ORIC Pharmaceuticals, Inc. (ORIC) Earnings Call Transcript & Summary

Good day, and thank you for standing by. Welcome to the ORIC Enozertinib Program Update Conference Call. [Operator Instructions] 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 Enozertinib Program Update Conference Call. Earlier this week, we issued multiple press releases highlighting updated data from our ongoing Phase Ib study of Enozertinib in non-small cell lung cancer patients. You may find the press release is posted on the investor page of oricpharma.com. We have prerecorded 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 Enozertinib trials as of the cutoff date set forth on applicable slide. During this presentation, we will not be speaking to any additional data to such date. Now turning to Slide 3. During today's call, we'll discuss Enozertinib's preclinical differentiation Phase Ib clinical highlights from [ ESMO ] Asia, new preliminary first-line data in EGFR pack mutations and next steps followed by Q&A. Joining me on the call today, we have Jacob Chacko, CEO; Lori Friedman, CFO; Pratik Multani, CMO; Matt Panuwat, CBO; and [ Keith Louis ], Senior Vice President of Commercial and Medical Affairs. Now let me turn the call over to Jacob.

Thank you, Dominic. Turning to Slide 5. We've obviously been busy at [ ESMO ] Asia with two oral presentations and one poster presentation that collectively summarize an enormous amount of Enozertinib data generated over the past 1.5 years in three different targeted therapy lung cancer population. This slide is a summary of the key takeaways from our Enozertinib enozertinib 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 pretreated and frontline 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 Enozertinib'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 Enozertinib points us to 80 milligrams 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 population with the next planned update in mid-2026, ahead of the potential start of one or more Phase III registrational trials. Slide 6 highlights why we are so passionate about developing Enozertinib as rapidly as possible for patients. EGFR Exon 20 and EGFR PACC mutation 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 mutation. And there is a complete lack of brain-penetrant 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 7 summarizes the key aspects of an ideal target product profile that has yet to emerge to serve these populations, although we believe Enozertinib is well on its way to doing so. While the next-generation inhibitors, and Enozertinib 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 the 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 8 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 8 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 9. You can clearly see that not only is Enozertinib demonstrating a response profile that is as good or better than competitor compounds, but you also see the preliminary evidence that for Enozertinib, 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 1, 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 Enozertinib before Pratik covers the Phase Ib 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. Enozertinib was designed to have multiple areas of differentiation. First, Enozertinib has strong cell potency against a wide variety of EGFR Exon 20 and atypical mutations and demonstrate tumor regression in vivo. Second, Enozertinib is notable for its selectivity towards EGFR and while sparing all other kinases. Third, a crucial feature of Enozertinib is brain penetrant. This high brain exposure drives regressions in [ cenograft ] 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 the breadth of EGFR mutations, selectivity translating into minimizing off-target [ tox ] liabilities, and bring penetrants resulting in robust intracranial responses in patients. Taking each area of preclinical differentiation in turn, starting first with potency on Slide 12. The A key differentiating feature of Enozertinib 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 Enozertinib is compared to competitors in head-to-head in vitro studies, you can see that Enozertinib stands out with excellent potency across the spectrum of mutations. Moving to Slide 13. A second differentiating feature of Enozertinib 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 ], Enozertinib is exquisitely selective, a key differentiation versus competitors. The table at the bottom of the slide summarizes the off-target data. Enozertinib has 0 off-target kinases inhibited, while other EDFR 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 Penetrant stands out as one of the most distinguishing features of Enozertinib especially given the inability of approved and late-stage EGFR Exon 20 and PACC agents to tackle brain metastasis. On the left, in head-to-head studies in rodents, Enozertinib 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 antitumor 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 Enozertinib 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 Enozertinib development program. All the data presented here at the [ ESMO ] Asia conference come from our global Phase Ib 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 with second-line post platinum-based chemotherapy in which patients were randomized 1:1 to receive either of the two provisional recommended Phase II doses we selected for dose optimization, namely 80 milligrams or 120 milligrams of Enozertinib 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 milligrams of Enozertinib after which the remaining 18 patients up to the data cutoff received 80 milligrams. This shift was based upon safety observations we made at the 120-milligram 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 Grade 1 or 2 and Grade 3 events occurred in roughly 1/3 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-milligram dose level with 57% of patients undergoing dose reduction down to 80 milligrams versus only 1/3 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-milligram 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-milligram dose level, there was also a higher frequency and duration of dose interruptions, which affected dose intensity. Thus, most patients assigned to receive 120 milligrams never truly saw that dose intensity and many fell well below even 80 milligrams. In contrast, the 80-milligram cohort was able to maintain this dose pointing towards 80 milligrams 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 milligrams and 67% at 120 [ milligrams ]. Thus, there seems to be little to no advantage to the higher 120-milligram dose. On Slide 20, we'll turn to efficacy. Given what I just noted above that the 120-milligram dose level compromised dose intensity, I'll focus my discussion on the 80-milligram dose level. Here, we are looking at the efficacy evaluable population, which consists of patients who have received at least one dose of Enozertinib have at least one measurable lesion at baseline and have had the opportunity for at least three post baseline stands. 