Thank you for standing by. This is the webcast operator. Welcome to the Repare Therapeutics Investor Update, focused on its lunresertib MYTHIC clinical trial. Please note that this webcast is being recorded. All participants will be in a listen-only mode. Should you need assistance, please signal a conference specialist by pressing Star, then zero. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press Star, then one on a touchtone phone. To withdraw your question, please press Star then two. I would now like to turn the webcast over to Steve Forte, Executive Vice President and Chief Financial Officer. Steve, please go ahead. Good evening, and thank you for joining us today to discuss the positive initial data from our MYTHIC clinical trial. Before we begin, I invite you to visit the Investors section of our website to view the webcast slides and today's press release on our ongoing MYTHIC trial. Today's presentation will begin with introductory comments by our President and CEO, Lloyd Segal. We are pleased to welcome Dr. Timothy Yap of the University of Texas MD Anderson Cancer Center, the principal investigator on the MYTHIC trial, who will review data presented earlier today at ENA, highlighting initial data from our ongoing MYTHIC clinical trial. Dr. Maria Koehler, our Chief Medical Officer, will provide insights on our clinical results to date, the conclusions we have drawn from this data, and will discuss next steps. Our CEO, Lloyd Segal, will conclude the presentation with a discussion on upcoming catalysts. Today's presenters, Lloyd, Maria, Dr. Yap, as well as Mike Zinda, our CSO, and myself, will be available for Q&A after the prepared remarks. Due to time constraints and to ensure equitable participation, we would kindly ask that you limit yourselves to one question and one follow-up. Before we dive into our MYTHIC update, I'd like to remind you that we'll be making forward-looking statements during the call. Various remarks that we make during this call about the company's future expectations, plans, and prospects can constitute forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. Forward-looking statements are based upon our current expectations and various assumptions and are subject to the usual risks and uncertainties associated with companies in our industry and stage of development. There are a number of reasons why our results may differ materially from these forward-looking statements, and we refer you to our latest SEC filings, where you can find a more detailed discussion of these risks and uncertainties. In addition, any forward-looking statements represent our views as of today and should not be relied upon as representing our views as of any subsequent date. While we may elect to update these forward-looking statements in the future, we specifically disclaim any obligation to do so, even if our views change. As a reminder, a recording of today's event will be made available on our website later today. I will now turn the call over to Lloyd. Thanks, Steve, and welcome to our call. Repare is a clinical-stage oncology company dedicated to delivering next-generation precision oncology medicines to the patients that need them. We're forging ahead with a deep and differentiated clinical stage pipeline using our proprietary SNIPRx and STEP2 platform, applying our advanced understanding of synthetic lethality, ENA damage repair mechanisms, and genome instability to drive our pipeline, the strength of which we have further validated with today's data. This evening's focus is to discuss lunresertib and, more specifically, our lunresertib/camonsertib combination data. Today's headline is that we believe we have established that lunresertib works and could present an impactful new precision oncology opportunity with this combination. We had the pleasure to report early top-line monotherapy data for this program last June. Earlier today, Dr. Yap presented positive and compelling initial data on this combination at the ENA conference. This call provides an opportunity to further expand on those exciting new data. I'll start here with a summary on lunresertib, a first-in-class oral small molecule PKMYT1 inhibitor discovered from our SNIPRx platform. We achieved compelling early antitumor activity that we would not have expected from either agent alone. In gynecological cancers, we saw a 50% RECIST response in the lunresertib plus camonsertib combination in 10 patients at the preliminary RP2D. We will use the next few quarters to validate this signal and craft a clinical path forward, which we expect is now in line of sight. The combination demonstrated proof of concept antitumor efficacy signals across multiple tumor types and all enrolled genotypes, which allowed us to continue to aggressively explore opportunities across those multiple tumor types in the ongoing trial beyond the obvious early opportunity in gynecological tumors. These results validated our preclinical synergy hypothesis and patient selection approach, nicely demonstrating the strength of our proprietary SNIPRx STEP2 platform. Our predicted PKMYT1 inhibitor sensitizing genes for enrollment have substantially validated, and I'll discuss the significantly expanded patient populations we can address, both in terms of better understanding these addressable patient population opportunities and validating our SNIPRx and STEP2 approach. Today's data demonstrated a highly encouraging safety and tolerability profile, with grade 3 anemia as the tolerability AE, and we'll discuss why we believe this well-understood phenomenon can be well managed as we advance the MYTHIC trial at our preliminary RP2D, and Maria has a couple of new figures to share with you on that today. MYTHIC set out to include only patients with tumors harboring three specific genetic alterations our step two platform predicted for susceptibility to PKMYT1 inhibition, notably Cyclin E1, FBXW7, and PPP2R1A. These alterations, as you can see here, are highly prevalent across a large number of tumor types with high unmet medical