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spk03: Good morning and welcome to Elevation Oncology's conference call. At this time, all participants are in a listen-only mode. The call is being webcast live on the Investors section of Elevation Oncology's website at www.elevationoncology.com. Please be advised that today's call is being recorded. At this time, I would like to turn the call over to Tammy Furlong, Chief Financial Officer of Elevation Oncology.
spk00: Thank you. This morning, we issued a press release announcing initial data from our Phase I clinical trial of EO3021. The full release is available on the Investor section of our website at www.elevationoncology.com. We also have slides today that are viewable if you are listening using the webcast. and the slides can be found under the Events section of the Investors section of our website. We will begin the call with prepared remarks by Joseph Serra, our President and Chief Executive Officer, Dr. Valerie Malevon-Jansen, our Chief Medical Officer, and Dr. Kohei Shatara, a medical oncologist and the Chief of the Department of Gastrointestinal Oncology at the National Cancer Center Hospital East in Kashiwa, Japan, and a principal investigator for our Phase I trial. We'll then open the call for questions. Dr. David Dornan, our Chief Scientific Officer, is also on the call and will be available for Q&A. Beginning on slide three, I would like to remind everyone that the statements we make on this conference call will include forward-looking statements. Actual event results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties, and other factors, including those set forth in the risk factor section of our annual report on Form 10-K that we filed earlier in this year, our quarterly reports on Form 10-Q that we have filed subsequently, and any other filings that we may make with the SEC in the future. Any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update or revise any forward-looking statements. With that, I would like to turn the call over to Joe. Joe?
spk07: Thank you, Tammy. Good morning, everyone, and thank you for joining us. Today is an important day for elevation oncology, as we are excited to share the first data from our phase one clinical trial of EO3021. We are very encouraged by these initial results, which demonstrate 3021's potential as a best-in-class Clawden 18.2 antibody drug conjugate, or ADC, and strongly support its advancement as a transformative treatment for gastric and gastroesophageal junction, or GEJ, cancers across lines of therapy. This conviction is rooted in early efficacy and safety data. Before we discuss the data in depth, on slide four, allow me to highlight key takeaways from today's announcement. First, in a biomarker-enriched subset of gastric and GPGA cancers defined as tumors with Clawdon 18.2 expression in greater than or equal to 20% of tumor cells at IHC 2 plus 3 plus, treatment with 3021 monotherapy resulted in a confirmed objective response rate of 42.8% and a disease control rate of 71.4%. Additionally, treatment with 3021 was generally well tolerated with no reported adverse events of neutropenia or peripheral neuropathy, known MMAE-associated toxicities that have historically challenged ADC-based therapeutics. Taken together, these data address two key questions we set out to assess in our trial. First, they confirm the importance of clodin-18.2 as a therapeutic target and the potential of a targeted approach to deliver outsized benefit to a biomarker-enriched population. And second, they demonstrate the power of site-specific conjugation at glutamine position 295 to increase ADC stability and minimize the potential for free MMAE and as a result, to provide a safer medicine with the opportunity for overall better profile. We are particularly encouraged by this finding, as differentiated safety will allow us to evaluate 3021 as both a single agent and in combination, potentially maximizing its reach. Based on these data, we are working quickly to advance a robust clinical development program evaluating 3021, both as monotherapy and in combination for the treatment of gastric and GEJ cancers across the first, second, and third line plus settings. We identified our go-forward doses for further exploration of monotherapy and are moving into the dose expansion portion of our phase one study with additional data expected in the first half of 2025. Also, as we discussed in June, we recently entered into clinical supply agreements with Lilly and GSK through which we will evaluate 3021 in combination with Ramisimirab and Dostarlimab, respectively. We expect to initiate dosing in the combination portion of our phase one trial by year end. This data readout represents an important first milestone for our 3021 program. We look forward to providing additional updates as we expand our phase one trial and advance towards introducing a prospective biomarker selection strategy and work towards our foundational vision of building a novel selective cancer therapy pipeline that delivers meaningful benefit to patients. Moving to slide five, before we get further into the data, I'd like to take a few minutes to provide some important background on the program. EO3021 was designed as a highly differentiated, potentially best-in-class Clawdon 18.2 ADC. It is comprised of a fully human IgG1 monoclonal antibody that is highly selective for Chloridin 18.2, along with an MMAE payload that is conjugated via a cleavable linker at glutamine 295, providing a homogenous DAR of two. This site-specific conjugation is intended to increase stability of the ADC and minimize the potential for free MMAE compared to ADCs with traditional cysteine-based conjugation. We believe this design contributes significantly to 3021's competitive differentiation. Not only does it offer a robust response rate in a Clawdon 18.2-enriched subset of gastric and GEJ cancers, but it does so without introducing the challenging toxicities associated with free MME, such as neutropenia or peripheral neuropathy, which may make patients more susceptible to infections and potentially limit their quality of life. As a result, we anticipate 3021 will be readily combinable with other drugs used to treat gastric and GEJ cancers, and there is a strong rationale to advance combination strategies in parallel with our ongoing monotherapy efforts. Moving to slide six, the data we are sharing today provide critical proof of concept for our approach and strongly support our path forward in gastric and GEJ cancers. As Valerie will detail shortly, initial data from the dose escalation portion of our trial demonstrated a 42.8% overall response rate in patients with gastric or GEJ cancer who present with Chloidin 18.2 in at least 20% of their tumor cells at IHC 2+, 3+. As compared to 0% in patients with Chloidin 18.2 in less than 20% of their tumor cells at IHC 2+, 3+. As I mentioned before, there were minimal MMA-associated toxicities observed across 32 patients evaluated for safety, including no neutropenia or peripheral neuropathy. On slide seven, these initial data are particularly meaningful given the magnitude of the opportunity in gastric and GEJ cancers. These are widespread diseases. In fact, gastric cancer is the fifth most frequently diagnosed cancer and the third leading cause of cancer deaths worldwide. There are over 150,000 patients with advanced or metastatic disease in our licensed territories, of which more than 70% express some level of Clawedin 18.2 and could benefit from treatment with the Clawedin 18.2 directed therapy, like 3021. Despite treatment advances, the only potential curative treatment approach is surgery, and many patients present with unresectable advanced or metastatic disease. Existing therapeutics offer moderate response rates initially, though most patients ultimately relapse. Based on the early data reported today, we are confident that 3021 could offer an important targeted option and deliver better outcomes for patients whose tumors express clot in 18.2. We believe 3021 has the potential to be used either as a monotherapy or in combination with a targeted agent, immunotherapy, or even chemotherapy, to address newly diagnosed patients with metastatic disease, as well as patients whose tumor have progressed on other therapies in the second or third line plus settings. And, as we'll discuss later on this morning's call, we are implementing a robust, multi-part clinical development strategy to evaluate our ADC across eligible gastric and GEJ populations. We are excited by these plans and are moving quickly to deliver the promise of 3021 as a paradigm changing treatment for gastric and GEJ cancers. I'll now turn the call over to Valerie to review the phase one data from patients treated in dose escalation and our next steps in greater detail. Valerie?
spk02: Thank you, Joe, and thank you all for joining us this morning. Allow me to begin on slide nine by walking through the design of the dose escalation portion of our phase one clinical trial. The dose escalation portion of the study enrolled patients with gastric, GEJ, pancreatic, or esophageal cancer. Claudine 18.2 expression was not required for enrollment. However, expression was retrospectively assessed using a Claudine 18.2 specific IHC assay. An exploratory objective is to understand the association of tumor Claudine 18.2 expression with objective response. We started the dose escalation portion of study at one milligram per kilogram given intravenously once every three weeks. and dose patients up to 2.9 mg per kg. 2 and 2.5 mg per kg have been identified as the recommended doses for further exploration. We are now moving into dose expansion, where we will focus on enrolling patients with advanced or metastatic gastric or GEJ cancer. As of the data cutoff of June 10, 2024, the study enrolled a total of 32 patients, including 26 patients with gastric or GEJ cancer. Of these 26 patients, 15 had CLAUDIN 18.2 IHC results and measurable disease with at least one post-baseline scan, which makes up the efficacy-evaluable population. On slide 10, you can see the baseline demographics and tumor characteristics for all 32 patients enrolled in the study. The median age across all enrolled patients was 65 years, and 70% of patients were male. Looking more closely at the 26 patients with gastric or GEJ cancer on the right-hand side of the slide, you'll notice that the study enrolled a heavily pretreated patient population. The median prior lines of therapy was three, ranging from one to seven. Eighty-one percent of patients were previously treated with a PD-1 or PD-L1 inhibitor, and 12% were previously treated with the non-ADC-based Claudine 18.2 directed therapy. In addition, and consistent with the scientific literature, you'll notice at the bottom that a majority of patients with gastric or GEJ cancer had tumors that expressed Claudine 18.2. Among 20 patients with available Claudine 18.2 IHC results, 13 had any level of expression. defined as greater than or equal to 1% of tumor cells at IHC greater than or equal to 1 plus staining intensity. And 9 had at least 20% of tumor cells with 2 plus 3 staining intensity. As you'll notice throughout our presentation, we bifurcated patients based on their available CLAUDIN 18.2 IHC results. Patients with at least 20% of tumor cells with IHC staining at 2 plus 3 plus and patients with less than 20%, 2 plus, 3 plus. The field of CLAUDIN 18.2-based medicines is new, and we and others in the industry are still learning exactly what level of CLAUDIN 18.2 expression is necessary to drive response to an ADC approach. While we did not require CLAUDIN 18.2 expression for enrollment in our study, we retrospectively explored a CLAUDIN 18.2 biomarker threshold at 20% 2 plus 3 plus. This captures a majority of patients with gastric and GEJ cancers and is a threshold that we believe gives us the opportunity to evaluate 3021 in patients who may benefit most from this treatment. Slide 11 shows the pharmacokinetic data, which underscores the benefit of site-specific conjugation, demonstrating the stability of our ADC construct and articulating EO3021's differentiation. The graphs on the right side of the slide show the ADC of total ADC and free MMAE, comparing 3021 with two representative approved MMAE-based ADCs for solid tumors. The goal with our ADC construct is to maximize target coverage while minimizing levels of free MMAE. As you can see, this is exactly what we observed in the trial. 