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

Ladies and gentlemen, thank you for standing by, and welcome to the ORIC conference call to review the initial data being presented at ASCO from the Phase Ib study of ORIC-101 in combination with nab-paclitaxel. [Operator Instructions] Please be advised that today's conference is being recorded. [Operator Instructions] I would now like to hand the conference over to today's first speaker, ORIC's CFO, Dominic Piscitelli. Thank you. Please go ahead, sir.

Good afternoon, and welcome to the ORIC Pharmaceuticals Business Update ASCO 2021 Conference Call. Following the market close today, we issued a press release highlighting the initial clinical data from our ongoing Phase Ib trial of ORIC-101 in combination with nab-paclitaxel in advanced solid tumors. You may find the press release posted on the Investor page of oricpharma.com. We are dialed in from different locations today, so please bear with us if we have any technical difficulties. Before we begin, starting on Slide 2, during this conference call, we will be making forward-looking statements. 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 Securities and Exchange Commission. ORIC specifically disclaims any obligation to update any forward-looking statements, except as required by law. This presentation contains interim results based on initial data from the ORIC-101 clinical trial in combination with nab-paclitaxel as of the database cutoff date of April 21, 2021. During this presentation, we will not be speaking to any additional data subsequent to such date. Now turning to Slide 3. I'll briefly walk you through our agenda and introduce our speakers. During today's call, we'll discuss background on glucocorticoid receptors and ORIC-101, followed by the initial data from the ORIC-101 plus nab-paclitaxel Phase Ib trial, followed by a deeper dive on ORIC-101 plus nab-paclitaxel in patients with advanced PDAC; and finally, a brief summary and pipeline update followed by Q&A. Joining me on the call today, we have Jacob Chacko, CEO; Lori Friedman, CSO; Pratik Multani, CMO; and our guest KOL, Dr. Pamela Munster. Now let me turn the call over to Jacob.

Thank you, Dominic. Turning to Slide 4. It's our pleasure today to share our first substantive clinical data set on our lead program, ORIC-101, specifically covering the first of 2 combination studies in which we are evaluating the ability of ORIC-101 to overcome resistance in cancer. While it's still early days for this study, during this call, we'll discuss why we are so enthusiastic about these initial data from our Phase Ib trial of ORIC-101 in combination with Abraxane in advanced solid tumors. As you'll hear today, we've accomplished a lot in a short period of time in terms of adding evidence to GR as a novel mechanism of action and the benefits of a GR antagonist that has been purpose-built for oncology. First, we've identified the recommended Phase II dose of ORIC-101 in combination with Abraxane, and this regimen has been well tolerated with primarily grade 1 or 2 treatment-related adverse events, no requirement for prophylactic G-CSF and no patients at the RP2D discontinuing to date due to treatment-related toxicity. We also see no evidence of drug-drug interactions between ORIC-101 and nab-paclitaxel. Second, our PK data show that we are achieving exposures of ORIC-101 at the RP2D that exceed the threshold for GR inhibition, which is further corroborated by our translational data showing consistent suppression of key GR-related biomarkers. Third, our extensive translational efforts have yielded tumor biopsy data that confirm high rates of GR expression across the tumor types of interest. And finally, even in the early stages of this study, we have already observed multiple compelling examples of antitumor activity, as evidenced by either significant tumor regressions or prolonged, stable disease in a heavily pretreated patient population, including in patients who previously received a taxane-based therapy. Later in today's presentation, we'll walk you through the details of several of these noteworthy patient cases. Now a natural question, the evaluation of a novel mechanism of action like GR that is part of a combination regimen, is how to tease apart the contributions of ORIC-101 in leading to noteworthy patient outcomes. Of course, a helpful fact is that taxane retreatment effect in most of the tumors we've studied thus far is generally quite modest. But one tumor in particular in which we've seen early evidence of beneficial clinical activity, pancreatic cancer, provides perhaps the best way to begin sorting signal from noise even in the context of single-arm data. Turning to Slide 5. Pancreatic ductal adenocarcinoma, or PDAC, makes up over 95% of pancreatic cancers and has certain specific characteristics that are well documented. First, there is no evidence of a taxane-retreatment effect in PDAC. In other words, once a patient with PDAC has progressed on a prior taxane-based therapy, there is zero expectation of seeing future antitumor activity with another taxane. Second, clinical outcomes in PDAC are modest in a second-line setting and only get worse in subsequent lines of therapy. Within second-line PDAC, single-agent chemotherapy ORRs are typically 0 to less than 5%, and combination regimen ORRs are typically 0 to less than 15%. So in the second line, it's PFS and OS, not ORR, that have become the benchmarks for clinical viability. On the left half of the slide, you can see the PFS of NCCN-recommended therapies in second-line PDAC is 3.1 months. In third-line PDAC, there are no approved regimens, and the PFS outcomes of active therapies drops to 2.4 months in this setting. The right half of the slide lays out our early experience with ORIC-101 plus nab-paclitaxel in all efficacy-evaluable patients with PDAC treated at the RP2D. And keep in mind, these patients from our study are third line, fourth line, fourth line and sixth line, as you see denoted on the slide. All of these patients received prior nab-paclitaxel prior to enrolling in our study. And as you can see, most of these late-line patients have demonstrated longer PFS than would be expected even in a second-line population treated with NCCN-recommended therapies. Of course, we recognize the limitations of drawing conclusions from a single-arm study testing a combination regimen. That said, we are quite pleased to have already observed several examples of antitumor activity that would otherwise be unexpected. Later in the presentation, we'll walk you through additional details on these patients with noteworthy outcomes, including with additional commentary from senior author and trial investigator, Dr. Pamela Munster, who treated several of these patients. Hopefully, you can see why we're cautiously optimistic even in these early stages of the trial. With that, let's turn to Slide 7, where we'll walk you through a brief refresher on GR and related preclinical rationale before diving into the clinical data. GR has relevance to 2 potential mechanisms of action that relate to therapeutic resistance in cancer. With regard to anti-androgen resistance in prostate cancer, our Phase Ib study of ORIC-101, in combination with Xtandi, is ongoing, and we expect to report initial data from this study at a medical conference in the second half of the year. With regard to chemoresistance in solid tumors, we and others have generated substantial preclinical evidence as well as early clinical evidence of the benefits of combining a GR antagonist with certain chemotherapeutic agents. Each of these novel MOAs has the potential to help address cancers in tens of thousands of patients in areas of high unmet medical need. Slide 8 highlights numerous retrospective studies that have observed a significant difference in the survival outcomes of cancer patients with low versus high GR expression levels. The low GR groups achieved superior survivor outcomes on the order of years. These results may be an indirect surrogate predictor of the benefits of a GR antagonist in patients with cancer. It's also important to note that the benefit identified in each of these studies has been related to survival outcomes as opposed to response rates. On Slide 9, we have the most direct evidence to date of the GR MOA in combination with chemotherapy in the form of the first randomized clinical data presented on GR in oncology. Within the past few weeks, the competitor shared top line results of a randomized Phase II study in patients with ovarian cancer that demonstrated a PFS benefit of the GR antagonist in combination with Abraxane versus Abraxane alone in platinum resistant ovarian cancer. These data are encouraging in demonstrating the potential for a GR antagonist to help patients achieve better outcomes but also potentially leave the door open for an even more pronounced benefit from a GR antagonist that's been specifically designed for oncology. And that brings me to ORIC-101 on Slide 10. ORIC was founded with a commitment to internal drug discovery and having all major preclinical functions in-house. Our chemists spent years designing from scratch and optimizing ORIC-101 for extremely potent, single-digit nanomolar GR inhibition without major CYP liabilities that might lead to DDI limitations. We believe that this profile ought to allow us to dose 101 to higher levels of GR exposure without problematic DDI when combining with anticancer therapeutics that carry their own safety liabilities. I'll now ask Lori Friedman, our CSO, to briefly walk through highlights of the preclinical evidence we've generated with ORIC-101 before turning the call over to Pratik Multani, our CMO, to discuss the clinical data. Lori?

Thank you, Jacob. As previously highlighted, there are 2 distinct mechanisms of therapeutic resistance driven by GR. The mechanism illustrated on the left half of Slide 11 shows the role of GR in prostate cancer, discovered by our Co-Founder, Charles Sawyers. I'll be brief here since it's not the focus of today's call. In this bypass resistance mechanism, GR becomes upregulated and activated when AR is inhibited with enzalutamide. On the right half of the slide are results from a preclinical experiment of prostate cancer cell growth. You can see the cells grow robustly in the first column, and enzalutamide treatment blocks cell growth in the second column. The activation of GR acts as an estate mechanism that drives cell growth, and that is reversed with the addition of ORIC-101 on the far right. Switching away from prostate cancer on Slide 12. We've summarized the body of literature on the role of GR in impeding the response to chemotherapeutics. The left panel illustrates pro survival mechanisms that GR transcriptionally regulates, while the right panel shows in-house results indicating that when GR is activated in the presence of cortisol, the addition of ORIC-101 strengthens the response to paclitaxel. We then assessed multiple models in chemotherapies, as shown on the next slide. Preclinically, we've seen compelling activity of ORIC-101 in combination with multiple classes of chemotherapies, including taxanes, platinums and antimetabolites and across multiple tumor types. On Slide 13, in vivo efficacy was assessed in xenografts from 3 different cancers, pancreatic, ovarian and triple-negative breast cancer. In each study, the vehicle control is shown in black; the chemotherapy in teal; and chemo, with addition of ORIC-101, in orange. ORIC-101 resulted in an increase in the duration of chemotherapy response in all 3 models, 2 of which were combinations with paclitaxel and 1 in combination with gemcitabine and carboplatin. These in vivo combination studies were the basis of the clinical trial that Pratik will tell you about next.

