort, here we did report on the patients who were assigned 120 mg dose level, but with the high number of early dose reductions. And the key here is they were early. These patients actually received an average daily dose of just about 80 mg. So we feel those data also reinforce the clinical activity of ORIC-114 at the 80 mg dose level. But of course, we have an ongoing 80 mg cohort in the first-line exon 20, so we'll report on that next year. And then finally, the sort of late-breaking data we disclosed on the call in the first-line EGFR PACC population. These patients are all receiving 80 mg, and we saw an 80% ORR in the first 10 patients evaluable. And on top of that, four of these patients had active measurable brain mets at baseline, and all four had an intracranial CNS response, 100%, including one CR. So I think collectively, these data really support our choice of 80 mg at the RP2D. Importantly, this is a highly active dose, and we're not leaving any efficacy on the table. So now, in terms of FDA and Project Optimus, as they've said, the objective of this initiative is to determine whether or not a lower dose of a given drug may be equally efficacious but better tolerated and trying to move away from the MTD paradigm. I think our data support that conclusion for ORIC-114 that 80 mg has a better safety profile while it's retaining clinical activity. Frankly, I think the clinical activity could be better than we saw at 120 because of the dose holds and interruption issues that I discussed. So we'll see how the cohorts play out, but I think we feel pretty confident about FDA's concurrence with our decision. Thanks so much for taking the question, guys, and congrats again on the data. Thank you, Anupam. Thank you. And our next question comes from the line of Prakhar Agrawal, Cantor Fitzgerald. Your line is now open. Hi. Congrats on the comprehensive data update, and thank you so much for taking my questions. I had two. So maybe first one, can you help us put into context the CNS activity of ORIC-114 relative to your competitors? And secondly, if you can just put more final details on how the overall profile of efficacy and safety you shared today compared to your competitors, especially for the first-line setting in both EGFR 20 and PACC mutations. Thank you and congrats again. Yeah, Prakhar, thank you for the question. Overall, I'll ask Pratik to address your first question. Overall, we believe that ORIC-114 data that we presented today, specifically at the 80 mg selected dose, which is what Pratik just highlighted in the last set of questions, are best in class for EGFR exon 20 and PACC mutations. Full stop. I'll ask Pratik to kind of elaborate that on the CNS side, and then I can address the other part of your question. So we presented quite a bit of CNS data, but in particular across the first-line patient populations, the first-line EGFR exon 20 and the first-line EGFR PACC. Across those, we had 12 patients with CNS disease. Seven of those patients had measurable CNS disease and all responded. So the intracranial ORR was 100%, and one of these was a CR. And then in the patients with non-measurable disease, we had five of them, and we had two more CRs in that group. And non-measurable, just for information's sake, are tumor lesions that are less than one centimeter in size. And then on top of this, this is out of these 12 patients, nine had active untreated brain mets. So these are patients who didn't have any other treatment to those brain mets apart from ORIC-114. Most of our competitors really don't claim to be CNS active, and the few that do haven't really shown convincing intracranial data as convincing as what we've shown today. And then one thing we didn't mention in the prepared remarks was we had the opportunity, which is very rare, to collect CSF from several of our patients to see whether the drug can be definitively identified in the CSF and having crossed the blood-brain barrier. I can report that with three samples of patients on ORIC-114, we're achieving therapeutic levels in the brain in every one of those patients. Yeah, I think the CNS penetrance has been demonstrated in humans, and the activity is clear. Prakhar, on the overall profile, I mean, the systemic response rates that we've observed with ORIC-114 as we profiled today are generally on par with, or they exceed the best competitor datasets from other multinational studies across these two EGFR populations that we reviewed. You have to keep in mind that our ability to equal or exceed those benchmarks is in the backdrop of the fact that our study enrolled more difficult patients to treat based on the higher percentages having baseline brain mets. Keep in mind, even in that group, most of those patients had active untreated CNS disease. Those are patients that were literally not enrolled in the early datasets from any of our competitors. On the tolerability front, clearly at 120 mg, we were kind of beyond the tolerability threshold of what we view to be competitive. But at 80 mg, the treatment discontinuation rates for ORIC-114 are generally similar to, if not better, than those from the competitor trials. And importantly, it has not been associated with significant off-target toxicities that you do see with the competitor compounds. And that comes in a variety of different combinations that include cardiovascular, hepatic, and hematological events. And we do not see those with