3021 achieved higher exposures compared to the approved MMAE-based ADCs at comparable doses with lower free MMAE. And the lower exposure of free MMAE translated directly into an approved safety profile with minimal MMAE-associated toxicities observed in the trial, including no neutropenia, peripheral neuropathy. Turning now to the clinical data, Slide 12 shows the treatment emergent adverse events, or TEAEs, reported in 10% of patients or more. Overall, 3021 was generally well tolerated across the 32 patients evaluable for safety. Across all grades, the most common TEAEs reported were nausea, decreased appetite, fatigue, and diarrhea. Four dose-limiting toxicities were observed at the 2.9 mg per kg dose level. leading to the selection of the 2 and 2.5 mg per kg for evaluation and expansion. In addition, we saw limited incidence of other AEs of interest. Keratitis, mostly of grade 1, was reported in 18.7% of patients and was effectively monitored through ophthalmic examinations and managed with prophylactic eye drops. And as we mentioned throughout this morning's call, we saw minimal MMAE-associated toxicities with no neutropenia, peripheral neuropathy, or AST-AALT increase. Finally, we were encouraged to see lower rates of vomiting compared to the initial data shared by our partner, CSPC, last year, reflecting the potential benefit of implementing antiemetic premedication with the first dose of 3021, which we've introduced specifically to mitigate some of the more challenging GI toxicities that occur as an on-target effect to Clawdin 18.2. On slide 13, you can see the initial anti-tumor activity data. As previously mentioned, we bifurcated patients based on their available Clawdin 18.2 IHC results. A total of 15 patients with gastric or GEJ cancers and available Clawdin 18.2 IHC results were evaluable for response as of the June 10th data cutoff. This included seven patients with at least 20% of tumor cells with IHC staining at 2 plus 3 plus and eight patients with less than 20% 2 plus 3 plus. We saw a marked difference in response among those with CLAUDIN 18.2 expression and those without. Among seven patients with at least 20% 2 plus 3 plus, the objective response rate was 42.8% and the disease control rate was 71.4%. This included three patients who achieved confirmed partial responses, all of which are ongoing, and two patients who achieved a best response of stable disease. In contrast, among eight patients with less than 20% 2 plus 3 plus, the objective response rate was 0%, and the disease control rate was 50%. Slide 14 shows the waterfall plot. The pink bars represent patients with at least 20% of tumor cells with IHC staining at 2 plus, 3 plus. The blue bars represent patients with less than 20%, 2 plus, 3 plus. And the gray bars represent patients without available CLAWDIN 18.2 results as of the data cutoff. This waterfall plot demonstrates what we showed on the prior slide. Patients with higher expression are likely to experience greater benefit from 3021 with all responses observed in patients with CLAUDIN 18.2 expression defined as at least 20% of tumor cells with IHC staining at 2 plus, 3 plus. As Joe noted earlier, we believe these initial data provide a compelling rationale to advance 3021, both a monotherapy and combination agent. We are looking to initiate our monotherapy expansion where we would evaluate doses of two and 2.5 mg per kg in patients with advanced or metastatic gastric or GEJ cancer. In addition, the data reported today suggests that a prospective biomarker cutoff will be an important part of the future development of 3.021. We are working towards implementing a cutoff as part of the expansion portion of the Phase I trial in order to focus our efforts on patients who are more likely to respond to therapy. Finally, as we shared in June, we are expanding the Phase I trial to include two combination cohorts. The first cohort will evaluate 3021 in combination with ramiserumab, a VEGFR2 inhibitor. As many of you know, the combination of chemotherapy and ramiserumab is the standard of care treatment for second-line gastric cancer. We believe there is an opportunity to combine 3021 with ramiserumab to potentially deliver improved safety and tolerability and better outcomes through targeted delivery of a cytotoxic drug directly to clotin 18.2 expressing cancer cells without damaging nearby normal healthy cells, which occurs with systemic chemotherapy. The second cohort will evaluate 3021 in combination with distarlimab, a PD-1 inhibitor. Immunotherapy is the mainstay of first-line gastric cancer treatment and we believe combining 3021 with Dostarlimab could drive further benefit, particularly as ADCs with MMAE-based payloads are known to induce immunogenic cell death. We expect to initiate dosing in the combination portion of our Phase I trial before year-end. In conclusion, I would like to thank the patients, their families and caregivers, and the investigators involved in our Phase I clinical trial. Their support and trust are critical for enabling elevation oncology to reach this milestone towards our goal to bring new treatments to patients living with cancer. We are incredibly excited by the promising data we are announcing today and look forward to building on these efforts as we advance the program. With that, I am now going to turn the call over to Dr. Kohei Shatara, a principal investigator on the Phase I trial, to provide additional detail on gastric and GEJ cancers and the current treatment landscape, and to share his perspective on the development of Claudine 18.2 targeting agents like 3021. Dr. Shatara is a global expert in gastric and GEJ cancer, and has served as a clinical investigator on multiple trials evaluating novel therapeutics. We're very fortunate to collaborate with Dr. Shatara on the EO3021 program, and are pleased to have him with us today. Dr. Shatara,
spk04: Thank you, Valerie. I'm Dr. Koishita, Medical Oncologist and Chief of the Department of Gastrointestinal Oncology at the National Cancer Center Hostel East in Kashiwa, Japan, and Principal Investigator on Elevation Oncology Phase 1 Clinical Trial. My primary research interest includes the development of new anti-cancer agents, and I have been involved in a number of clinical trials for patients with GASIC and GGA cancers. These slides show my disclosures. So I'm going to begin today with a brief overview of the current treatment paradigm for metastatic GASIC and GGA cancers before providing my perspective on the opportunity for Cloven 18.2 targeted treatment. Until recently, only a handful of chemotherapeutic or molecular-targeted agents were approved for gastric and IgG cancers. Fortunately, we have seen a number of recent breakthroughs, including antipyretic therapy, anti-HER2 ADT, and anticoagulant 18.2 therapy. and the landscape has evolved significantly since 2015. As a result, in recent years, the treatment of graphic energy cancers has become increasingly informed by biomarkers, Once patients are diagnosed with gastric or GG cancer at my institution, they undergo a panel of pathologic tests, including for