need. We estimate that there are approximately 90,000 patients annually across all tumor types and 65,000 in top tumors that could potentially benefit from this combination. Notably, FBXW7 and PPP2R1A significantly expand patients in the relevant patient population beyond Cyclin E1, which had some precedent in the field, and these alterations are largely mutually exclusive. As excited as we are about the validation of our expanded precision oncology approach, this chart nicely captures the off-the-radar opportunity we're now positioned to capture with FBXW7 and PPP2R1A altered tumors, where we have a compelling early signal today and are not aware of any competitors in this sizable precision oncology population. Take note that there is virtually no overlap in target patient populations between our lunresertib sensitizing genes and our previously published chemosensitive sensitizing genes. If we look at the gynecological opportunities noted here, this is a completely incremental population to what we've explored with chemosensitive in TRESR and ATTACC, and the same applies throughout. With that, I would like to introduce Dr. Timothy Yap of MD Anderson, our distinguished guest and principal investigator on the MYTHIC trial, who's here with us this evening to share the MYTHIC data that he presented earlier at ENA today. Dr. Yap, thank you for joining us this evening. Thanks very much, Lloyd. Before I begin, I'd like to quickly call your attention to my disclosures. Thank you very much. So CCNE1 amplification leads to cyclin E overexpression, which drives premature S phase cell cycle entry and overloads the DNA replication machinery, increasing replication stress, resulting in genome instability and eventual tumorigenesis. Importantly, there are no currently approved drugs for the treatment of patients with CCNE1 amplified tumors, representing a critical area of unmet need in the clinic. In order to identify synthetic lethal partners for CCNE1 amplified tumors, Durocher's group and Repare conducted a genome-wide CRISPR-Cas9 dropout screen and found that the loss of the serine threonine kinase PKMYT1 is synthetic lethal to cyclin E overexpression cells and the highest-scoring druggable hit. To target CCNE1 amplified cancers, Repare Therapeutics then developed lunresertib, a potent and oral first-in-class PKMYT1 inhibitor. To expand the patient population and find additional alterations, where PKMYT1 is essential, loss-of-function chemogenomic screens were then conducted. These screens identified that in addition to CCNE1 amplification, loss-of-function alterations in the tumor suppressors FBXW7 and PPP2R1A are indeed synthetic lethal when PKMYT1 inhibition. Again, similar to CCNE1, there are no currently approved drugs for the treatment of patients with FBXW7 or PPP2R1A mutated tumors, truly representing an unmet need in the clinic. CCNE1 amplification leads to cyclin E overexpression, which drives premature S phase cell cycle entry and overloads the DNA machinery, resulting in genome instability and tumorigenesis. If you can look at the actual profile, you can see that lunresertib is highly potent and selective inhibitor. If you look at the table, it has enzyme potency in the low nanomolar range. It is highly selective, with greater than 100-fold selectivity for PKMYT1 over WEE1. It has no hERG activity. It has a favorable preclinical PK profile and no potential for clinical drug-drug interactions. These are the preclinical data showing the xenograft growth inhibition across different doses, as shown in the graphs on the right, on the left-hand side, and across different schedules, as shown on the right. You'll see that there are similar anti-tumor activity between both continuous and intermittent dosing, and this is important in terms of informing the clinic with regards to the schedules to pursue. In order to actually enhance and to, increase the patient population by enhancing the anti-tumor activity-... Rational combinations with lunresertib were also explored, including the ATR inhibitor camonsertib. The whole thinking and rationale behind this is that lunresertib sensitizing alterations such as CCNE1 amplification, as well as inactivating mutations of FBXW7 and PPP2R1A, essentially drive replication stress, activating ATR, and through a CHEK1-mediated inhibition of CDC25, leads to inaccess of CDK1. It certainly makes sense to combine an ATR inhibitor, such as camonsertib, as shown in the figure on the right, together with a PKMYT1 inhibitor lunresertib, which will enhance the CDK1 activation, drive cells into premature mitosis, and ultimately catastrophic DNA damage. These are the combination data showing that this treatment is active in CCNE1 amplified ovarian cancer CDX models, as shown on the left, and FBXW7 knockout colorectal cancer models shown on the right, showing regression. Importantly, the combination treatment was found to drive tumor regressions at sub-efficacy single-agent doses. Next slide. With that strong preclinical rationale and data, we then proceeded to first-in-human phase 1 trial of the first-in-class PKMYT1 inhibitor lunresertib, and we initiated the trial assessing single-agent lunresertib in April 2021. Inclusion criteria included patients who were at least 12 years of age with advanced solid tumors who are resistant or intolerant to standard therapy. Tumors were mandated to have CCNE1 amplification, deleterious FBXW7, or PPP2R1A alterations, and these alterations were all confirmed centrally using the Precision Oncology Decision Support Group at MD Anderson. All patients were required to have an ECOG performance status of 0-2 and acceptable organ function, including a hemoglobin level of at least nine grams per deciliter. Primary endpoints were pretty standard for a phase 1 trial, including safety, tolerability, and establishment of the recommended phase 2 dose and schedule. Other endpoints included PK/PD and paired tumor biopsies, preliminary anti-tumor activity, and ctDNA kinetics. These are the patient demographics. You'll see that there were