ORIC-114. So that's on the tolerability side. Then as Pratik did say on the CNS, and as he covered quite nicely, we've obviously demonstrated definitive and profound CNS activity with 100% intracranial response rates in first-line EGFR exon 20 and first-line PACC mutations, which are our target populations moving forward. There's actually no benchmark to date on the EGFR exon 20 side from any competitor. On the PACC side, our CNS ORR is significantly higher than the top datasets in first-line PACC. It's obviously the last piece of the puzzle here is durability. It's obviously too early to compare on durability at this point, just given where our datasets are. But as you can see from the swimmer plots and as you look at those early signs even of durability, and we look forward to updating on that next year, we believe that the strengths of ORIC-114's compelling systemic activity, the improved tolerability, the strong CNS activity, all collectively should lead to significantly better long-term clinical durability in the future. Thank you. Thanks, Prakhar. Thank you. Our next question comes from the line of Maury Raycroft of Jefferies. Your line is now open. Hi. Congrats on the data updates, and thanks for taking my questions. Following up on the brain mets line of questioning, your dataset contains a higher proportion of brain mets at baseline versus comp datasets. And you said in the prepared remarks you didn't exclude any patients with active brain mets at baseline. Can you talk more about how this factors into enrollment? Was there a concerted effort to do this, or was there any enrichment for these patients? Yeah, let me have Pratik take that. Thanks for the question, Maury. Yeah, so you're right. So from the beginning, we've been confident about ORIC-114's brain penetrance properties based upon how it was originally designed and all the subsequent preclinical profiling that we've done, which is why, as you said, we've allowed enrollment of these patients with stable untreated brain mets from the very beginning of dose escalation, which is different from the more narrow enrollment criteria used by a lot of other agents that are in the same space. Just as a reminder, I mean, our original Phase 1 dose escalation data that we presented at ESMO two years ago, 86% of patients had brain mets at study entry at a very high rate, which sets that study apart from all the other agents. But to answer your question, the short answer is no. We haven't made any special effort to disproportionately enroll patients with brain mets into our study. But I guess I'd just say investigators are voting with their feet or enrolling with their feet, so to speak, by enrolling these patients onto our trial. I think it goes to show the overall need for a CNS penetrant drug. We've been enrolling these patients in the face of other competing trials that are enrolling the same patients. So now that we have many examples of clear CNS activity, including a 100% intracranial response rate in our first-line patients with measurable disease, I'm sure we'll continue to get these patients. Got it. That's helpful. And for patients with brain mets, you were breaking out if brain mets were active and untreated and whether the lesions are measurable for your naive patients. Are these specific parameters representative? And can you talk about why these distinctions matter relative to competitor programs? Sure. Yeah, I'll have Pratik continue on that one more. Yeah, no, that's a good question. I think we have been kind of explicit about sort of breaking out active, as you said, and measurable. And that's because many members of our team have lived the importance of CNS activity and how the FDA wants to see it demonstrated. Both myself as well as many of, as I said, members of our team worked on entrectinib, whereas CNS activity was a key differentiating feature. So with that program in our discussions with FDA, and they've since made sort of more formal guidances that captured those discussions that we had, there's a number of important considerations that they outline in terms of how they like to see CNS activity demonstrated. First of all, for them, CNS mets to be truly considered evaluable, they must be active. So either they haven't been treated, or if they're treated, then the mets have progressed since that last treatment, or there's been a sufficient interval since they were last treated, so something on the order of 12 weeks. So the mets need to be active, and then they look at measurable disease looking RANO criteria, and that's the metric by which they judge CNS activity. So that's why we're focusing on active measurable brain mets because it's the regulatory basis for ultimately getting a CNS efficacy claim. Got it. Okay. Thanks for taking my questions. Thank you, Maury. Thank you. And our next question comes from the line of Brad Canino from Guggenheim. Your line is now open. Hey, team. Great to see all these data really all at once here. I'm probably going to put the cart before the horse a bit here on this question because I know it's too early for any sort of median PFS or DOR, but what can you say about the durability you're seeing thus far? You're really calling out two elements, it seems like, dialing in the right dose for a safety profile around the 80 mg and the CNS responses. So when do you think you'll have a good sense for whether those properties are resulting in an improved