HER2, MMR, PD-L1, and Chordia 18.2 expression, which then determines the recommended course of treatment. In my experience, a substantial portion of patients tested positive for Chloride 18.2 expression consisted with literature around the prevalence of Chloride 18.2 in gastric and gingival cancers. Today, we use a cut-off aligned to the approved monoclonal antibody zirptaximab level. So, looking at the first-line patients with greater than 75% IC2+, or 3+, chlordane kinpoid 2 expression, we see approximately 35% patients as eligible for treatment with zirptaximab. This is already a substantial portion of the population, and it will, of course, grow as we adopt new agents like ADCs, which could treat patients with a wider range of COVID-19 18.2 expression and treat patients with underlying disease. On slide 21, you can see the recommended treatment for first-line advanced metastatic gastric and GG cancer according to the ESMO Living Guidelines and the updated Pan-Asian Adapted Guidelines, which are similar to NCCN guidelines commonly used in the U.S. As we will note, multiple biomarker tests are needed to inform the best treatment options for patients. While anti-PD-1 therapy plus chemotherapy improves survival and has become the standard of care, the efficacy benefit is mainly limited to patients with high PDRR expression or MSR high status. Very recently, job taximab in combination with chemotherapy was approved in Japan for a subset of patients with high chlorine 18.2 expression. Despite these advances, oncologists want and patients need new treatment options. On slide 22, moving into second-line setting, TDXC as anti-HER2 ADC is the only available targeted therapy for patients with persistent HER2-positive status after first-line trastuzumab. This actually represents a very small number of patients, making up less than 10% of the overall population. Paclitaxel plus ramsumab, a VEGF inhibitor, is a standard second-line for other patients with an objective response rate of 25% to 30% and a median PFS of 4.5%. So second-line patients are also clearly a met-need operation. Turning into the third-line setting in the right-hand side of the slide, TDXD can also be used in heart-positive cases, but the only other choice for patients is another cytoxib treatment. The response rate in third-line setting is less than 10%, and the median PFS is approximately 2 months. Clearly, we need a better treatment. So now let's review where Chlorine 18.2 targeted medicine fits into the treatment landscape. Chlorine 18.2 belongs to a family of high junctional proteins which serve as a barrier and regulate dish permeability. COVID-19.2 is mainly expressed on normal gastric mucosal cells, especially the apical site of the tight junction. But during malignant transformation to gastric ulcer, it is exposed on the tumor cell surface with disruption of the tight junction, and they become accessible to cancer treatment. Additionally, while Ch18.2 is commonly expressed in GASIC or GG cancer, it is also ectopically expressed in other types of tumors such as pancreas, esophageal, mutinous ovarian, or lung cancers. On slide 25, interestingly, the distribution of Ch18.2 expression in GASIC cancer looks like U-shape. About 20-30% of patients have completely lost any COVID-19 18.2 expression. Another 20-30% of patients show low or heterogeneous COVID-19 18.2 expression. Then the remaining 30-40% of patients maintain high or very high COVID-19 18.2 expression. In total, more than 70% of Gashika and GJ tumors expressed Chlorine 18.2 at any staining intensity, and approximately 60% expressed Chlorine 18.2 in at least 20% of tumor cells with IC2 plus or 3 plus. Currently, Cloud N10.2 expression is commonly accessed using an IT assay, and there are several IT assays available in development. Furthermore, there is no consensus on what defines Cloud N10.2 positive, and different definitions of Cloud N10.2 positivity have been used in trials of various agents. In recent years, Chlorine 10.2 has become a very exciting therapeutic target, and today there are more than 30 agents that are being investigated in clinical trials. As shown on this slide, there are many different modalities, including ADC like EO3021, which appear promising to address the unmet needs in GASIC and GG cancer. as shown on the next slide. This program with variety of different mechanism of action have applicability across distinct subsets of patients with COVID-19 form 2 expressed in GASIC or GG-CAMPERS. For example, CAR-T or vascular-specific T cell engager called BITE might be used in patients with tumors expressing a moderate level of protein 18.2 compared with monoclonal antibodies like drosotaximab because they drive T cell antitumor response. And the ADCs, on the other hand, with the cleavable linker and cytotoxic payload can induce the bystander effect, which may enable them to reach an even broader patient population, including patients whose tumors have lower levels of COVID-19.2 expression. As the elevation quality team alluded to this morning, it will be important for an exact threshold or quality 18.2 biomarker cutoff to be qualified in future studies for each agent. Finally, on slide 28, I'd like to summarize my presentation. First, there is a significant need for new treatment for patients with GASIC or GG cancer across lines of therapy. Second, Claudine 10.2 is a well validated biomarker for GASIC and GG cancers with approximately 16% of tumors expressed in Claudine 10.2 in at least 20% of tumor cells with IC2 plus or 3 plus. Third, I believe coding a 10.2-targeted therapy can improve outcomes in this biomarker-in-list operation, and I am excited that there are various coding 10.2-targeted therapies in development across a range of modalities. I'm particularly excited by the opportunity for RADCs, which may avoid some of the toxicities that limit existing standard of care options and deliver better efficacy and durability to a broader targeted population. I believe ADT can be a life-changing medicine for patients, and I'm particularly encouraged by the data shared today, which refers to the correlation between target expression and efficacy with a novel agent that demonstrates manageable tolerability and strong efficacy. We are still early in the development of EO3021, but it's clear this is a program that could deliver meaningful benefits, not only as a non-therapy, but given its favorable safety profile, potentially in the combination setting. Thank you for the very kind attention, turning it back to Joe.