similar patient characteristics in monotherapy and combination therapy cohorts. We enrolled more patients who are female than male because of the types of cancers enrolled. The median age was 60 and 65, respectively. All patients had an ECOG performance status of zero to one, apart from one patient. You'll see that this was an extremely heavily pre-treated patient population, with the majority of patients receiving at least 3-4 prior lines of therapy, and the majority of patients receiving prior platinum chemotherapy. The most common tumor types included endometrial, colorectal, and ovarian cancer, and the most common genotypes included CCNE1 amplification and FBXW7 mutations, followed by PPP2R1A mutations. Co-mutations in these alterations was not common. You'll see that during dose escalation, we tested multiple doses and schedules of lunresertib using an adaptive Bayesian design. We started off with QD dosing, exploring a dose of 5 mg as a starting dose, up to the highest dose of 600 mg, given once a day continuously. Once the half-life of the drug was known, we then explored BID dosing, looking at doses of 60 mg and 80 mg BID, given continuously. Importantly, preclinical efficacy models then showed that both continuous and intermittent schedules of lunresertib showed similar activity. Because of that, we then pivoted to an intermittent weekly schedule, looking at 60 mg to 140 mg BID, given intermittently. The main DLT during this dose escalation was transient reversible rash, and this intermittent weekly schedule minimized this rash that was observed. The exposures with and without food were similar at this preliminary recommended Phase 2 dose range of 80-100 mg BID, given intermittently. These are the treatment-related adverse events. You'll see that we observed limited and reversible low-grade toxicity with monotherapy, and this is certainly encouraging as we think about combination strategies. We observed infrequent Grade 3 toxicities and certainly no reported Grade 4 treatment-related AEs across all doses evaluated. At the preliminary recommended Phase 2 dose range, there was encouraging tolerability, with only 15% of patients requiring dose reductions. The transient rash improves as early as 48 hours with supportive care or lunresertib drug interruption.... These are the PK data showing target PK exposures were indeed achieved with lunresertib monotherapy. You can see that the PK was linear up to daily doses of 160 mg to 240 mg, and the half-life of lunresertib was approximately 9 hours. PK exposures were similar between the QD schedule, as shown on the left, and BID schedules, as shown on the right, and importantly, exceeded the target exposures for inhibition of phospho-CDK1. These are the pharmacodynamic activity, as shown in paired biopsies, demonstrating the lunresertib monotherapy mechanism of action confirmed in paired biopsies. As shown on the left, from data from 17 paired biopsies taken at pretreatment and on treatment, you'll see direct target inhibition by IHC of phospho-CDK1 at threonine 14 of greater than -50%. On the right-hand side, you'll see pretreatment and on-treatment paired biopsies from 25 patients, confirming induction of γH2AX of greater than 2-fold, showing induction of DNA damage. During dose escalation, we observed 1 RECIST responder with lunresertib monotherapy. This was a 73-year-old female with metastatic recurrent uterine carcinosarcoma, with inactivating FBXW7 and PPP2R1A mutations. She was heavily pretreated with 3 prior lines of therapy, and you'll see that she achieved a confirmed partial response by RECIST criteria, with a decrease of greater than 40% of her target lesions, and the patient was on trial for greater than 8 months. Apart from this patient, 7 other patients had tumor shrinkage, not amounting to a RECIST response, and 2 patients had a PFS of greater than 6 and 14 months, respectively. Now pivoting to the combination of lunresertib with camonsertib, to date, we've treated a total of 59 patients. During dose escalation, we combined the dose of camonsertib of 80 milligrams QD, given intermittently on 3 days on, 4 days off schedule. We increased, we combined that with escalating doses of lunresertib, looking at 40 mg BID continuously, going up to 120 mg QD continuously. We then pivoted to an intermittent 3 days on, 4 days off schedule, and escalated from 60 mg to 80 mg, and also explored a dose of 240 mg QD. We then established a preliminary recommended phase 2 dose at 80 mg QD, given on a 3 days on, 4 days off schedule of camonsertib, and 80 mg BID of lunresertib given on a 3 days on, 4 days off schedule. This was based on not just toxicity and safety, but also PK, PD, and strong efficacy. These are the treatment-related adverse events. You'll see that at the preliminary recommended phase 2 dose, there were no grade 4 treatment-related AEs. As you can see from the table, anemia was the most common treatment-related AEs, and as you know, anemia is a well-recognized class effect of ATR inhibitors. Interestingly, the dose of camonsertib in this combination is approximately 50% lower than the monotherapy recommended phase 2 dose of camonsertib. Therefore, we strongly believe that this is likely to be due to the synergistic interactions between both lunresertib and camonsertib. On the trial, we saw two patterns of anemia, one that occurred and was detected early at less than 6 weeks, and this was really observed in patients with high-risk features such as, for example, preexisting anemia and also patients with multiple lines of prior therapies. The second pattern was late anemia occurring at greater than 6 weeks on trial. Now, importantly, the anemia did not lead to discontinuations in patients and usually improved with a 1-week drug hold. We did observe low-grade nausea and vomiting, but this was alleviated once we started to dose patients, with food with the trial drugs. Other toxicities were mainly low grade, grade 1-2, and included fatigue, rash, leukopenia, neutropenia, and headaches. These are the PD data, and you can