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, Enozertinib, 80 milligrams 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-milligram dose level in the second-line patient population. You can see that responses on Enozertinib generally occurred by 4 weeks which is the first on-study scan time point, but there are multiple examples of later responses occurring up to 4 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, 2/3 of the responders remain on treatment. On Slide 22, a 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 milligrams but then shifted to 80 milligrams. Turning to Slide 23. Our first-line experience to date consists of 15 patients who received 120 milligrams of Enozertinib followed by 18 patients who received 80 milligrams. 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-milligram 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 milligrams with a 17% of patients undergoing dose reduction. Again, there were no significant off-target toxicities and a low rate of discontinuation. And as with the second-line cohort, the most common treatment-related adverse events were diarrhea, [indiscernible] and stomatitis. Note that of the dose reductions at 120 milligrams, 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 we're receiving an average 80-milligram dose for their time on treatment. It was this observation that prompted us to shift from a 120-milligram dose and start a new cohort of first-line patients at the 80-milligram 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 milligrams followed by a second cohort 80 [ milligram ]. As of the data cutoff, only the first group of patients are on long enough to read out for efficacy, follow-up is still in progress for the 80-milligram dose group. Now based on my earlier comments on dose intensity, these patients, although they were signed 120 milligrams because of the early and rapid dose reductions, they effectively received an 80-milligram dose. And so these data actually read more on the 80-milligram 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 Enozertinib occurred as early as 4 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 that masses were 1 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 nonmeasurable disease, meaning that the metastases in their brains were smaller than 1 centimeter, with nonmeasurable 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 the CNS ORR based on an independent third-party assessment using current CNS response criteria, we can confirm the CNS potency of Enozertinib 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 were presented with five nontarget lesions in the brain. These lesions had not been previously treated and therefore, would be considered active disease. She received 120 milligrams of Enozertinib 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 Enozertinib's brain penetrant properties because these smaller nontarget 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 [ penetrant ] agents can achieve some tumor regression. This distinction is important because one of the key properties of a brain-penetrant 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 a 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 harbor and EGFR atypical mutation, which includes [ P-A-C-C ] 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 A typical 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 are receiving their third line of therapy. A total of 47 patients were enrolled and randomized to receive either 80 milligrams or 120 milligrams of Enozertinib 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 a 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 milligrams with 68% of patients dose reducing. And 80% of those reductions occurred early in the first 8 weeks on treatment. This cohort was the last of the dose optimization cohorts to start enrolling. So by this time, investigators are quick to dose-reduce patients from the 120-milligram dose down to 80 milligrams, leading to a dose intensity in these patients of approximately 80 milligrams once daily. For this reason, they were analyzed by combining them with the 80-milligram 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 signed the 80-milligram dose or if they were assigned to 120 [ milligram ], they actually received dose intensity of 80 milligrams. So of the 22 patients represented here, 12 patients started at 80 [ milligram ] while 10 patients started at 120 [ milligram ], but had an early dose reduction. Focusing on these 22 patients, you'll see that the best ORR is 36%, all confirmed 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 the same patient population. Slide 34 shows the swimmer plot for these patients. And as before, we see many responses to Enozertinib occurring at the 4-week mark with additional examples of late responders, with a median follow-up of approximately 33 weeks, 35 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 pack cohort who are all receiving the 80-milligram 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 milligrams of Enozertinib 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-milligram dose level in other cohorts. Turning to efficacy. Of these 10 patients, eighthas had a partial response giving an [ ORR ] of 80%. So far, three responses are confirmed and five are yet unconfirmed with 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 have brain metastases of study entry four has measurable lesions and all responded with three partial responses and one complete response, resulting in an intracranial [ ORR ] of 100% for patients with measurable disease. The other patient has nonmeasurable disease, which right now is non-CR, non-PD. While still early, we are very encouraged by these data and the potential of Enozertinib to be a best-in-class molecule in both the EGFR Exon 20 and EGFR PACC mutated patient population. 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, who received Enozertinib at 80 milligrams 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 5 as of the data cutoff. And hot off the press, we learned from the patient's position 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? So 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 Enozertinib 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 which is summarized on Slide 40. You can clearly see that not only is Enozertinib demonstrating a response profile that is as good or better than competitor compounds, but you are already seeing the preliminary evidence that for Enozertinib, 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 Enozertinib are focused on frontline populations in both EGFR Exon 20 and EGFR PACC mutations. We believe today's substantial update establishes Enozertinib'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, out two populations of interest. We have continued to demonstrate Enozertinib'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 milligrams 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, and ahead of the potential start of one or more Phase III registrational trials. We'll wrap up our prepared remarks on Slide 42. We're very proud of the team and pipeline that we have assembled here at ORIC, and we're looking forward to providing additional updates for both Enozertinib 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 worked diligently to tackle our mission on behalf of patients. And most importantly, I'd like to thank our patients and their families who we hope to help overcome resistance in cancer. With that, let's open it up for Q&A.