Thank you, Lori. On Slide 15, you can see that we are conducting 2 clinical trials of ORIC-101, each examining a distinct mechanism of action of GR inhibition to reverse resistance in cancer. One study is a combination of ORIC-101 with enzalutamide in patients with advanced prostate cancer. We identified the RP2D for this combination earlier this year and are currently enrolling patients to the expansion cohort. The second study, which is the subject of our upcoming ASCO presentations and what I will review today, evaluates a combination of ORIC-101 with nab-paclitaxel in patients with advanced solid tumors. Slide 16 depicts the design of this study. It is a multicenter, open-label trial that is being conducted in 2 parts. The first dose escalation part has been completed, which was conducted in patients with advanced or metastatic solid tumors who have received prior standard therapies. They were enrolled independent of baseline GR status at successive dose levels that explore dose and schedule of ORIC-101 along with nab-paclitaxel. The primary endpoint of Part 1 was to identify the recommended Phase II dose and schedule of the combination with additional endpoints of pharmacokinetics, the examination of GR immunohistochemistry as well as disease and GR-related molecular markers in tissue and blood. The second part of the study is the dose expansion portion. It is currently ongoing and is enrolling patients with specific tumor types of interest, namely pancreatic ductal adenocarcinoma, ovarian cancer and triple-negative breast cancer, along with a fourth tissue-agnostic cohort. Again, patients are not being selected based upon baseline GR status, but they are all required to have previously been treated with, and progressed on, a taxane-based therapy. The primary endpoint of this portion is efficacy, as measured by objective response rate as well as duration of response in progression-free survival. Slide 17 shows our progress as of the enrollment cutoff of March 31, 2021. We have examined 5 dose levels, exploring different dosing schedules of ORIC-101 with nab-paclitaxel. After dose level 1, we did not identify any additional dose-limiting toxicities. Through this dose escalation process, we determined the recommended Phase II dose to be ORIC-101 160 milligrams once daily using a continuous dosing regimen in combination with nab-paclitaxel at 75 milligrams per meter squared once weekly for 3 weeks on a 4-week cycle. This regimen requires no prophylactic use of growth factor support. In addition, the pharmacokinetics of ORIC-101 were dose proportional, and the combination showed no evidence of drug-drug interaction with nab-paclitaxel. Most importantly, biomarker data using peripheral blood mononuclear cells indicated that we were achieving on-target GR pathway inhibition and that continuous dosing showed a sustained pharmacodynamic effect at the recommended Phase II dose. Turning to Slide 18. Let me walk through the safety and efficacy analysis populations used for this ASCO presentation. Our safety analysis population consists of all 31 patients who were enrolled as of March 31 this year. The efficacy evaluable population includes only those patients who also had an opportunity for at least 1 on-treatment tumor assessment by March 31, which means they had to be enrolled by January 31, since the first set of protocol-defined restaging CT scans takes place after 8 weeks on study. 23 patients make this cut and will be displayed in the swimmers plot that I will be showing shortly. The waterfall plot that I will also be showing excludes 4 of these 23 patients because they either had no scans due to rapid clinical progression or their scans were incomplete. Slide 19 depicts the patient baseline characteristics. Of the 31 patients who have been enrolled across Parts 1 and 2, 19 were treated at the recommended Phase II dose, and the remaining 12 patients received non-RP2D doses and/or regimens. This study enrolled patients with a diverse set of tumor types. However, about 1/3 consisted of pancreatic cancer with 13% ovarian and 6% triple-negative breast cancer. Overall, this population of patients was heavily pretreated, and at the recommended Phase II dose, the median number of prior therapies was 4 and ranged up to 12. And importantly, all patients have previously received a taxane-based therapy. Slide 20 shows the safety profile of the combination. In particular, at the RP2D, the regimen was well tolerated with the vast majority of treatment-related adverse events being Grade 1 or 2. Only 3 Grade 3 treatment-related adverse events were observed, consisting of 2 events of neutropenia and 1 Grade 3 rash, all of which resolved upon dose interruption. There have been no treatment-related discontinuations at the RP2D, and as I stated previously, there was no requirement for prophylactic G-CSF in order to enable this combination regimen. This study included a comprehensive translational effort, and to discuss this work, I'll ask Lori to cover the next 3 slides. Lori?

Thanks, Pratik. On Slide 21, we evaluated GR protein status in pretreatment biopsies of 19 patients in the Phase Ib dose escalation using our proprietary IHC assay. GR protein was present in 53% of tumors with IHC H-scores exceeding 200. GR protein levels were consistently high in pancreatic, lung and ovarian cancers, while GR was low in colorectal cancer and hormone receptor-positive breast cancer. On the right half of the slide are the GR H-scores in the stroma, where GR levels are consistently high. The exceptions with high stromal GR but no tumor GR staining were in colorectal cancer and HR + breast cancer. Slide 22 shows that ORIC-101 PK demonstrated excellent target coverage and no drug-drug interaction with nab-paclitaxel in the Phase Ib. In the graph on the left, ORIC-101 doses above 80 mg provided target coverage even at trough level after 1 week of dosing. The continuous dosing regimen of 160 mg has a lower peak to trough while maintaining target coverage. On the right half of the slide is a plot demonstrating that the nab-paclitaxel population PK modeling revealed no changes in PK of paclitaxel, regardless of the dose of ORIC-101 used, demonstrating no evidence of drug-drug interaction. The next slide illustrates PD modulation, which was assessed by measuring the expression of 3 GR biomarkers, FKBP5, GILZ, and PER1, in peripheral blood mononuclear cells. Shown here are data from the RP2D with PBMCs collected on days 1 and 8 of the first cycle, with samples taken before ORIC-101 administration, and at 2.5 or 6 hours after ORIC-101 administration. Systemic cortisol levels were assessed in parallel with rise or decrease in cortisol shown along the horizontal axis at the bottom of the plot. Individual data points show the average change in expression of all 3 biomarkers after ORIC-101 administration with a rapid decrease in PD biomarker expression observed for all patients at the RP2D, as captured by the data points below the horizontal dash line. Further taking into account cortisol fluctuations, PD modulation occurred both in the context of rising cortisol induced by GR feedback, as depicted in the samples on the right half of the plot, as well as in samples in the context of natural decrease in cortisol, as shown on the left side. Together with the PK data, these results indicate that GR target coverage at the RP2D is sufficient to maintain GR suppression even in the face of rising cortisol levels. Pratik?