see on the right-hand side that more tumors had a greater than 50% reduction in phospho-CDK1 at threonine 14 with the combination versus the monotherapy PD, as shown on the left-hand side. These are the efficacy data. You'll see that we observed responses to the combination across different tumor types, including endometrial, ovarian, cervical, colorectal, bile duct, and breast cancers. We also saw these responses across the three different lunresertib sensitizing alterations, including CCNE1, FBXW7, and PPP2R1A. In total, we had 14 patients who responded. There were eight confirmed partial responses by RECIST criteria. Three patients had unconfirmed PRs. One of them is still on trial at approximately 11 weeks, so it's still early, and the patient has not had a confirmatory scan, although she's already had a -44% in reduction in her target lesions. Three patients had GCIG CA-125 responses. All three patients are still on treatment, and two of these patients have already had reductions in the target lesions. You'll see that the best percentage change in the target lesions for baseline was deep, up to -100%. The responses are durable. We can see that multiple patients still continue on treatment. And again, we shouldn't forget that these are heavily pretreated patients, up to 9 prior lines of treatment, including chemotherapy. And all of these patients, bar one, had received prior platinum. This is a waterfall plot including all patients who are evaluable across all tumors and all doses. The overall response was 23.6%, the clinical benefit rate was 41%, molecular response rate was 50%, and at the preliminary recommended phase 2 dose across all tumors, the overall response was 33.3% and the clinical benefit rate was 50%. Most patients with gynecological cancers, so those with ovarian, endometrial, and cervical cancers, had tumor reductions with this combination. As you can see from the waterfall plot on the left-hand side, there were meaningful tumor reductions, and as shown in the swimmer plot on the right-hand side, durable clinical benefit that was observed in these very heavily pretreated gynecological cancers. Across all doses in 26 patients, the overall response was 38.5%, the RECIST response was 26.9%, and the clinical benefit rate was 57.7%, and out of 10 patients, the molecular response rate was 80%. Now, at the preliminary recommended phase 2 dose, we have treated a total of 10 patients to date. The overall response was 60%, RECIST response was 50%, and the clinical benefit rate was 70%. And again, these patients are heavily pretreated with a median of three prior lines of therapy, up to nine prior lines of therapy. Treatment is currently ongoing in 11 patients, and enrollment is currently ongoing in the expansion cohorts at the recommended phase 2 dose. These are the waterfall plots showing meaningful tumor reductions across lung resistive sensitizing alterations. The CCNE1 amplification shown on the left in dark blue, FBXW7 alterations in green in the middle, and PPP2R1A mutations are shown on the right in light blue. The overall response across all genotypes were as follows: 33.3% in CCNE1 amplified tumors, 17% in FBXW7 mutations, 21% in PPP2R1A mutations. The clinical benefit rate was promising across these genotypes: 44% in CCNE1 amplified tumors, 35% in the FBXW7 mutations, and 50% in PPP2R1A mutations. These are the swim plots showing clinical benefit across patients. Again, CCNE1 amplified tumors in dark blue at the top, FBXW7 mutations in the middle in green, and PPP2R1A mutations in light blue at the bottom. You can see that treatment is currently still going in multiple patients, in 16 patients, and currently, efficacy and tolerability assessments continue to optimize the recommended phase 2 dose in tumor and alteration-selected expansions. There were significantly higher molecular responses, which indicate the benefit of combination treatment, with the molecular response rate, for example, in the combination therapy on the right-hand side, was significantly higher than with monotherapy, and this was statistically significant, with a p-value of 0.003. I'd now like to end by discussing three patients who responded. The first one is a 63-year-old patient with recurrent colorectal cancer, who had an inactivating FBXW7 mutation. This is a heavily pretreated cancer patient with three prior lines of therapy. You can see that the patient achieved a confirmed partial response by RECIST criteria and a 43% reduction in target lesions. The patient was on trial for approximately 27.6 weeks. You can see some nice TD data there, with a reduction in phospho-CDK1 at threonine 14, an induction of γH2AX, but with the on-treatment biopsy versus pretreatment at baseline. You can also see that the patient had clearance of her ctDNA on treatment. This is the second patient, a 56-year-old patient with high-grade serous ovarian cancer with a CCNE1 amplification. Two prior lines of therapy. The patient achieved a confirmed partial response by RECIST criteria, with a reduction of her target lesions by 70%, -70%. Therapy is currently ongoing for greater than 21 weeks. The patient also achieved a GCIG CA-125 response and had clearance of her ctDNA. The final patient is a 66-year-old female with recurrent cervical carcinoma sarcoma, who had an inactivating PPP2R1A mutation. Patient achieved a confirmed partial response by RECIST criteria, and RECIST target lesion decreased by -44%. Therapy is currently ongoing in this patient at 11 weeks, and the patient had a GCIG CA-125 response as well. In summary, these initial safety, tolerability, and efficacy data are very promising. The clinical activity, coupled with the manageable safety profile, introduces the potential of lunresertib in combination with camonsertib as a new therapeutic option. I look forward to continuing to work with Repare to advance the development of this very promising and exciting combination therapy. I'd now like to turn the call over to Dr. Koehler, Dr. Maria Koehler of Repare. Thank you, Dr. Yap. As Dr. Yap just