spk07: Thank you very much, Dr. Shatara, and thank you for your partnership throughout our development efforts. We are grateful to you and to your fellow investigators and their staff for your diligent efforts to advance the program. Thank you as well to the dedicated Elevation Oncology team, who continues to work relentlessly toward our vision of delivering novel, selective cancer therapies to the patients and caregivers who are participating in our trial and entrusting us with their care. Moving to slide 30, in conclusion, I hope you all share our excitement around the potential for EO3021 to be a best-in-class CLAUDIN18.2 ADC. Based on the data shared today, we are working hard to implement a broad development plan which leverages 3021's differentiated safety profile and competitive anti-tumor activity to address a substantial unmet need across lines of therapy. More specifically, we are advancing into monotherapy dose expansion in patients with second or third line plus gastric or GEJ cancer and look forward to sharing additional data in the first half of 2025. Also, by year end, we expect to initiate dosing in the combination portion of our phase one trial, where we will evaluate 3021 in combination with ramisumarab in the second line setting and in combination with dostarlimab in the first line setting. As we've said throughout today's call, We believe 3021's differentiated safety profile allows us the opportunity to think more broadly about our clinical plans, including to explore combination regimens that are not accessible to other assets in development, such as combining with standard of care chemotherapy, and we plan to evaluate additional combination approaches as we advance forward. Finally, slide 31 shows recent and upcoming milestones across our portfolio. 2024 has already been a transformative year for Elevation, marked by strong execution across both of our programs. As we announced in our earnings release this morning, we are fortunate to be operating from a robust financial position, and we look forward to building on this momentum as we advance 3021 and share additional details on our HER3 ADC program in the months ahead. With that, I want to thank you for your attention And I will now turn the call over to the operator for questions. Operator?
spk03: Thank you. At this time, we will conduct the question and answer session. To ask a question, you will need to press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. Please stand by while we compile the Q&A roster. Our first question comes from the line of Biren Amin from Piper Sandler. Your line is now open.
spk06: Yeah. Hi, guys. Thanks for taking my questions. Maybe let me just start with, I guess, the cutoff. Are you requiring 2 plus greater than 20% going forward for the combination and the ongoing monotherapy? And then, you know, the second question is, do you know if the expression level changes within gastric GEJ cancer over lines of therapy? And if so, you know, would you be able to, like, characterize what these changes are? Because I think the one slide showed about 55% to 60% of patients would be eligible for 2 plus greater than 20%. And then I've got a follow-up after that.
spk07: Thanks, Barron. Thank you for the questions. Valerie?
spk02: Yes. Thank you, Barron. So, in terms of the cutoff at 20% 2 plus 3 plus, you know, this is the initial data and we chose to present our data in that manner. Going forward, we are continuing to evaluate what that prospective cutoff would be. You know, of course, we are looking at ways to identify patients and enrich for patients who would benefit the most from 3021 treatment. In terms of your second question about does Clawed-in 18.2 expression changes with treatment, really we and others in the industry are continuing to learn about Clawed-in 18.2 as a biomarker. This is where I would like to invite Dr. Shatara to provide his perspective around Clawed-in 18.2 expression after treatment. Dr. Shatara?
spk04: Yeah, thank you. I believe this is a very relevant question. And actually, some research, including ours, tried to compare the clotting status before and after certain kind of chemotherapy. And there's around 70% concordance before and after chemotherapy. So in general, clotting can be maintained even after some types of chemotherapy. But some patients show reduced expression clotting. But this doesn't mean change from 100% expression to zero, but to still show some level of change, for example, 60% to 40%. So since this ADC can target 20% or more based on current phase one trial, I believe this drug can target a relatively wide range of population.
spk02: Thank you, Dr. Sutrara. So, Barron, as we look for a selection biomarker in terms of the cutoff, we want to identify the most patients that could potentially benefit. And then we know from these initial data, as you're aware, we did not enroll patients based on CLAUDIN 18.2 expression, but we collected tumor tissue to retrospectively look at the CLAUDIN 18.2 expression. And what we're showing today, it's very clear that which we knew and what science predicted that target expression is necessary, but how much? And so we're pleased to see these initial data with a bifurcation of patients based on 20% 2 plus 3 plus to see that those patients with tumors that express clot in 18.2 benefited the most. And as we move forward in our development of 3021, we are seeking to look at a prospective cutoff to enroll patients. What that cutoff for a CDX would be, it's still too early to premature to decide what that cutoff is, and we look forward to sharing more details around our biomarker selection strategy and patient enrichment.
spk06: Got it. And maybe if I could have another follow-up on the safety. You didn't see any heme talks. nor ALP-AST elevation at least above 20%, nor vomiting above 20%. And I just wanted to, at least for the first two, when you go into combination studies, how do you think that's going to resonate in terms of overlapping toxicities given, I think we've seen with the ASHRAE program and with the InnoVent program, some heme tox as well as liver enzyme elevations?