[Operator Instructions] and our first question comes from the line of Anupam Rama from JPMorgan.

Congrats on the data and go [ Buckeyes ]. So within the second-line EGFR Exon 20 data set, you guys talked about how your response rate was lower than at the 120 mg than 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 III dose? And when do you think you might have FDA sign-off to move forward with the dose?

Anupam, thanks for the question. Go [ Trojan ], and I'll ask Pratik to address your questions.

I think I'd have to take the [ Buckeyes ] side of things. So thanks for the questions. I'll take them in order. So yes, you're right. We did see a lower response rate in the second-line EGFR Exon 20 cohort at the 120 [ milligram ] versus the 80 [ milligram ] there was a higher rate of Grade 3 diarrhea at the 120-milligram dose level, which largely explains the higher rate of dose reductions as well as some of the skin [ talks ] we saw again at the 120 [ milligram ]. But beyond the higher rate of dose interruption, there were also more dose holes. And the issue with those holes 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-milligram dose group, with the dose reductions and interruptions, although they were assigned 120 milligrams, 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-milligram dose where patients had lower rated dose reductions and dose holds, and so most of those patients actually saw the effective dose of 80 [ milligram ], 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 milligrams are dose moving forward to Phase III and our sort of feeling about FDA's what there are will be as well. So I think at this point, we've generated a robust data set with Enozertinib at both the 120 [ milligram ] and the 80-milligram 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 milligrams 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-milligram dose level, we saw a 45% confirmed ORR which compared to other benchmarks where it's 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 signed 120-milligram dose level, but with the high number of early dose reductions and the key here they were early, these patients actually received an average daily dose just about 80 milligrams. So we feel those data also reinforce the clinical activity of Enozertinib at the 80-milligram dose level. But of course, we have an ongoing 80-milligram 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 milligrams, 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 at all four had an intracranial CNS response, 100%, including one [ CR ]. So I think collectively, these data really support our choice of 80 milligrams at the [ RP2D ]. And 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 Enozertinib that 80 milligrams has a better safety profile, while it's retaining clinical activity. And frankly, I think the clinical activity could be better than we saw at 120 because of the dose hold 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.

Our next question comes from the line of Prakhar Agarwal of Cantor Fitzgerald.

I have two, so maybe first one, can you help us put into context a CNS activity of Enozertinib 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.

Yes. Prakhar, thank you for the question. Overall, I'll ask Pratik to address your first question. Overall, we believe that Enozertinib data that we presented today specifically at the 80-milligram 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 nonmeasurable disease, we have five of them, and we had two more CRs in that group and nonmeasurable just for information's sake are tumor lesions that are less than 1 centimeter in size. And then on top of this, this is all 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 Enozertinib most of our competitors really don't claim to be CNS active and a 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 a [ blood brain ] barrier. And so I can report that with three samples of patients on Enozertinib, we're achieving therapeutic levels in the brain in every one of those patients. So yes, I think the CNS penetrant has been demonstrated in humans and the activity is clear.

And then Prakhar, on the overall profile, I mean, the systemic response rates that we've observed with as we profile today are generally on par with or they exceed the best competitor data sets 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. And then 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 data sets from any of our competitors. On the tolerability front, clearly, at 120 mg, we're kind of beyond the tolerability threshold of what we view to be competitive but 80 mg, the treatment discontinuation rates are for 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 Enozertinib. So that's on the tolerability side. And then as Pratik did say on the CNS and is 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. And our -- on the PACC side, our CNS is significantly higher than the top data sets in first-line pack. So 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 data sets 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 Enozertinib compelling systemic activity, the improved tolerability, the strong CNS activity all collectively should lead to better long-term clinical durability in the future.

Our next question comes from the line of Maurice Raycroft of Jefferies.