presented, our ongoing clinical trial, MYTHIC, yielded very positive and very satisfying data of two oral agents and showed significant synergy. This innovation is meaningful for patients, with roughly 30% of them responding in our phase 1 trial. Ideally, we would like to bring this innovation to earlier disease, though by necessity, we are starting with the heavily pretreated patients in a phase one study. Despite being a late stage and heavily pretreated population, these results, to me, are really, sign me up for this trial type. Here I am, presenting a key finding from MYTHIC trial monotherapy and our camonsertib combination. We evaluated lunresertib as monotherapy in 67 patients in dose escalation and schedule testing trial, and proposed a recommended dose range of 80-100 mg twice daily, given intermittently. As you saw, while this was a very well-tolerated drug, the antitumor activity, as monotherapy, was insufficient for monotherapy development. This was, however, an easy decision as we generated data in combination with lunresertib, based on the elegant preclinical evaluation that documented synergy resulting in tumor shrinkage and intermittent doses with camonsertib. This combination was tested in clinic in 59 patients and was proven to be safe and well tolerated. We were very pleased with this promising antitumor activity across several tumors and all lunresertib sensitizing genomic alterations. There were 55 or 59 enrolled patients that were evaluable for efficacy, thus having at least one scan, and the overall response by protocol across all doses and tumors was 23.6%, with clinical benefit rate of about 42%. Importantly, across this all tumors and all doses tested. When we look at the right dose at preliminary RP2D, overall response rose to 33% and more than half of these patients stayed on study for more than four months, and several had tumor shrinkage. Half of these patients had gynecological malignancies, and in those, the response rate was 38%, and further, at the preliminary RP2D, in 10 patients, the RECIST response was 50%. We cannot wait for more patients and the maturity of the data in the ongoing patients as we continue to enroll at the established preliminary RP2D. I will talk about these patients in more details later. Here are few additional items that I believe are important to keep in mind. First, a reminder that this is a phase 1 dose-finding study. We've put a lot of work into getting our preliminary RP2D, which is a critical in this type of drugs, and we are in the process of optimizing further. So far, we have only 18 patients at the preliminary RP2D range, and I will show you why it is critical. Anemia is the only element left for us to optimize around these efforts, and the efforts are ongoing. We have significant experience and clear understanding of what to do, and there is a range of simple solutions to deploy for the benefit of patients to manage it. As we have shown, gynecological tumors were our largest trial population and shown the strongest signal so far. We are delighted with the results in gynecological cancers. Remember that this is practically a fifth-line population, and the recent paper by Kessous has shown that the expected response rate to standard of care chemotherapy in this population would be about 15%-16%. Our results show massive opportunity for this chemotherapy-free combination in earlier stages of gynecological cancers. We look forward to increasing the number of patients and our refined dose and schedule with an aim to build on what we achieved so far. We are not stopping at gynecological cancers. We are highly interested in multiple other tumors and where we are beginning to see numerous opportunities to present themselves, and nothing yet is off the table. This slide shows why we focus so much on the dose and schedule optimization in our phase 1 study. The impact of the RP2D we are beginning to see is profound. While this is an ongoing study and the patient's numbers are smaller so far, we do see an obvious trend for better results in the RP2D column in every parameter examined. We still consider this a preliminary RP2D, and we are still optimizing the way how to give the two compounds together. We obviously enrolled the patients at our preliminary RP2D. What I would like to tell you is that as of September 5th cutoff, since then, we had 18 evaluable patients, and 10 of them had gynecological malignancies. We are continuing to enroll at this dose. On the next slide, you see our understanding of anemia. As you know, we recorded 40% of Grade 3 anemia. While this is the only tolerability issue, we definitely need to decrease this number. Here is a detailed data that support our conclusion regarding anemia and our optimism that the anemia can be alleviated with the learning, and how to do it. On the left foremost chart on this slide, you can see that a substantial subset of patients, specifically more than 35%, did not develop anemia during this study. They are presented as green boxes in the chart. And this is true even for patients who received more than 7 cycles, and this is all across all doses and are truly reassuring. Then there is a group in the middle who developed anemia on the top panel in the middle, and you can see the Grade 3 in the red, in the red boxes. This is about 22% of these patients who developed this type of anemia. This is early anemia, frequently recurrent on multiple evaluations. These patients, however, frequently have pre-existing anemia already of Grade 2 that was actually allowed by our entry criteria. The consequence of the exhausted marrow is repeated anemia and the signal to physicians to intervene to modify the dose in these patients. We are now testing how to help those patients. On the right of the slide, you can see another pattern. Those patients rarely have anemia on entry, and tolerate the combination, but occasionally develop anemia later. This is less significant for patients, requires less support, and we have a solution that can modify the anemia with treatment modification