Thank you, Lori. Slide 24 presents the waterfall plot for the 19 patients enrolled by January 31, who had at least 1 post-baseline tumor assessment. The bars represent the maximal change from baseline of measurable target tumor lesions in each patient. The bars are coded by dose level and prior taxane treatment history, with red representing patients treated at the RP2D, and the solid bars identifying patients with a prior taxane treatment history. Along the bottom, tumor type as well as the baseline H-score of the tumor and the H-score of the surrounding stroma for each patient are displayed. We see here evidence of antitumor activity across multiple solid tumors, in particular, in heavily pretreated patients with pancreatic ductal adenocarcinoma, endometrial cancer and breast cancer, patients who had previously progressed on or after a taxane-based therapy. Overall, we saw 5 partial responses, representing at least a 30% decrease in the sum of target lesions, of which one was confirmed. Slide 25 presents the swimmers plot of the 23 patients enrolled by January 31. The bars represent time on treatment, with symbols depicting points of response and progression as well as ongoing status. The bars are coded just like in the prior slide, and the specific tumor type is displayed along the Y axis. As with the waterfall plot, you can see further evidence of antitumor activity based upon prolonged disease stabilization of greater than 3 months in this advanced, heavily pretreated solid tumor patient population. We see this activity across multiple solid tumors, including pancreatic, breast, gastric, esophageal and testicular cancers. In particular, there are extended progression-free intervals in patients with pancreatic ductal adenocarcinoma who are treated at the RP2D, all of whom had previously progressed on or after nab-paclitaxel and who are now receiving nab-paclitaxel again on our study in combination with ORIC-101. Slide 26 calls out 7 patients with noteworthy outcomes from our experience to date. Let me first draw your attention to the 3 far-right columns, detailing 2 patients with upper GI malignancies, gastric cancer and esophageal cancer as well as the patient with large cell neuroendocrine tumor of the lung. Although these patients had no prior taxane treatment history, they all had been previously treated with one or more standard therapies and progressed. And despite having solid tumors that are generally not responsive to single-agent chemotherapy in the relapse setting, they all showed evidence of clinical activity. The patient with large cell neuroendocrine tumor of the lung had a 55% decrease in target lesions, while the patient with esophageal cancer had a confirmed partial response with 56% decrease in target lesions and a progression-free interval of 3.8 months. And then similarly, the patient with gastric cancer was progression-free for 4.4 months. Now turning to the 4 columns on the left. These patients represent a heavily pretreated group, who all had progressed on a prior taxane-based therapy and whose significant tumor regressions and/or progression-free survival on this study would not otherwise be expected simply due to nab-paclitaxel retreatment. On the subsequent slides, I'll dive into each of these patients in greater detail. On Slide 27, we present the details of a 54-year-old woman with endometrial cancer metastatic to the lung, liver and peritoneum. We had discussed her case previously as a demonstration of tumor regression in a patient who had previously been treated with a taxane-based therapy. This patient was enrolled at our lowest dose level of ORIC-101 and achieved a 38% total decrease in target lesions with a progression-free survival of 2.7 months, which she developed new pleural lesions. On the right, you can see evidence of this tumor regression in our chest CT images at baseline and then after 8 weeks on study. On Slide 28, we present the details of a 54-year-old woman with ER-positive, PR-positive metastatic breast cancer. She previously received nab-paclitaxel and has an overall treatment history of 8 prior lines of therapy. She was treated on study at the recommended Phase II dose and had a 100% decrease in her target lesions, but because of residual, nonmeasurable bony disease, her response was not called a CR. On the right, her CT scan images show complete resolution of a large 3.6-centimeter by 2-centimeter target lesion in her right lung. This patient had a progression-free interval on study of 4.4 months when she ultimately progressed with new lesions in the brain, although she did not progress systemically. Of interest, this patient is one of the few for whom there was significant discordance between the baseline tumor and stromal H-scores. Her tumor stroma was near maximally GR positive at 290 out of 300, indicating a high level of GR expression in the surrounding immune infiltrate. This finding raises the possibility that an additional mechanism of action of GR inhibition might be at work, namely activating the immune system against the tumor by removing glucocorticoid-mediated inhibition. Separately, and also of interest, was that her tumor was progesterone receptor-positive, and as shown on an earlier slide, ORIC-101 is a potent progesterone receptor inhibitor. And in fact, therapies for breast cancer targeting the progesterone receptor have been the subject of investigation. For example, onapristone, a potent PR inhibitor, showed meaningful efficacy in clinical trials, although its development was subsequently halted due to hepatic toxicity. Finally, we cannot rule out that she may have experienced a retreatment effect to taxane, which can be seen in a minority of patients generally less than 15%. We cannot draw firm conclusions from this single patient, but in order to further explore the potential PR antagonism of ORIC-101, we plan to enroll additional patients with progesterone receptor-positive metastatic breast cancer into our tissue-agnostic cohort. Finally, on Slide 29, we present the details of a 66-year-old man with pancreatic ductal adenocarcinoma metastatic to the liver. He received prior FOLFIRINOX chemotherapy and then received gemcitabine with nab-paclitaxel. When he later progressed, he was enrolled on our study at the recommended Phase II dose and experienced a 47% decrease in his target lesions. On the right, you can see his baseline CT scan at the top showing multiple liver lesions and a follow-up CT scan below demonstrating significant regression of his disease. Restaging studies at the end of cycle 5 showed growth of these target lesions as well as a new liver lesion, which translates into a progression-free interval of 4.5 months. We continue to enroll to all the expansion cohorts of our trial, but already, we have accumulated a notable experience in patients with relapsed pancreatic cancer. And so I would like to spend a few minutes describing the landscape of available therapies for this disease and define what constitutes an active regimen in this refractory setting. Turning to Slide 31. Approximately 60,000 patients are diagnosed with pancreatic cancer with 48,000 deaths each year in the United States. Although there are multiple histological subtypes, by far, the most common is pancreatic ductal adenocarcinoma, which represents over 95% of cases and is well recognized as a highly life-threatening malignancy. If caught early, when surgery is feasible, which represents only about 10% to 20% of patients, treatment may involve neoadjuvant or adjuvant chemotherapy. However, once the disease is metastatic, first-line therapies typically only confer progression-free survival of approximately 6 months, while in the second-line metastatic setting, disease progression typically occurs after just 3 months. Thus, current standards of care uniformly confer short progression-free survivals, which are accompanied by very low response rates. Of note and relevant here is that there are no reported response rates to taxane therapy in the post-taxane setting. And finally, of paramount concern is that many of these patients are of poor performance status, and therefore, the significant toxicities associated with current treatments significantly affect choice of therapy. On Slide 32, you can see a treatment overview for metastatic pancreatic cancer according to NCCN guidelines. For patients with good performance status, the standard frontline regimens are either FOLFIRINOX or the combination of nab-paclitaxel and gemcitabine, which is one of the approved indications for nab-paclitaxel. However, even in the first-line setting for patients with poor performance status, single-agent chemotherapy is often the only choice. And for the low percentage of patients who have mutations of BRCA 1, 2 or PALB2, a gemcitabine/cisplatin combination is also a preferred regimen. In the second-line setting, again, in patients with good performance status, they typically receive a regimen that they did not receive in the first-line setting, and so nab-paclitaxel and gemcitabine is given here in patients who previously received FOLFIRINOX, while the converse is true for those who received nab-paclitaxel and gemcitabine in the front-line setting. There's also another option, which is the approved indication of liposomal irinotecan in combination with 5-FU leucovorin, And finally, for patients with poor performance status, single-agent chemotherapy remains the only recommended option. But for many of these patients, investigational therapy is the preferred treatment approach. And certainly, in the third-line setting where there are no approved therapies, investigational therapies represent the only recommended option. Slide 33 presents safety and efficacy data for the main approved regimens used either in first-line or second-line pancreatic cancer. As you can see, the efficacy of these mainstay regimens is limited and a progression-free survival of 5.5 to 6.5 months in the front-line setting and only 3 months in the second-line setting. For the third line or later setting for which nothing is approved, the efficacy bar would be expected to be even lower, less than 3 months. Moreover, these outcomes are at the expense of significant safety risk, including high rates of Grade 3 or higher neutropenia and GI toxicity. Slide 34 represents additional published single-agent and combination chemotherapy regimen data with both NCCN-recommended therapies as well as other available therapies for patients with pancreatic cancer in the second-line treatment setting. It is important to note that these data represent regimens that are being administered to patients who are naive to one or more components of the regimen of interest. They are not retreatment experiences. Instead, the effort has been to identify novel therapies or novel combinations of available agents to use in patients in the relapse setting. In this relapse setting, the ORR is typically 0 to less than 15% for combination regimens, but for single-agent chemotherapy, it's generally minimal, from 0 to less than 5%. So ORR is not a useful index of clinical activity. PFS and OS are more relevant, and you can see the PFS of therapies that are considered active in the second-line setting is consistently around 3 months regardless of regimen. For active therapies in the third-line setting where nothing is approved, the PFS bar would be expected to be even less than 3 months. And retreatment, including retreatment with a taxane after prior treatment with a taxane-based therapy, would be expected to have no therapeutic benefit. Now coming back to our data. On Slide 35 gives you the patient-by-patient detail of all 4 patients with relapsed pancreatic cancer who are efficacy valuable and who were treated at the RP2D. The GR H-score of the tumor was 150 or higher in all 4 patients, and the stromal score was elevated as well. These patients all received nab-paclitaxel plus ORIC-101 as their third or later systemic treatment for pancreatic cancer. But more importantly, unlike in the literature we just reviewed, these patients have already seen nab-paclitaxel and are now getting it again with ORIC-101. So nab-paclitaxel alone would not be expected to generate any antitumor activity. With that in mind, you can see that 3 of these patients had extended progression-free survivals, ranging from 3.6 months to 4.5 months to 5.3 months in a patient that is still ongoing on treatment as of the data cutoff, longer than the median seen with active second-line therapies despite receiving third- or fourth-line systemic therapy. We can add further context by comparing the outcomes for these patients to their immediately preceding therapy before they came on trial. Since we don't have PFS information for these prior therapies, we are using time on treatment as a close surrogate. For 2 of these patients, their PFS on ORIC-101 plus nab-paclitaxel is longer than their time on treatment with their last therapy, 4.5 months versus 2.8 months and 5.3 months versus 2.0 months, respectively, again, suggesting that these outcomes depart from what one would expect with standard, late-line treatments and represent preliminary evidence for potential clinical benefit in what is otherwise a highly refractory malignancy in a heavily pretreated setting. I would now like to shift gears and take the opportunity to introduce our expert guest today. Dr. Pamela Munster, clinical investigator on the study and senior author of the ASCO clinical abstract. Dr. Munster, welcome to our call today.