Congrats on the data update. Following up on the brain [ mets ] line of questioning. Your data set contains a higher proportion of brain mets at baseline versus comp data sets. 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?

Yes. Let me have Pratik take that. Thanks for the question Maurice.

Yes. So you're right. From the beginning, we've been confident about certain brain penetrant 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 have 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. And just as a reminder, I mean, our original Phase I dose escalation data that we presented at [ ESMO ] 2 years ago, 86% of patients had brain [ method ] study entry a very high rate which set 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 [ met ] 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 CNS penetrant drug. We've been enrolling these patients in the face of other competing trials that are enrolling the same patients. And so now that we have many examples of clear CNS activity including 100% intracrenal 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're 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. Yes, I'll have Pratik continue on that one more.

Yes. No, that's a good question. I think we have been kind of explicit about breaking up 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 ], where 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 outlined 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 and the [ mets ] have progressed since that last treatment or there's been a sufficient interval since there were latest treated, so something on the order of 12 weeks. So the [ met ] need to be active. And then they look at measurable disease looking [ RENO ] 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.

And our next question comes from the line of Brad Canino from Guggenheim.

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? And 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?

Sure. So yes, I mean, we don't right now have [ estimal ] medians that we can provide. We did provide the [ swimmer ] plots, and as you can see from the multiple [ swimmer ] plots, most of our responders are still on treatment. So at the second-line EGFR Exon 20 cohort at the 80-milligram dose, six of nine are still on treatment after immediate follow-up of 30 weeks, which is about 7 months in the first-line EGFR Exon 20, 8 of 10 are still on treatment, same follow-up about 7.5 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 goal, given that we had anywhere from 40% to 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 any chemo combo. But with CNS active drug, which we believe certainly is the PFS shouldn't dramatically be different between those two patient populations. So we expect to do an update on next year, and we should have the mature data to confirm that.

Our next question comes from the line of Colleen Kusy from Baird.

Congrats on the data presentation. So you talked about 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 [indiscernible] the 80 mg dose appeared a little bit higher than the 120 mg dose, even though we saw higher talk the 120 mg dose. So just any color on why you might be seeing that higher discontinuation rate?

Yes. Coleen, I want to clarify my comments should what it should have reflected is essentially the safety profile at 80 mg obviously, overall is better tolerated than at 120 mg. Some of the individual stats are actually turned around on 120 [ milligram ], but I'll ask Pratik to kind of walk you through the reasons for why that is.

Sure. 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 milligrams across the entire patient experience that we presented at 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 -- yes, it place me as well when we first half, 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 up 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-milligram dose. So that's sort of the explanation. That as the investigators got more experience with the drug, especially at the 120 milligram, as I said in my remarks, they started to dose escalate very quickly and maintained dose intensity, but now it is at the 80-milligram dose level testing because that's the dose reduction from 120 milligram.

Got you. That's super helpful. And then not sure how many members of the team are in Singapore for [ ESMO ] that we in. But just curious any color from the general feedback that you're hearing from investigators on the data update.

Yes, Colleen. There's four of us here in Singapore, but I'll ask Pratik, Pratik have obviously spoken to a lot of investigators here in Singapore.

Yes. So this conference, I encourage people to attend. 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 were 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 cleared 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 is the 80-milligram dose level that people feel comfortable moving forward with. So that's the feedback we've gotten so far.

Our next question comes from Derek Archila from Wells Fargo.

Congrats on the update, and thank a couple of questions here. So again, I wanted to get your thoughts on a potential Phase III design in the first-line EGFR Exon 20 patient population, particularly given that any chemo is already approved there and just how you're thinking about maybe relative to some of the other Phase III trials? And then just one follow-up, since you're already evaluating [ ENO and combo with AMY ], I guess any color on the potential treatment are you might pursue in that trial?

Derek, thanks for the good questions. Yes, 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 pack 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 III trial design for both of those populations. So let me ask Pratik to hit that.

Yes. So you're right. So any chemo has been approved in the frontline 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 III. Despite the fact that any chemo is approved for first line, we haven't had any trouble getting patients who are second line post chemotherapy only post -- 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 any chemo label was approved in March of 24, just 6 months after the [ Thermo ] Phase III started. And FDA had the [ AMI ] chemo NDA in their hands well before then. And I don't think [ Arvan ] has said that they ever had to consider changing the 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 III 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. And then I think you asked about, yes, what regimen we might take into Phase III, given that we are also besides all of the single agent data generating any combo data Enozertinib plus Amivantamab is ongoing in a separate trial. We also have ongoing now a little dose expiration of Enozertinib plus platinum-based chemotherapy. So there's actually three options that we're looking at for a potential Phase III for the Enozertinib 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.