on demand. This is likely the true pattern of the drug-induced changes that we are expecting to observe in a later stage trial, where the patients are not so heavily pretreated and do not have pre-existing anemia. Important for this analysis is that the same pattern we observed on the lower part of this slide, where we are analyzing the Grade 2 anemia, which strengthens the conclusion. What is critical to remember is that this is an ongoing study, and we are learning from every patient. We have clear understanding of the anemia and how to alleviate it. On... Gynecological cancers are our early focus, as we have the best data in this cohort, and it is our largest cohort. You saw the data in Dr. Yap's presentation. This is the introduction of the first-in-class agent, a new target with an ATR inhibitor, a result of excellent science we are creating, rationalizing the synergy. This is a chemotherapy-free combination, something that patients really want. What we are showing here is that if the patient has a recurrent cancer, this is an appealing option. 30% of these tumors respond overall at all doses. Now we have the RP2D, and the benefit is even clearer. The responses are higher. The data is emerging very fast. Compare the data from June to September, and we since then had four confirmed responses in the last four weeks, five weeks. The molecular response rate is 80%. This is a known predictive antitumor activity measure. This is a highly competitive space, but these are differentiated data. Remember, all patients had platinum. Those eligible for PARP got it. Many received bevacizumab. Interestingly, all patients with endometrial cancer had previous checkpoint inhibitors. We plan to quickly enroll additional patients and move to next steps with our trials. This slide addresses our focus on investigating tumors beyond gynecological malignancies. Here you can see that this is a small set across all doses, and among those patients, we had 11 different tumors. Each of the tumors was represented by 1-3 patients, a very small number to declare any conclusions regarding efficacy in any other tumor. However, there are patients here, like patients with gastric cancer or non-small cell lung cancer, who were on trial for more than 10 months, which is very unusual for this type of diseases. We also had 2 responders in breast cancer and cholangiocarcinoma. These are all small signals of clear interest, including in this specific alterations. Notice on the bottom of the slide, we had 13 patients throughout this trial with colorectal cancer. We are keenly interested in this tumor, as 12-15 patients of those tumors had FBXW7 alterations. Of these 13 patients, only 4 were at RP2D. We observed one patient with confirmed PR, and a few others remained on study for a long period of time. We all know that patients with colorectal cancer, recurrent colorectal cancer, do not tend to shrink tumors easily. For recurrent colorectal cancer, response to multimodal chemotherapy is in the range of about 10%. And what is important for these patients is that we are delaying the progression. This seems to be very promising, but we need more patients at RP2D to have a firm opinion. In short, beyond gynecological malignancies, where we have most of the data, there are a number of very interesting additional patterns that are starting to emerge, and we believe with more patients selected with the right genomic alteration, we may find additional promising early signals, similarly to what we find in gynecological malignancies. Here is the evolving broad trial program, based on the data and a significant oncology community interest in this oral combination. In addition to the ongoing trials, with various combinations and some of the cooperative groups, our Repare trials now are ongoing all at RP2D, and we are in late stages discussions with both cooperative groups and individual investigators on additional trials. These additional data gathered from these trials have a goal to signal confirmation and further discussion regarding later-stage trials. We will definitely focus our options carefully to open the late-stage trials. Our immediate goal of expansion of module two of the combination is to confirm the RP2D, decrease the frequency of anemia, and get larger N, in our small number of patients, in our small number of tumors of immediate interest. This process will be fast and should only take us a couple of quarters. Ultimately, this should enable us to bring the combination to a broad set of patients globally. We are focusing on the fastest, most efficient, and the best decision for definitive trial, among all the options. Here is the most important and exciting takeaways based on this data. Lunresertib works. We validated lunresertib mechanism of action and our SNIPRx preclinical patient selection approach. It's satisfying to be able to validate it in the clinic, and show what we expected, and show that it meaningfully helps patients. Safety, tolerability, early efficacy have all been confirmed for the combination with camonsertib. We have shown the importance and strength of thorough dose and schedule work, with 50% recent response rate in gynecological cancers at the preliminary RP2D. This is an extraordinary result in an early readout from an ongoing phase I study, and not only are we very excited about it, we believe that there are other tumors with similar high opportunities may present themselves as we enroll more patients. I would like to now ask Lloyd to conclude. As we gained clear understanding of anemia, which will facilitate patient-friendly and simple management, we believe we can bring down the grade 3 anemia rate significantly and expect to provide an update in 2024. We now expanded MYTHIC trial to evaluate combination therapy in patients with select tumor types and genomic alterations. Our goal is to increase the number of patients at preliminary RP2D in these subsets, and record and report additional data in second part of 2024. This would be sufficient to direct late-stage trial decisions. The 