Oric Pharmaceuticals, Inc. Common Stock Study update

Good afternoon, and welcome to the Oric Pharmaceuticals enozertinib Program Update conference call. Earlier today, we issued a press release highlighting updated data from our ongoing phase I-B study of enozertinib in first-line non-small cell lung cancer patients with EGFR atypical mutations. You can find the press release on the investor page at oricpharma.com. We have pre-recorded our prepared remarks, after which we will host a live Q&A session. Before we begin, starting on slide 2, during this conference call, we will be making forward-looking statements, including those based on our current expectations and projections about future events and trends that may affect our business, utilizing data available to us as of the cutoff date set forth on the applicable slide. Oric's actual results may differ materially from those expressed in or indicated by such forward-looking statements.

For a description of risk factors associated with investing in Oric, please refer to our recent filings with the SEC. Oric specifically disclaims any obligation to update any forward-looking statements except as required by law. This presentation contains interim results based on the data from enozertinib clinical trial as of the cutoff date set forth in the applicable slide. During this presentation, we will not be speaking to any additional data subsequent to such date. Now turning to slide 3. During today's call, we'll discuss preclinical differentiation, clinical data highlights, and next steps, and finally, the commercial opportunity, followed by Q&A. Joining me on the call today, we have several members of the Oric management team and our guest KOL, Dr. Joshua Sabari. Now, let me turn the call over to Jacob.

Thank you, Dominic. Turning to slide 5. We're excited today to review the updated global phase I-B data from our first-line EGFR atypical cohort, which are being presented at ESMO. This slide summarizes the key takeaways, which we believe further reinforce enozertinib's potential best-in-class profile in this population and support our plan to move rapidly into phase III. First, the opportunity. First-line EGFR atypical non-small cell lung cancer has a market opportunity of more than $2.5 billion in the U.S. alone, and it lacks a best-in-class therapy that combines meaningful systemic efficacy, compelling CNS activity, and favorable tolerability. Second, today's enozertinib data set a new benchmark for best in class within EGFR atypicals. To level set, we enrolled a population with more than twice the rate of baseline CNS disease as seen in competitor datasets, and most of these patients had no prior treatment for their CNS metastases.

Even with that context, enozertinib delivered an 84% confirmed systemic response rate, a 70% confirmed CNS response rate with multiple complete responses, and an 88% six-month landmark progression-free survival. Third, safety. Enozertinib continues to show no significant off-target toxicity, and there were no treatment-related discontinuations. Finally, supported by these stellar data, we plan to initiate REDWOOD-1, a global phase III trial in first-line EGFR atypical non-small cell lung cancer in the first half of 2027. Turning to slide 6. We are developing enozertinib for two sizable patient populations within non-small cell lung cancer that have thus far been woefully underserved by the currently approved and late-stage development therapeutics, all of which suffer from a lack of compelling CNS activity and come with meaningful toxicity challenges.

Collectively, there are over 11,000 patients annually in the U.S. with these mutations, representing a combined commercial opportunity of more than $3.5 billion annually in the U.S. alone, with more than $2.5 billion in atypical and more than $1 billion in exon 20. We believe each of these first-line opportunities has blockbuster potential in the U.S. on its own, and we see a comparable ex-U.S. opportunity. An oral, well-tolerated CNS-active agent should garner substantial share in these settings. Keith will walk through the market assumptions later in the call. I have already mentioned the importance of CNS activity, and slide 7 helps explain the rationale. Approximately 35% of patients with EGFR mutated non-small cell lung cancer present at diagnosis with CNS disease. That figure does not include the patients who have micrometastases that are not yet detectable on conventional imaging. Over time, about half of patients will develop brain metastases.

The bottom half of the slide shows why this matters. With drugs that are not CNS active, outcomes are dramatically different for patients with versus without brain metastases, and we show two examples here from EGFR exon 20. For both sunvozertinib and the combination of amivantamab plus chemotherapy, you can see the dramatically different hazard ratios achieved in patients with versus without baseline brain metastases. This is perhaps most noticeable in the sunvozertinib example, with only a 4% risk reduction or 0.96 hazard ratio in the patients with baseline brain metastases. An effective brain penetrant therapy, many of which exist for other targets in non-small cell lung cancer, can drive long-term outcomes by treating existing CNS metastases and preventing the development of new CNS lesions. Turning to slide 8. This is not a new concept in targeted therapy across multiple lung drivers, including classical EGFR, ALK, RET, and ROS1.