Thank you.

Could you tell us a bit about your academic work and clinical practice?

Yes. Hi. Good afternoon. I'm a professor in the Department of Medicine, and I direct the early-phase clinical trials unit. I'm also the co-leader of the Center for BRCA Research, and I co-lead their molecular oncology program. I'm a medical oncologist by training, but I also have a wet lab where my focus of my research is really evaluating combination and interference with hormone pathways. My clinical practice is very heavily geared towards Phase I patients. And commensurate with my research, of course, I would be interested in HRD mutations and breast cancer, ovarian cancer. But because of BRCA mutations and other HRD mutations are common in pancreatic cancer, our practice has been significantly built around pancreatic cancer.

Thank you. Now you've been involved for some time now in clinical research of glucocorticoid receptor inhibitors as a way to address cancer drug resistance. Could you expand a bit on what you've seen that convinces you that this may be an important therapeutic approach?

As I said, my research has always been focused around hormone receptor and glucocorticoid receptors pathways. In that sense, there is a strong indication that the GR-related effect on inflammatory pathways and poor apoptotic genes may really be effectively used in combination with chemotherapy. And I think particularly to -- I mean most of my research is really geared towards reversing resistance.

Thank you. Now turning to our study. As we mentioned earlier, you've been involved from the very beginning, and you've enrolled a number of patients on our Phase Ib. So if we start with the safety of the regimen. Could you comment a bit on your experience with the overall tolerability of the combination regimen?

Yes. I want to take this back a little bit as like a -- as one listens to data on trials in pancreatic cancer, what is not coming through was like just how ill and sick patients with pancreatic cancer are when they come to second- and third-line therapy. And most patients, even in second-line therapy, barely have a performance status to tolerate a regimen. So what I'm trying to say is particularly striking how we can get patients with pancreatic cancer to stay on this regimen without dose modifications, and how well tolerated this is in an overall very ill patient population.

Thank you. Now you are -- as I said, you were working with us, along with the other investigators, in helping select the final recommended Phase II dose, and one of the discussion points we had was around the appropriate Abraxane dose, nab-paclitaxel dose. And you were not supportive of pushing the dose to 100 per meter squared because of your concerns about tolerability in this patient population. Could you expand on your rationale for this recommendation?