50% recent response rate in gynecological cancer would, in fact, already have an emerging line of sight for late-stage trial. And all this is generating excitement with the oncology and patient communities, who are taking high interest in the emerging data. We believe this will help accelerate the extension of lunresertib as the development as MYTHIC moves ahead. I now would like to turn it back over to Lloyd. Thank you. As Maria and Dr. Yap have highlighted, our ongoing phase 1 lunresertib plus camonsertib combination has unlocked compelling safety, proof of concept, and clear early efficacy signals. We are aggressively accelerating development of this combination into signal-seeking expansion cohorts across key tumor and genotypes, with clear line of sight into later-stage trials, including, and we believe, beyond the clearest early signal in gynecological tumors. These exciting plans for our lunresertib franchise, as well as new emerging clinical opportunities, continue to fill out the depth and breadth of our portfolio. We reiterate previous guidance for milestones for the remainder of 2023, and look forward to an investor event in the coming weeks to unveil two new clinical programs: RP-1664, where we will share the details on this exciting new target, our new compound, and our clinical entry expected in very early 2024. RP-3467, our novel Polθ inhibitor, which we aim to bring into the clinic in the second half of 2024. Next year, we aim to report data across all ongoing lunresertib trials, including fulvestrant, gemcitabine, and the results of the expansions Maria just described in our ongoing MYTHIC trial. This concludes our prepared remarks. I'd like to now open the floor to Q&A. Operator? We will now begin the question-and-answer session. To ask a question, you may press star, then one on your touchtone phone. If you're using a speakerphone, please pick up your handset before pressing the keys. If at any time your question has been addressed and you would like to withdraw your question, please press star then two. In the interest of time, please limit yourself to one question and one follow-up. At this time, we will pause momentarily to assemble our roster. Our first question comes from Jeff Hung with Morgan Stanley. Please go ahead. Thanks for taking my questions. For Dr. Yap, can you just talk about how you and other clinicians think about RECIST response rates versus the protocol-defined overall response that includes the CA-125 responses when you're considering treatments for patients? And then I have a follow-up. Yeah, thanks very much for that question. So, you know, GCIG CA-125 responses, you know, are recognized as, you know, a key indicator of patient benefit. If we actually go back to, you know, the olaparib palbociclib trials that, you know, we published in the past, certainly, GCIG CA-125 responders are certainly considered within, you know, the antitumor response data. So I certainly think it's a valid endpoint, and it was certainly clearly defined prospectively in the protocol that we actually use for the lunresertib trial. So, I certainly think a GCIG CA-125 response is indeed meaningful. Jeff, you said you had a follow-up? Yeah. And then I guess for management, you kind of touched upon this, but are you surprised that colorectal didn't generate as meaningful tumor reductions as the other tumor types? And what might be the biologic hypothesis behind that? Thanks. I'll let Maria expand on it, but you know, she did note just the sheer low number of patients. We had such a preponderance of gynecological tumors, just that's what's with colorectal. Yeah. So we had thirteen patients with colorectal cancer, of whom it happened so that were the initial patients who were enrolled at low doses. So it's very hard to say really what the effect is. We had four patients out of those 13 that were enrolled as RP2D. In addition, we know that patients with colorectal cancer do not tend to tumor shrink, so the recent responses in these patients to standard chemotherapy is in the range of 10%. So it's very difficult to take a percent in these patients, and this is definitely one of the tumors where we are going to enroll more patients as RP2D to figure out the response rate. Great. Thank you. Our next question comes from- Next question. Our next question comes from Chris Shibutani with Goldman Sachs. Please go ahead. Hi, everyone. This is Charlie on for Chris. Thank you for taking our questions. I have a question about the continued dose optimization for the lunresertib combo. You're looking at weekly versus potentially two weeks on, one week off. I'm just wondering, is that one week off potentially going to be applicable for both lunresertib and camonsertib? I'm just wondering, considering the clean safety profile for lunresertib monotherapy, whether there's an opportunity to leave patients on lunresertib monotherapy for that week when maybe they take a break from camonsertib. That is exactly what we are doing, which means we are continuing the lunresertib throughout and possibly eliminating for a week the dose of ATR. However, the key of our approach is to individualize the dosing, because as you saw, some patients just don't have anemia. So it's more about—it's not necessarily, and I, I, you know, it's, it's not a nice thing to say, but it's not always about the drug, it is also whom you are giving the drug. Because if you, if we are giving the drug to a patient who has already anemia in, you know, or was just transfused before and has previous four therapies and is older, the probability of developing anemia in the phase one study is very, very high. And this is what we are calling the high-risk patients. Basically, whatever you do to these patients, you will always get anemia. So we are trying the approach to individualize the care, and we are hoping that we will not see patients with very much beaten-up marrow in our trials, where you are planning to go to second or maximum third-line trials eventually. So this problem will hopefully solve itself with a