PFS versus the benchmarks? Thanks. Sure. Yeah, I mean, we don't right now have estimated medians that we can provide. We did provide the swimmer plots. As you can see from the multiple swimmer plots, most of our responders are still on treatment. At the second line, EGFR exon 20 cohort, at the 80 mg dose, six of nine are still on treatment after median follow-up of 30 weeks, which is about seven months. In the first line, EGFR exon 20, eight of ten are still on treatment, same follow-up, about seven and a half months. And in the third line, EGFR PACC, similar follow-up, 6 of 8 responders are still on treatment. So that's kind of what we have right now. But you're right, the CNS activity will play a key role given that we had anywhere from 40%-55% of patients with brain mets at study entry. A non-brain penetrant drug would have a very different PFS in patients with brain mets versus those without. And we saw that with mobocertinib and with the amivantamab combo. But with a CNS-active drug, which we believe ORIC-114 certainly is, the PFS shouldn't dramatically be different between those two patient populations. So we expect to do an update next year, and we should have the mature data to confirm that. Thank you. Our next question comes from the line of Colleen Kusy from Baird. Hi. The line is now open. Hi. Thanks so much for taking our questions, and congrats on the data presentation. So you touched on this a little bit, Jacob, but just on the treatment-related AE discontinuation rates, you said, I think, relative to competitors was low. But I was just curious, the discontinuation rate for the 80 mg dose appeared a little bit higher than the 120 mg dose, even though we saw higher tox at the 120 mg dose. So does any color on why you might be seeing that higher discontinuation rate? Yeah. Colleen, I want to clarify my comment. What it should have reflected is essentially that the safety profile at 80 mgs, obviously, overall is better tolerated than at 120 mgs. Some of the individual stats are actually turned around on 120, but I'll ask Pratik to kind of walk you through the reasons for why that is. Sure. Yeah. So that second line, EGFR exon 20 cohort was the first cohort we started enrollment with. And so there was sort of some investigator learning along the way. But if you look at the discontinuation rate at 80 mg across the entire patient experience that we presented, it's 6%. So that number is the sort of collective rate, and that's as good, if not better, than the other agents in this class. The reason for the low discontinuation rate in the 120, and it's kind of, yeah, it perplexed me as well when we first saw it, but it's really sort of safety and efficacy being two sides of the same coin. And so at the 120, we had the dose reductions. And as I said earlier, those dose reductions come with dose holds, and those dose holds lead to impaired efficacy. And so instead of these patients coming off for safety events, they come off because they either don't respond and progress, or they progress. And so what might have been a safety discontinuation ends up being a progression discontinuation at the 120 mg dose. So that's sort of the explanation. As the investigators got more experience with the drug, especially at the 120 mg, as I said in my remarks, they started to dose escalate very quickly and maintained dose intensity, but now it was at the 80 mg dose level interestingly because that's the dose reduction from 120. Gotcha. That's super helpful. Thank you. And then not sure how many members of the team are in Singapore for ESMO Asia this weekend, but just curious on any color from the general feedback that you're hearing from investigators on the data update. Yeah, Colleen, there's four of us here in Singapore, but I'll ask Pratik. Pratik and Edna have obviously spoken to a lot of investigators here in Singapore. Yeah. So this conference, I'd encourage people to attend. Edna and I came to this conference when it first started 10 years ago, and it's grown considerably, and so it's a good chance to see a lot of our Asian investigators from Korea, Taiwan, Hong Kong, Australia. So we're able to link up with both our investigators as well as just other KOLs here who are giving talks and such, and I think the biggest flash was clearly the CNS data. I think people were impressed with the response rates, with the fact that it was in patients with active disease, and now we're moving beyond anecdotal case vignettes, but really sort of response rates where the safety profile at the 80 mg dose level that people feel comfortable moving forward with. So that's the feedback we've gotten so far. Great. Thanks so much for taking our questions, and congrats again. Thank you, Colleen. Thank you. Our next question comes from Derek Archila from Wells Fargo. Your line is now open. Hey, guys. Congrats on the update, and thanks for taking a couple of questions here. So yeah, just wanted to get your thoughts on a potential Phase 3 design in the first-line EGFR exon 20 patient population, particularly given that amivantamab is already approved there and just how you're thinking about maybe relative to some of the other Phase 3 trials, and then just one follow-up, since you're already evaluating ORIC-114 in combo with amivantamab, I guess any color on the potential treatment arm you might pursue in that trial. Thanks. Hey, Derek. Thanks for the good questions. Yeah. I mean, I'll ask