Our next question comes from the line of Yigal Nochomovitz of Citigroup.

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 U.S. in the neighborhood of around $3 billion, $3.5 billion for [ Enzo ], 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 frontline Exon 20 and frontline 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.

Yes, sure. [ Keith Louis ], 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.

This is Keith. Thanks for the question. Regarding the EGFR Exon 20 population, that accounts for about 2% of [ nonlocal ] lung cancer and the EGFR pack atypicals are slightly higher, about 2.5% of [ NFC ]. And that's just based on the literature out there. And then regarding our duration assumptions in Exon 20, we see [ interim ] duration of close to 1 year. And then in PACC, we assumed duration of about 16 months, and both of these numbers are premised on the current debt 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 and [indiscernible] lung cancer. And I think the second question you asked about was around why we think [ Enozertinib ] could be potentially successful commercially in these base populations, frontline Exon 20 and [ frontline ] PACC. And as we discussed, as Jacob and Pratik mentioned in their presentation, we think Enozertinib has the potential to be a best-in-class drug in this space, specifically addressing [indiscernible] needs of frontline patients with EGFR Exon 20 and PACC mutations. Given the 30% rate of brain mets at presentation for [indiscernible] cancer patients and the fact that about half of these patients will develop [indiscernible] the course of their disease, we think a confirmed brain penetrant properties are going to be a key differentiator and really a game changer for treating oncologists and for [indiscernible] 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 as a selected 80-milligram dose that we are going to take into potential Phase III with no significant off-target toxicity and low rate of discontinuation, I think this really sets us to be an ideal product profile and particularly on the manageable safety profile, it's especially important because patients made chief responses in later cycles, as you saw as late as the fourth or fifth cycle and may continue to respond on therapy for years.

And then Yigal, you mentioned you had a question on the data as well.

Yes. Thanks. Yes, it was just sort of a quick one. I was just curious, in the frontline PACC patients where you have the 10% response rate in those with the measurable CNS disease. I was just curious of those, how many also had the systemic responses.

So yes, I mean, by RECIST, they were also responders. All of them.

Our next question comes from the line of Matthew Biegler from [ OpCo ].

This is Tracy on for Matt. We just had a couple of questions. Are the responses seen in EGFR Exon 20 near loop or [indiscernible] mutations? And are the responses seen in the tumor common PACC mutations or complex type mutuations?

Yes. Thanks, Tracy. I'll ask Lori, our CFO, to take those.

Thanks for that question. So we use the [ Garden ctDNA ] assay to really exhaustively characterize the EGFR mutations. And as expected, we enrolled patients with a broad spectrum of EGFR mutant. 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. And then in the EGFR PACC cohorts, we also had robust responses in [ singletons ], including the two most common mutations, the [ G719X ] and [ X768I ] as well as responses in a variety of complex mutations. So our response rates, for instance, in the first-line treatment right naive PAT cohort are comparable for the [ Singleton ] mutations at 75% for best [ ORR ] and the complex mutations at 83% best [ ORR ]. So we feel that the preclinical data has translated very nicely to the clinical responses.

Our next question comes from the line of Corinne Johnson of GS. .

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 inflection and stratification in the registrational programs?

Yes, sir, I can answer that. I mean, I think -- as I said, there's a number of factors that we -- that still have to play out in terms of how we design our Phase III 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-milligram dose as a single agent. Then within the EGFR Exon 20, there is 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-milligram dose is able to achieve that in so far in 100% of patients in the first-line setting with measurable disease. So I think there's a number of factors that you still need to sort of have to 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 are considering.

And Corinne, it's a good question. I'll just add on to a couple of things that -- add on a couple of things to what Pratik mentioned, which is one of the reasons we obviously went out of our way in the presentation to highlight and specify exactly which patients had measurable disease in the brain. And then which of those were active in 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-penetrant compound that several of us were involved in and [ Ignyta ] where if you want to get 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 in an untreated disease. And so that's why we made such a point to highlight those 2 aspects of the data.

And our last question comes from [ Johnny Fan ] from EVR.

It's [ John Afric ] from Evercore. I wanted to ask you guys had any more details you just shared about the kinetics of the response and how they differ for patients on the 80 mg dose and versus those at the 120 mg dose that got dosed down?

Sure, John. Thanks for the question. I think it was coming out a little bit, but I think you were asking about response kinetics in the patients. I'll ask Pratik take that.

Yes, it's the same. So in the 80-milligram dose level, we see the responses majority happen at the 4-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-milligram dose response are as quick as what we saw at the 120 [ milligram ].

Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.