There are best-in-class TKIs that combine meaningful systemic efficacy, compelling CNS activity, and good tolerability. Those drugs were often third, fourth, or even fifth to market within their respective categories. But what most prominently differentiated them from their predecessors was profound CNS activity that led to superior PFS. Ultimately, those brain-penetrant drugs became the market leader within a few years of launch. For EGFR atypical and EGFR exon 20 mutations, no agent, either approved or in late-stage development, combines all of these attributes. Slide 9 provides a snapshot of the enozertinib data that underlie our excitement for this opportunity in first-line EGFR atypicals. The slide also lays out the comparator data within atypicals for afatinib, osimertinib, which is in the NCCN guidelines, and the two late-stage investigational therapies, amivantamab with lazertinib and firmonertinib. It is worth spending a moment on the enrollment criteria.

While afatinib did not allow patients with untreated CNS metastases and did not report any CNS data, the other comparators all enrolled those patients at or near the rate seen in the general population, around 30%. In the case of enozertinib, an astounding 65% of patients had CNS metastases at baseline. We weren't trying to enrich for these patients. Physicians in the trial believe enozertinib is profoundly CNS active, and so they disproportionately enrolled their most challenging patients onto the trial. What's even more impressive than this exceptionally high rate of baseline CNS metastases is that from day 1, we have allowed patients with untreated brain metastases onto the trial. Again, as you can see from the chart, it is relatively uncommon for trials to allow the enrollment of patients with brain metastases if they haven't already been treated with radiation or surgery.

In the enozertinib cohort you will hear about today, nearly half of all the patients had untreated brain metastases upon study entry. It is with that backdrop that enozertinib still managed to achieve an impressive confirmed systemic response rate of 84%, confirmed intracranial response rate of 70%, and 6-month landmark PFS of 88%, with each of these efficacy measures being the highest ever seen in EGFR atypicals based on published data. It did this while demonstrating a well-tolerated safety profile with no significant off-target toxicity and no treatment-related discontinuations. What is clear from these data is that enozertinib is emerging as the potential best-in-class therapeutic option for frontline EGFR atypical mutations. With that, let me hand it over to Lori to remind you of the preclinical profile before Pratik covers the detailed phase I-B results.

Lori? Thank you, Jacob. Slide 11 highlights our key aims in identifying a clinical candidate that would support a best-in-class profile for EGFR atypical mutations.

Enozertinib was designed to have multiple areas of differentiation. First, enozertinib has strong cell potency against a wide variety of EGFR atypical mutations and demonstrates tumor regressions in vivo. Second, enozertinib is notable for its selectivity towards EGFR while sparing all other kinases. Third, a crucial feature of enozertinib 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 compelling intracranial responses in patients.

Taking each area of preclinical differentiation in turn, starting first with potency on slide 12. A key differentiating feature of enozertinib is strong cell potency across a variety of EGFR mutations. In this figure, cell potency in EGFR PACC and classical-like mutations is compared to EGFR wild-type potency. For any given compound, you want to see as many mutant symbols as possible falling below the gray horizontal bars that depict EGFR wild-type potency for that compound. For enozertinib, nearly all the mutant potencies are below its wild-type potency, indicating a promising predicted therapeutic index. But this clearly isn't the case for the competitor compounds. Enozertinib stands out with excellent potency in mutants and a favorable potency ratio versus wild type. Moving to slide 13, another key differentiating feature of enozertinib is selectivity. 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 kinase results, with enozertinib having no off targets, while competitor EGFR compounds have multiple off targets. Off-target binding 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 enozertinib, especially given that best-in-class molecules for lung cancer must be able to tackle and prevent brain metastases. On the left, in head-to-head studies in rodents, enozertinib has a high free brain to plasma ratio similar to osimertinib, which is a brain penetrant drug that has demonstrated strong CNS activity in the clinic. Shown on the right are results of an in vivo study measuring anti-tumor activity in the brain.