Pratik to kind of cover off on the detail of your questions, but at a high level, we're obviously going to see, we presented a huge amount of data here at the conference. We'll see a lot more of our own data in the two first-line settings, first-line EGFR PACC and first-line EGFR exon 20, over the next coming quarters. We'll also see a lot of competitor data over the coming quarters. And so all of that will have a bearing on the questions you asked. But we've been actively thinking about that Phase 3 trial design for both of those populations. So let me ask Pratik to hit that. Yeah. So no, you're right. So amivantamab has been approved in the first-line setting. But the approval of a new agent, or in this case, a regimen, doesn't automatically make it the standard of care that needs to be the sort of control arm of any future Phase 3. Despite the fact that amivantamab is approved for first line, we haven't had any trouble getting patients who are second-line post-chemotherapy only, without any amivantamab, and that's in the U.S. So chemotherapy is still widely used in the first-line setting. It's still in the guidelines, not just in the U.S., but European and other guidelines. I think just indirectly, you can get some read as well. The amivantamab label was approved in March of 2024, just six months after the PAPILLON Phase 3 started. And FDA had the amivantamab NDA in their hands well before then. And I don't think Janssen has said that they ever had to consider changing their control arm or are concerned that their control arm of chemotherapy is going to be invalid. So as it stands right now, chemotherapy remains an acceptable standard of therapy for first-line EGFR exon 20. And a big consideration is that any Phase 3 would be a global trial. So you have to consider global clinical practice where chemo remains an option on all the guidelines, as I said. Then I think you asked about, yeah, what regimen we might take into Phase 3, given that we are also, besides all of the single-agent data, generating amivantamab combo data. ORIC-114 plus amivantamab is ongoing in a separate trial. We also have ongoing now a little dose expansion of ORIC-114 plus platinum-based chemotherapy. So there's actually three options that we're looking at for a potential Phase 3 for the ORIC-114 regimen: single-agent, combo with chemo, and combo with ami. So we're going to let those data play out, especially the combo with chemo and ami, to see what makes sense moving forward. Got it. Very helpful. Thanks. Thank you, Derek. Our next question comes from the line of Yigal Nochomovitz of Citi. Your line is now open. Hey, thanks, and congrats on the data. I had two related commercial ones and then one on the data itself. In the past, you've talked about a commercial opportunity in the US in the neighborhood of around $3 billion-$3.5 billion for NSCLC. I'm wondering if you could just walk us through a little bit how you get to that number. And then, obviously, as you've already highlighted on the call, it is a competitive landscape, both for front-line exon 20 and front-line PACC. So could you just kind of discuss in a little more detail your views as to what supports success commercially in both of those settings? Hey, Yigal. Yeah, sure. Keith Lui, who's heading up our commercial and our medical affairs efforts at ORIC, is here with us in Singapore. So I'll ask him to take both of those. Hey, Yigal. This is Keith. Thanks for the question. Regarding the EGFR exon 20 population, that accounts for about 2% of non-small cell lung cancer, and the EGFR PACC atypicals are slightly higher, about 2.5% of NSCLC. And that's just based on the literature out there. And then regarding our duration assumptions in exon 20, we assume treatment duration of close to a year. And then in PACC, we assume duration of about 16 months. And both of these numbers are premised on the current best data from the competition. And then, obviously, there's upside to those duration numbers if our CNS profile that we discussed on today's call translates into a durability benefit. And then regarding pricing, we take into account the current market pricing of various TKIs in non-small cell lung cancer. I think the second question you asked about was around why we think ORIC-114 could be potentially successful commercially in these patient populations, front-line exon 20 and front-line PACC. As we discussed, as Jacob and Pratik mentioned in their presentations, we think ORIC-114 has the potential to be a best-in-class drug in this space, specifically addressing the medical needs of front-line patients with EGFR exon 20 and PACC mutations. Given the 30% rate of brain mets at presentation for non-small cell lung cancer patients and the fact that about half of these patients will develop CNS mets over the course of their disease, we think ORIC-114's confirmed brain penetration properties are going to be a key differentiator and really a game changer for treating oncologists and for non-small cell lung cancer patients. I would also say, adding to this ideal product profile, is the convenience of an oral once-daily regimen. And then when you couple that with a manageable safety profile at the selected 80 mg dose that we are going to take into potential Phase 3 with no significant off-target toxicity and low rate of discontinuation, I think this really sets up to be an ideal product profile. And particularly on the manageable safety