spk02: Yes. Thank you for that question. And so that's exactly why we think in terms of 3021, the safety profile is generally well-tolerated. And as you noted, it makes it a combinable agent, particularly with the agents that we're looking at, ramicerumab and esterlimab, very few overlapping toxicities. What's been in terms of challenging for patients in second-line treatment is peripheral neuropathy, particularly with Paclitaxel. So we see this as an opportunity to improve on patient outcomes and, frankly, in terms of safety and tolerability. These patients obviously have metastatic disease. However, quality of life is very important. In terms of the nausea, we believe that to be an on-target toxicity. So yes, in terms of the site-specific conjugation, we're actually seeing the safety profile play out We believe that site-specific conjugation of our ADC construct leads to a more stable ADC, and that stable ADC actually gets to the tumor cells expressing CLAUDIN18.2 versus the payload falling off too early, per se, and causing some of the untowards adverse events that one might see with traditional base cysteine conjugation. So we're really excited with this initial look at the safety and tolerability profile and, of course, robust anti-tumor activity as we move to advance 3021 as a monotherapy as well as combination therapy for patients with gastric DHEA.
spk07: And I'll just add, I mean, we've been saying for a while about this update. It's all about getting to the profile and learning more about the profile of 3021 now that we're enrolling our own patients in our own trial. And this data clearly shows that with the competitive anti-tumor activity and the differentiated safety profile, it gives us a lot of room to think broadly about how to expand the reach of 3021 and think really broadly about how we can improve the standard of care across lines of therapy. And of course, that starts with later lines of therapy, but it's also going to be incredibly important as we move towards first-line therapy and thinking about combinations and giving us an opportunity to combine where other CLOD and 18.2 ADCs are gonna struggle because of things like HEMETOX that you mentioned, Barron.
spk06: Great, thank you.
spk01: One moment for our next question.
spk03: Our next question comes from the line of Mark Fram with TD Cohen. Your line is now live.
spk10: Thanks for taking my questions. Maybe just for a little bit of housekeeping on the patient flow through here. The baseline characteristic slide shows 20 patients with or 26 gastric patients and 20 with Clawdon IHC data available, which becomes 15 valuable. Can you just confirm the other five that have IHC data but aren't valuable? How many of them are still on trial and were just waiting on scans versus maybe have discontinued for some reason? And then kind of the same question for the other getting up to 26. How many of those are maybe just waiting on IHC data, but they are still being followed? And then I have a follow-up question also.
spk02: Thanks, Mark. So as we pointed out, there were 15 patients with gastric GEJ with CLAWDIN 18.2 IHC results who had measurable disease and at least one post-baseline scan as of the data cut off. So that made up our efficacy evaluation population. As Mark noted, we enrolled patients, 26 patients with gastric GEJ. So of those patients on the waterfall plot, you'll notice that three patients have CLAWDIN 18.2 IHC results unknown at this time. And so those are patients that potentially will have known CLAUDIN 18.2 IHC results. However, at the time of data cutoff, we did not have those results or were awaiting the tissue for CLAUDIN 18.2 testing. In terms of why the other patients are not evaluable or included in the efficacy, those are patients newly enrolled in the study and had not yet made it to their first scan as of the data cutoff. That's the majority of patients and why they were excluded from the efficacy-evaluable population. And in terms of the question about which patients are ongoing, at this time, we are not providing patient level. However, as I noted in the presentation, the three patients with confirmed partial responses are ongoing at the time of data cutoff.
spk10: Thanks. That's very helpful. And then maybe just on the... the selection strategy going forward. Can you discuss, and maybe Dr. Shatara may also have opinions here, and just how comparable the different thresholds are between the different programs that are out there, both from where they're setting the threshold, but then also maybe the assays and how that may be leading to the same or different patient populations.
spk06: Sure. Valerie?
spk02: Yeah, so I'll start off, and then, yes, certainly Dr. Shatara would be great to weigh in as a treating oncologist. So as you know, we and others are still learning about Claudium 18.2 expression in gastric GEJ. As you alluded to, there are different IHC assays available with different clones, and that'll be an important aspect of developing a CDX as well. And so we think that these are all comparable expression level. Dr. Shattar showed in his presentation, in terms of the Claudium 18.2 expression, And it does appear that majority of gastric GEJ do express some level of Claudine 18.2 at any staining intensity. And then those that do express it tend to express higher levels of it. So I think that, you know, as we look toward a prospective biomarker selection, that'll be important because we obviously want to identify the most number of patients that could benefit from EO3021. Dr. Shatara, do you want to provide your perspective in terms of in the clinic and your patients?
spk04: Thank you. So as I've already mentioned, to define the exact threshold, we need more patient cooperation to compare responder versus non-responder. But I agree with previous comment that since we have a clear difference between the responder and the non-responder, if we apply the 20% cut-off level. As ADC, I always want to see this kind of relationship between efficacy and the target expression. If not, I'm not sure it is ADC. But this agent showed a clear such relationship. On the other hand, I'm not sure whether 25% cut-off level and 20% cut-off level is exactly different or not. Again, we need more data to conclude.
spk07: Thank you, Dr. Shatara. Thanks, Mark.
spk03: One moment for our next question. Our next question comes from the line of Andy Behrens from Leerink. Your line is now open.
spk05: Hi, Jo. Thanks for the questions. Can you give us some idea of the durations that you're seeing in the trial? I know it's early. If you're not prepared to tell us the median DOR, can you let us know what the median duration of treatment in the trial was? And then maybe the doctor would comment on what he would eventually like to see in regards to DOR for the drug to be competitive. And then in terms of safety and tolerability, I think one of the things you had hoped to show was that prophylaxis for GI pox could allow you to dose higher than CSPC, which it doesn't sound like you got to that point. Maybe Dr. Shatara can give us some color on his experience with the anti-emetic prophylaxis in his patients during the regimen.