Mainly 2 reasons. One is this is not a short-term adjuvant regimen. When we give taxanes for longer, there's a price to pay in terms of the neuropathy. And neuropathy, these are cumulative side effects. And what we see is, like, first of all, I think in a metastatic setting, we have proven we do not need the typical taxane doses that we see end up at -- commonly used in the adjuvant setting. But on the other hand, it's like we're treating for success here. If you want to have patients stay on for longer and really benefit from this regimen, we can't expose them to too many side effects upfront. And I think in the -- the data suggests that we have efficacy with the dose used, and I know I would not try to push this dose for the second-, third- and fourth-line therapy. Patients will not tolerate this. And frankly, I don't think it's needed.

Thank you. Shifting to clinical activity now. As you saw in the presentation, we've seen a number of examples of tumor regression, a number of partial responses, but not all of them were confirmed partial responses. Is that something that you would have expected to see? Or how meaningful is stable disease in this patient population?

When we treat patients in the third- and fourth-line setting, we're actually quite happy to see any benefit. And as I said before, it's really actually surprising that we can continue patient on -- because at that time, there's a pretty significant compromise on -- bone marrow reserve is a compromise in overall long-term toxicity with neuropathy. A lot of the patients, particularly pancreatic cancer patients, have gotten taxanes before or gotten oxaliplatin before, have neuropathy. I actually think it's quite striking that we can keep people on. And stable disease, from an oncology standpoint, quite frankly, response versus stable disease is not that different because in the end, what translates into meaningful survival is duration on treatment and not necessarily how much the tumors responded.

Now as this is a combination therapy that we're developing, and so it's always challenging to sort out what's from one agent versus the other in the combination. So just to ask you straight out, would any of the activity that you've been seeing and that we've been seeing in the study as a whole, could that simply be the result of an Abraxane retreatment effect?

No. In my opinion, I don't think so because most of the time, if other clinicians, we believe there will be a benefit on taxane retreatment, we would just do that. We will not refer patients to a clinical trial because even for most patients, being in the clinical trial is quite burdensome, with coming to a center, being exposed to multiple extra studies or biopsies. So no, I don't think so. And we have a pretty good assessment on how patients did on prior taxane or whether they have progressed. So I think we can say that I don't think this is a single-agent Abraxane effect. Of course, the randomized trials at some point will tell us, but in my opinion, no.

And so getting to your patients, in particular, you've enrolled a number of patients. In particular, many of the patients with pancreatic cancer are yours. I think it would be very helpful and interesting if you could comment as their primary oncologist on what you observed in one or more of these patients.

What's striking is what I said is like how tolerable this combination is because, as I said, our patients who occasionally gets referred to our Phase I program, they often have exhausted prior options, and their performance status has significantly decreased, particularly our patients who has been on for longer, was real ill, had a lot of pain, was unable to do much. And you may not appreciate as much, pain is a pretty significant issue in patients with pancreatic cancer because pancreas sits in a very unfortunate spot with the solar plexus right behind it. So often when tumors grow locally, there's quite an impact on the solar plexus and pain related to the solar plexus whereas patient with liver metastases often are not as compromised. So in pancreatic cancer, having tumor stabilization -- and often the tumors may not shrink a lot, but patients just feel better. Like one of my patients went out biking. I would get nicely -- nice reviews on Strava on all the biking he was doing. Strava is a shared exercise and trail running and biking program, so -- for those aware of Strava. But strikingly, it's always like how well this is tolerated and how much patients actually manage to get a little bit of their life back.

Yes. That's very nice to hear. So stepping back a little bit. I presented a bit on the landscape of pancreatic cancer. And you yourself, besides your clinical work, have a research interest. Could you provide some additional insight into how you approach patients with this cancer, especially in the relapse setting?

For pancreatic cancer?

Yes. Yes.

Unfortunately, like, as I said, a lot of the patients with pancreatic cancer are too ill to even go in second and third line. And I may sound like a broken record, but this is really a key part to finding regimens for such a patient population that's actually doable for them. Often, there is a function compromise. There's speed and movement compromise. So we need to have a regimen that can be given with a liver that's not completely functional where patients have anxieties. So what most people who deal with pancreatic cancer do now is like they give everything they have upfront. And that also means there's very little that we can do at the beginning. But I think if I would -- where I would like to see this going forward is like to really provide a regimen for patients with pancreatic cancer coming or just too sick to be treated with FOLFIRINOX or a combination of FOLFIRINOX, which is now the frontline therapies, is comprised of 3 treatments is actually quite toxic and then added other things. So I think we need a regimen that's well tolerated in the upfront setting. And of course, we need a regimen that's active, but we also need a regimen that's livable.

Sure. Sure. And so yes, I mean I think we've had a number of discussions. You came to us with your thoughts on where you think we ought to further develop this combination. Obviously, we are currently developing it in patients with relapsed pancreatic cancer in combination with Abraxane, but you had thoughts about moving it earlier.

I think many of -- about half of the patient actually never receive FOLFIRINOX because [ in general ], Abraxane. I think improving on the front-line Abraxane will be a huge step forward. Using ORIC-101 in combination with a taxane before patients have been refractory would probably make quite a difference. So I mean it's -- where I would like to [ be ] then, that question is could we have something in the adjuvant setting. And what I'd like to point out is like when someone has surgery and they had a Whipple, that has quite an impact. Again, tolerability for our regimen in this patient population is actually really paramount.

Sure. I understand. And so I presented a bit of the landscape of the therapeutics in this area. And at least based on my review of the literature, PFS to second-line therapy, not even third-line, but second-line therapy was on the order of 3 months. Is that something that you would agree with in your experience?

Yes. I think -- and again, this is probably on the 3 month of clinical trials, that is not factoring all the people who never made it on the clinical trial.

Fair enough. Thank you.

Yes. I would totally agree. And I think -- I mean we are not surprised to see the short PFS, but I think this is very real and, as I said, probably even a little bit more optimistic than the real world is.

Thank you. Thanks for your insights. Anything else you'd like to add that I didn't ask you about today?

No. I think just again, we are reiterating that I'm really excited about this because it's -- it provides patients a tolerable option, and I'm quite impressed with the efficacy. And I think response rate is probably not the right measure for success in this disease.