profile, it's especially important because patients may achieve responses in later cycles, as you saw as late as the fourth cycle, and may continue to respond on therapy for years. And then, Yigal, you mentioned you had a question on the data as well. Oh, yeah. Thanks, Jacob. Yeah. It was just sort of a quick one. I was just curious. In the front-line PACC patients where you had the 100% response rate in those with the measurable CNS disease, I was just curious, of those, how many also had the systemic responses? Oh. So yeah. I mean, by RECIST, they were also responders, all of them. Okay. Okay. Great. Thank you. Thanks, Yigal. Thank you. Our next question comes from the line of Matthew Biegler from Oppenheimer & Co. Your line is now open. Thanks, everyone. This is Tracey on for Matt. We just had a couple of questions. Are the responses seen in EGFR exon 20 near loop or far loop mutations, and are the responses seen in the two most common PACC mutations or complex PACC mutations? Thank you. Yeah. Thanks, Tracey. I'll ask Lori, our CSO, to take those. Thanks for that question. So we use the Guardant360 ctDNA assay to really exhaustively characterize the EGFR mutations. As expected, we enrolled patients with a broad spectrum of EGFR mutants. Specifically, in the EGFR exon 20 cohorts, we do see responses in both the near loop and the far loop mutations, which is consistent with our preclinical data. Then in the EGFR PACC cohorts, we also had robust responses in singletons, including the two most common mutations, the G719X and S768I, as well as responses in a variety of complex mutations. Our response rates, for instance, in the first-line treatment naive PACC cohort, are comparable for the singleton mutations at 75% for best ORR and the complex mutations at 83% best ORR. We feel that the preclinical data has translated very nicely to the clinical responses. Thanks so much. Very helpful. Thank you. Our next question comes from the line of Corinne Jenkins of GS. Your line is now open. Good evening, guys. And maybe you could talk a little bit more about your registrational trial plans. And in particular, I'm curious how you plan to further build the case for differentiation against these CNS metastases. And how does that kind of feature as you think about patient selection and stratification in the registrational program? Yeah. Sure. I can answer that. I mean, I think, as I said, there's a number of factors that still have to play out in terms of how we design our Phase 3 plan. First of all, which one are we going to prioritize? First-line EGFR exon 20 or first-line EGFR PACC? I think we have great activity both systemically and in the CNS in both of those indications at the 80 mg dose as a single agent. Then, within the EGFR exon 20, there's the, as I mentioned earlier, the options of single agent, combo with chemo, and combo with amivantamab. So those are considerations. I think, as we have already done, we're always going to lean heavy into the CNS activity. We feel that the 80 mg dose is able to achieve that so far in 100% of patients in the first-line setting with measurable disease. So I think there's a number of factors that we still need to sort of have play out to make those decisions. And then, obviously, the durability assessments in the various indications as well. So I think it's too early for us to kind of give you the actual sort of decision, but these are the variables that we're considering. And Corinne, it's a good question. I'll just add on to a couple of things to what Pratik mentioned, which is one of the reasons we obviously went out of our way in the presentations to highlight and specify exactly which patients had measurable disease in the brain and then which of those were active and untreated diseases. Because, as Pratik mentioned in the prepared remarks, those are the two variables that matter to FDA. And so we have experience of this directly from developing entrectinib, which is a brain-penetrating compound that several of us were involved in at Ignyta, where if you want to get the CNS data into the label, the FDA wants to see patients with measurable disease in the brain, and they want to make sure that those patients have active and untreated disease. So that's why we made such a point to highlight those two aspects of the data. Great. Thank you. Thank you. And our last question comes from Jonathan Miller from Evercore ISI. Your line is now open. Hi, this is Jonathan from Evercore. Thanks for taking the question. I wanted to ask, do you guys have any more details you could share about the kinetics of the responses and how they differ for patients on the 80-mg dose versus those at the 120-mg dose that got dosed down? Thank you. Sure, Jonathan. Thanks for the question. I think it was cutting out a little bit, but I think you were asking about response kinetics in the patients. I'll ask Pratik to take that. Yeah. It's the same. So in the 80 mg dose level, we see the responses' majority happen at the four-week mark, which is the first time we check. We saw that in the second-line EGFR exon 20. We're seeing that in the first-line PACC, EGFR PACC. So even with the lower dose, that's why, like I said earlier, we don't feel like we're leaving any efficacy on the table because the kinetics of the 80 mg dose response are as quick as what we saw at the 120. All right. Awesome. Thank you. Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.