spk07: Thanks, Andy. Appreciate the questions as always. Valerie, you want to take them in order?
spk02: Yeah, I'll start off and then certainly welcome Dr. Shatara to weigh in. In terms of the duration of response, you know, it is too early. At this time, we're not providing that level of granularity. But as you'll note on the waterfall plot, There was a patient with confirmed partial response at 1 mg per kg. So as you may recall, we initiated the study and dosed the first patient back in August of 2023. As I mentioned, that patient is still ongoing on study. So that gives you an idea of the potential duration response. And just as a benchmark, you know, this is a heavily pretreated patient population with a median of three prior lines of therapy ranging from one to seven. In the second-line setting, the standard of care offers about a 4.4-month median PFS, so that gives you an idea. In terms of the safety and tolerability, so as you may recall, CSPC saw DLT dose-limiting toxicities of GI tox, nausea and vomiting, at the 3 mg per kg dose level. So we were pleased to see that with the anti-medic premedication, we were able to mitigate the more severe GI toxicity of vomiting. So patients you saw had nausea, however, they do not have associated emesis. The DLTs that we did see were different from what CSPC saw. So in some ways, I believe that the pre-medications with anti-medics certainly help that. I'll turn it over now to Dr. Chachara to comment on those in terms of the duration of response that he would like to see
spk04: For this agent and then the safety and tolerability around nausea as well Yeah, thank you for such a question and I have enrolled around 10 patient for these studies and Not a few patients are relatively new cases and duration of treatment is not so long but most of the patient remained on treatment and that reason two of my patients are doing well with very nice response, maybe duration of response more than four or five months. And one of these patients had a peritoneal metastasis with ascites accumulation, but now ascites disappeared and she's doing fine. And regarding toxicity, as Baradei mentioned, on targeted GI toxicity, it's always one of the concern for clotting. 18 targeted treatment. Any kind of agent should have such toxicity. But because of the previous experience, many patients treated with resorptaximab, I learned we need enough pro-medication using NK1 inhibitor, corticosteroid, and 5-HT3 inhibitor. And for some cases, I also use orazepine. And usually, these treatments are enough to manage these mild-degree geotoxicity. I don't have any patients who discontinue treatment because of such toxicity. So that being said, I think combination with ramshirumab or pyririne inhibitor is quite feasible. I'm very confident about such next step. And we can also combine with the 5-Berry-Fewer capsaicinib-R-treat. This is my expectation. Thank you.
spk02: Yeah, thank you, Dr. Shatara. And I'll just like to circle back in terms of the duration response. You know, as Dr. Shatara mentioned, once we get into third line and later, this is where the median PFS is only about two months. And so definitely a clear unmet medical need. And then in terms of the nausea and vomiting, as we've shared externally that We have a recommendation in terms of anti-medics that could include the four drug regimen that Dr. Shatara alluded to that does include olanzapine potentially with steroids, PHYHT3 inhibitors, NK agonists as well. So this is all toxicities that oncologists like Dr. Shatara are used to managing in the clinic in this particular patient population.
spk07: Okay, thank you. Thanks, Andy.
spk03: One moment for our next question. Our next question comes from the line of Sylvan Turkin from JMP. Your line is now open.
spk08: Yeah, good morning, and congratulations on the data, and thanks for taking my question. I think the first question for Dr. Shitara Could you please speak to the safety profile? You know, it's early days here with a few patients, but how is that differentiated from the other cloud and ADCs that you may have experienced or seen at conferences? And how do you view the profile in the setting of your gastric patients? How compatible is it with, you know, the profile of these patients? Thank you.
spk04: Thank you. Honestly, you know, it's not easy to compare a different log for different operation or different patient actually other code. He also showed her some cross profile which are associated with her. some degree of geotoxicity. But this agent is clearly very feasible at this dose level. And as mentioned before, if we can use antiemetics, I don't have any patients who discontinue treatment. And some patients have eye toxicity, ocular toxicity, like keratitis, but this is also very And I don't have any patients who have a bone marrow suppression, myosar pressure. So this is a very important aspect to combine with an additional cytotoxic chemotherapy, as mentioned before. I also don't have any patients with severe peripheral neuropathies. Most of my patients already treated with a So, usually, they have some degree of peripheral neuropathy, but there's no worsening of such symptoms. So, again, I'm sorry, it is very difficult to compare different ADC, but this ADC is quite feasible at this dose level.
spk02: Thank you, Dr. Shakara. All right, Sylvan, I'll also add that, you know, this is where, in terms of our site-specific conjugation with an MMAE payload, you know, the stability of the ADC construct. Of course, as Dr. Shatara mentioned, it's difficult to make cross-trial comparisons. Other agents have different payloads and, of course, would have a unique safety profile. But we are encouraged by the safety tolerability profile of 3021. And as Dr. Shatara mentioned, leading us to evaluate combination approaches, including potentially combination with standard care chemotherapy that would improve on patient outcomes.
spk08: Great. Thank you. And maybe a quick follow-up. It's hard for me to follow all the patients onto the waterfall plot, but could you maybe comment on a high level about Is there any relationship between, you know, response rates perhaps by line of therapy or prior therapy? It seems like you've seen responses across patients that have, you know, had all the various treatments, PD, PD-L1, taxa, and VEGF, and even clotting therapy.