Thank you. Thank you, Dr. Munster, for your insights you've shared with us today. And of course, we'll have you back in a few minutes during the Q&A session. But let me just close out the clinical piece in -- on Slide 37. So these initial data from our Phase Ib study of ORIC-101 with nab-paclitaxel in patients with advanced solid tumors has identified the recommended Phase II dose of ORIC-101, specifically 160 milligrams daily in combination with nab-paclitaxel, 75 milligrams per meter squared weekly. This regimen appears to be well tolerated with primarily Grade 1 or 2 treatment-related adverse events. No requirement for prophylactic growth factor support and no patients discontinuing to date due to a treatment-related toxicity. Our PK data show that we are achieving exposures of ORIC-101 at the RP2D that exceeded the threshold for GR inhibition, which is corroborated by our translational data showing consistent suppression of key GR-related biomarkers. We also see no evidence of drug-drug interactions between ORIC-101 and nab-paclitaxel. And our tumor biopsy data confirm high rates of GR expression across the tumor types of interest. And then finally, preliminary antitumor activity has been observed in multiple heavily pretreated patients, including patients who previously received a taxane-based therapy. This clinical activity was particularly evident in patients with pancreatic ductal adenocarcinoma, who have previously received nab-paclitaxel and who demonstrated notable tumor regression and prolonged disease stabilization on our study when compared to historic data. As we look to the next steps on Slide 38 for development of this combination, our main focus will be completing enrollment of the 3 tumor-specific cohorts of pancreatic ductal adenocarcinoma, ovarian cancer and triple-negative breast cancer as well as the tissue-agnostic cohort. Based upon the results from our expansion cohorts, our path forward will depend on the nature of any efficacy signal that we may observed. Specifically with respect to pancreatic cancer, if we see evidence for a prolonged, progression-free survival, then we would plan to pursue a path to full approval by conducting a randomized controlled study. By doing a little extra clinical work to add in gemcitabine to the regimen, which is supported by our preclinical data, we could also seek development in either the first-line or second-line setting. On the other hand if, with further enrollment, we see evidence of responses, then even if -- then if we have some degree of durability, that leads to a possible accelerated approval strategy through a single-arm trial in a taxane-resistant or third-line patient population. For ovarian cancer, we are encouraged by the relacorilant data in this disease that was recently reported, but we will await data from our own Part 2 expansion cohort before making any decisions regarding next steps. For triple-negative breast cancer, it will similarly depend on what we see in our expansion cohort and how that fits in with the evolving landscape in TNBC, including the potential for atezolizumab/nab-paclitaxel triple combination. Finally, as I stated earlier, we plan to enroll additional patients with progesterone receptor-positive metastatic breast cancer into the tissue-agnostic cohort, and future development here will also be data driven. And across all of these efforts, we will simultaneously refine our biomarker strategy with respect to baseline GR expression in the tumor and the stroma and its relationship to patient outcomes. We look forward to providing updated data from the expansion cohorts in this study in 2022. With that, let me hand the call back to Jacob.

Thanks, Pratik. As you can see, we're quite pleased with this initial data set for ORIC-101. While our immediate next steps are focused on completing enrollment in the expansion cohorts throughout the remainder of this year and into 2022, we are highly encouraged by the early data we've already thinking -- and we're already thinking through potential next steps we would pursue in response to more definitive efficacy signals we may see across the full set of expansion cohort data. We look forward to presenting more data from this study next year. Now stepping back, beyond ORIC-101, as you can see on Slide 40, we've assembled a robust pipeline of differentiated product candidates sourced from both our internal discovery efforts and targeted, opportunistic business development. We expect to file 3 INDs or IND equivalents this year. And by early next year, we anticipate having an additional 3 programs beyond ORIC-101 in clinical studies. We had an action-packed AACR conference just over a month ago, during which we presented substantial preclinical data that make the case for the potential best-in-class profile of each of these product candidates. We've summarized the key highlights of those posters on the next few slides, but I'd encourage you to take a look at those detailed posters, which are available on our website. Slide 41 shows a snapshot of ORIC-533, designed by ORIC chemists as a small molecule inhibitor, CD73, with picomolar potency, good oral bioavailability and retained significant potency and function even in a high AMP environment, more so than any other CD73 inhibitor or adenosine receptor antagonist we've tested. Importantly, and different from the rest of the field that is pursuing combination studies for their CD73 inhibitors, we plan to initiate clinical trials in the second half of this year as a single agent in an undisclosed tumor type in which we've observed compelling, single-agent activity in patient-derived models. We're also pleased to announce that we've recently filed the IND for ORIC-533 with the FDA. Slide 42 shows a snapshot of ORIC-944, an allosteric PRC2 inhibitor that we in-licensed last year from Mirati. This molecule targets the EED subunit of PRC2 and has been optimized to overcome some of the biological and drug property limitations of the EZH2 inhibitors, the first-generation approach to tackling PRC2-related epigenetic dysregulation. With this molecule, Mirati demonstrated in vivo preclinical activity superior to that of an approved EZH2 inhibitor in a DLBCL model. ORIC has further demonstrated compelling in vivo activity in 2 different enzalutamide-resistant prostate models. We are on track to file the IND for 944 in the second half of this year, after which we intend to initiate single-agent studies in prostate cancer. And finally, Slide 43 shows a snapshot of ORIC-114, a brain-penetrant, orally available inhibitor targeting EGFR and HER2 Exon 20 mutations that we in-licensed last year from Voronoi. The outcomes for patients with EGFR Exon 20 mutations have been subpar thus far as molecules in the field have been limited, first, by a lack of selectivity for the target versus wild-type EGFR and various off targets; and second, by a lack of CNS activity, which is critical when over 1/3 of patients develop CNS metastases. Our comprehensive preclinical profiling of 114 demonstrates an exquisitely clean kinome tree, good therapeutic window versus wild-type EGFR, significant tumor regression in multiple in vivo models without signs of meaningful toxicity and compelling brain exposure and intracranial antitumor activity. We are on track to file a CTA in Korea for 114 in the second half of this year, after which we intend to initiate clinical studies. We'll wrap up our prepared remarks on Slide 44. We're very proud of the team and the pipeline that we've built here at ORIC. Today's initial data readout for ORIC-101 helps further support the role of GR as a novel target in chemotherapy resistance and the potential best-in-class profile of 101. Later this year, we look forward to providing an initial update on our combination study of 101 and Xtandi in prostate cancer. Beyond ORIC-101, we've put together one of the most robust pipelines of potentially best-in-class molecules in small-cap biotech, going after an array of validated targets. Before we open it up to Q&A, I'd like to thank Dr. Munster for joining us today to provide her perspectives and for her leadership as a trial investigator. I'd like to thank all the investigators and the entire ORIC team who've worked valiantly throughout the COVID pandemic to continue tackling 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] Our first question comes from the line of Anupam Rama from JPMorgan.