spk02: Thank you for the question. So at this time, you know, obviously with three responses, all of which are confirmed, we're not sharing the granular data in terms of patient-level data. But as you can see that this is a heavily pre-treated patient population that re-enrolled, the median prior lines of therapy was three. And as you saw, majority of patients did receive the appropriate standard of care, including over 80% of patients had seen a PD-1, PD-L1 inhibitor. And as you noted, approximately 12% of patients had been exposed to a prior non-ADC clot in 18.2-based therapy. As we continue to advance the program and enroll more patients, we look forward to sharing those level of details.
spk08: Great. Thanks for taking my question.
spk07: Thank you, Sylvan. Appreciate it as always.
spk03: Thank you. As a reminder, to ask a question, you will need to press star 1-1 on your telephone and wait for your name to be announced. Our next question comes from Suden Luganathan from Stevens. Your line is now open. Hi.
spk09: Hi, Joe, Tammy, Elevation team, and Dr. Sitara. Thank you for your time to take our questions. My first question is regarding the trial design for monotherapy and the combination. Once both monotherapy and combination trials are in full swing, what will be the differentiating criteria for a patient to determine if they have failed on first-line prior therapy should either start on monotherapy 3021 as their second line or be enrolled straight into a combination with ranguceramab for the second line treatment.
spk07: Thanks for the question. Appreciate it. Valerie, you want to?
spk02: Yeah. Thanks for the question. And so right now, in terms of monotherapy expansion, you know, we are moving into monotherapy expansion. And this is a patient population that has seen at least one prior line of systemic therapy You know, as Joe mentioned, with a combination with Ramicerumab, so Ramicerumab plus chemotherapy is the standard of care in the second line gastric cancer treatment. So when we open up expansion in the combination of 3021 with Ram, that is the patient population that we were targeting. So patients in the second line who have seen, who have progressed on or after a fluoroperimidine and a platinum-based chemotherapy in the first line setting. In terms of combination with Dostarlimab or PD-1 inhibitor, we know that that's a first-line treatment, and so we will be targeting that patient population. There will be minimal overlap, and this is where if patients are eligible for a combo with RAM or a monotherapy, it is up to the treating physician where the patient, in terms of which arm or which cohort they would enroll into. Dr. Shattar, do you want to comment on that from your perspective?
spk04: Yeah, thank you. Especially in second-line setting, I think combination with ramsumab is quite reasonable because targeting VEGF may increase the distribution of ADC to local tumors. And ramsumab is usually a very feasible drug to combine with any cytotoxic reagent. I'm not sure whether it would also require component contribution or not, but at least I believe a combination could be better if we want to fight against paclitaxel and ramsilumab, such two drug combinations. And in combination with PD-1 therapy is very attractive because of some MMA, ADC showed a very good combination activity with PD-1 blockade. Actually, ADC with a top-1 inhibitor is not so good in terms of safety profile, so MMA-ADC is very attractive. I'm not sure, but if safety is PD-1 inhibitor like Dostoevsky's is confirmed, maybe we can also combine with capsaicin B05A-FU because these are all very feasible drugs, and depending on its efficacy, hopefully we can fight against chemotherapy plus the reduction of OI checkpoint inhibitor as a standard of care. But the independent are actually also the result.
spk09: Got it. Thank you. And I got one more question for Dr. Shatara. So broadly speaking on the therapeutic technologies, as you see the multiple drugs kind of targeting Claudine 18.2 coming through the pipeline, you know, despite the limited information we may know now as they develop, Do you have a sense of some redeeming qualities in your view of an ADC versus a monoclonal antibody, bispecific antibody, or CAR-T when looking at clubbing 18.2 targeting agents for gastric and GEJ cancer? Yeah, thank you.
spk04: It is a little bit difficult to answer in one word, but as a clinician, I want to have more and more drugs because any one kind of drug is not perfect. And first, the chemo plus the tax model is the kind of standard of care, especially patients with high clothing expression. But unfortunately, even after some response, most patients eventually experience disease progression. And another few patients maintain clothing expression. So clearly, we need additional treatment. And targeted population is only for high clothing expression. And T-cell anguillage is also very interesting, but one of the difficult aspects is toxicity management, not only for GI toxicity, but also cytokine release syndrome, as you may know. At first infusion, second infusion, usually we have a CRS, and management of such toxicity, or especially in combination with chemotherapy, is not so easy. So clearly, we need some running curve and not easy to develop for wide population. And finally, CAR-T is also very interesting, and Chinese studies showed a very promising result, but it requires many complicated process, manufacturing process, cost, or other very difficult aspects to develop such kind of drug. for lower countries. So I believe ADC is quite, I don't want to say like that, but easier compared with the current key. And it could be easily managed as shown today. So there is some difference of such toxicity profile, but eventually we need a randomized study to conclude.
spk09: Thank you for that insight. Really appreciate it. And congrats on hitting the milestone, Elevation team.
spk07: Thank you, Savannah. Appreciate it, as always.
spk03: I'm showing no further questions at this time. I would now like to turn it back to Joseph Farah, Chief Executive Officer of Elevation Oncology, for closing remarks.
spk07: Thank you, operator, and thank you all for joining us. We appreciate your interest in and your ongoing support of Elevation Oncology and certainly look forward to providing additional updates as we move 3021 forward in the clinic and continue to help make a better difference for patients with better outcomes. Have a good day.
spk03: Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.
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