A couple of questions here. The first is just thinking about the GR hypothesis. Based on the totality of the data that you have, any thoughts about how you might use GR cutoff levels or as a predictive marker, say? Second question for Dr. Munster. You talked a little bit about the clinical relevance of stable disease. Maybe you could expand a little bit on that, in particular, about the rate of progression that you're seeing in some of the patients that actually do see some of the antitumor activity from the swim lane plot. And then a final question on -- is at the RP2D, the 2 cases of neutropenia that you saw, how do we think about that being 101-related versus, say, Abraxane-related?

Sounds good, Anupam. There was a lot bundled up in there, so let me parse those out. Let me ask Pratik first to talk about our views on whether GR is predictive of response, after which I'll ask Lori to comment on your question about H-score cutoffs, and then we'll go to Dr. Munster for your second question.

So in terms of just whether GR is predictive or response, I think it's a little hard to draw a definitive conclusion at this stage. But we are collecting the appropriate data in terms of patient biopsies to make this determination later in the study. But I would draw your attention that our biggest data set currently is in PDAC, and that's where we've seen the most interesting activity so far. And they're -- all patients from whom we got biopsies, had GR H-scores in the tumor and stroma of greater than 150. And it's a small experience at the RP2D, but patients with the higher GR H-scores in the tumor had the longer PFS on study and also shorter time on treatment to their last prior therapy. So there may be a story there developing, but we need more data to flesh it out.

And Lori, do you want to just talk briefly about how we think about H-score cutoffs?And then let's go to Dr. Munster.

Sure. In terms of the GR H-score for patient selection, this is a very active question for us. In some tumor types like pancreatic ductal adenocarcinoma, they'll have a uniformly high tumor H-score, so patient selection may not be necessary. Other tumor types, though, might require selection, and we need to determine what the therapeutically relevant H-score is. So a more definitive view on H-score cutoffs will be a key output we're looking for from the full set of expansion cohort data.

Thanks, Lori. And then Dr. Munster, could you comment on Anupam's question around stable disease? And do you remember the question? Or would you like him to restate it?

No. One was stable disease, and the other one was neutropenia, and whether this is ORIC-101-related. I can address that pretty easily. Neutropenia is our daily bread and butter in oncology, and that's a matter of how much bone marrow involvement and how much prior therapy. I don't think this is an ORIC-101 problem. I think this is an Abraxane problem, so I don't think that's an issue. With regard to stable disease, we know from that -- from treating patients with estrogen receptor-positive breast cancer and where we lived with years we've never seen a response. I mean if you look at the [ enrollment case ] inhibitors, we barely find anything, and even early on -- and we have seen patients live for years with this stable disease so -- and without shrinkage of their tumors at all. So as I said, from an oncologist -- and from an oncologist and a patient's representative, it's really important to have -- progression-free survival is really important. And I think the prolonged stable disease is important because the measure for Phase II and Phase III trial is really how you measure up in progression-free survival. And the moment you leave Phase I, the response rates become less meaningful, and the duration of responses, the duration of clinical benefit becomes the relevant marker.

Our question comes from the line of Michael Schmidt from Guggenheim.

I just had a few on development strategy. I guess in pancreatic cancer, what you need to see over the -- in the remainder of the cohort to determine whether you plan to pursue a single-arm registration study or perhaps a randomized controlled trial?

Yes. Thanks, Michael. Let me ask Pratik to take that one.

Sure. So I think let me break that out into 2 parts. One is regulatory approval, and then one, I guess, is sort of commercial uptake or clinician interest. In terms of regulatory approval, based on the overview I gave of the pancreatic treatment landscape, we think that a PFS in a late-line setting of over 2.5 months would be indicative of an active therapy and sufficient for full approval. Just to put that into a specific context. Nanoliposomal irinotecan was approved in the second-line setting based upon a PFS of 3.1 months versus 1.5 months with the control, and this was done with a study of about 400 patients in size. So that would be one development approach based upon PFS. Alternatively, we are enrolling more patients to our expansion cohort. And so if we see the potential for -- if we see responses, then we may pursue an accelerated approval strategy. Now in terms of the response rate. I mean we are looking to essentially rule out something that's de minimis ORR. It could even be 0% at the lower limit of the top of its intervals since you saw that many agents that I presented with a track record in the late-line setting have a 0% ORR. So that could represent an accelerated approval approach based upon the data that we generate from our expansion cohort. In terms of clinician interest, oh, go ahead.

No. I'm sorry.

In terms of -- just in terms of clinician interest, just to close the thought. I think seeing some -- a PFS of 3 months in this late-line setting would be immediately embraced by clinicians, frankly, be on par with the approved agents in earlier-line settings. And we would have the added benefit, I believe, of a more tolerable safety profile, something that I believe Dr. Munster underscored multiple times. So -- and then also, as we've also touched on, trying to increase the degree of benefit if -- to move ORIC-101 earlier in the treatment paradigm potentially with the gemcitabine combination.