better patient population. Okay, got it. Thank you very much, and if I could just sneak in a quick follow-up. On the FBXW7 cohort- Yeah. Just wondering, you know, it looks like maybe that population has a bit more variability in the responses that you see, and just wondering, what did that population look like at the recommended phase 2 dose range? Well, that's a sort of I sort of explained it because the population of the FBXW7 contains at least, I don't know, six patients with colorectal cancer that was treated at low doses. And I do not know-- You know, we totally have 18 patients, of whom 10 has gynecological malignancies, so I don't feel comfortable talking about specific subsets at the dose. But we do not believe that there is a problem with the FBXW7. Actually, we believe that this is an outstanding population to test. Okay, great. That's very helpful. Thank you very much for taking our questions. Our next question comes from Marc Frahm with Cowen. Please go ahead. Hi, thanks for taking my questions. Maybe to start on the efficacy side, you know, pretty encouraging from a response rate, basic, you know, signal in gynecological cancers, you know, even at that recommended phase two dose. Can you speak to the kind of relative efficacy within the individual tumor types, you know, ovarian, endometrial, and is there any rationale for it to be potentially more or less effective in, in specific, any, you know, gynecological cancers? So we had the gynecological cancers. You see, there was a slide with the responses, which I can show. It's slide 26. Maybe we can show it. I don't know whether this will... Yeah. So as you can see here, we see responses in endometrial and ovarian cancer. All the responses with ovarian cancers are still ongoing, and the endometrial cancer, we have two patients ongoing. So these, and we only had actually one patient with cervical cancer who was enrolled in the study, and the patient happened to respond. So does it mean that there is response rate 100% in cervical? I cannot really say it. I, you know, because we only had 10 patients with RP2D in gynecological malignancies, I don't feel comfortable, and I don't think that anybody should do it, to call percentage out of 5 patients or 8 patients or whatever. The other important note is on slide 28, when we are showing clearly in the shaded area that the responders in gynecological cancers are mostly at the recommended doses, which is, again, very satisfying that the dose was chosen right. I do not want to comment any further because we have only 18 patients between, I don't know, 8 tumors, who responded. Let us give you another two quarters, and we will tell you more. Okay, that's helpful. And then maybe on the anemia, just you mentioned kind of these two modes or scenarios that lead to anemia, the early onset and high risk or the later onset. And maybe this is for Dr. Yap as well. Do you see any kind of difference in the responsiveness of those patients to your interventions, either kind of trying to adjust on the fly or, you know, as you started to kind of refine the dose up front, you know? I can tell you that there is no difference, but I would like him to add something about, you know, how the patients start, and it's just serendipity how the patients are, you know, already anemia. I think, you know, in general, if you put a patient on who's got preexisting anemia, who's had multiple lines of therapy, multiple chemotherapy agents, they're gonna be essentially high risk of developing anemia very early on. And that was essentially what we're seeing. And that was certainly one clear group there versus the patients who did not have any treatment related anemia. And also, obviously, another group that took a much longer time to develop an anemia. But, you know, overall, it did not lead to, you know, dose modifications, and it did recover pretty swiftly. You know, I think what was nice is that we didn't actually observe any thrombocytopenia or neutropenia that was problematic. You know, anemia, in general, similar to drugs like olaparib that are approved, you know, are easy to manage overall, right? Because, you know, if you need to manage it, you give patients a drug holiday, and they usually have a good recovery from that within a few days to a week, and that was indeed what we were seeing. But again, not all patients had anemia. And, you know, it did not impact the dose in the patients ultimately, and that, to me, is the most fun thing. Okay, that's very helpful. Maria, just last thing. You mentioned, you know, with these adjustments you're making and further optimizations you're making, you really wanna try to get that rate down. Just what is kind of the goal rate there? Like, what's what... I mean, obviously, lower is always better, but you know, what's the acceptable rate in your head? You know, I think that it needs to be acceptable to the treating physicians, and I believe that it needs to be acceptable to eventual agreement with FDA that the dose is sufficiently optimized. We are not going to get rid of this anemia completely, and I do believe that anemia is a tolerability issue that we rather not have. But it is, you know, the drug needs to have some side effects, and, you know, that's the best side effect to have if you have it. I mean, it's much better than liver tox or CNS or, you know, other things. Or thrombocytopenia, neutropenia, or diarrhea, right? It's, it's- Yep. Okay. Makes sense. Thanks a lot. We have time for one more question, I think. Yeah, or two. Okay, let's... Next question. The next question comes from Joe Catanzaro with Piper Sandler. Please go ahead. Hey, everybody. Thanks for taking my questions. Maybe I'll just follow up on, on Marc's there, last question, and, and Maria, your response on, you know, what's an acceptable rate for treating physicians and directed to Dr. Yap and, you know, what's an acceptable rate of, of high-grade anemia if it's no-- comes along with no clinical consequences and you're just not really continuing drug? Thanks. You know, for me, I think, you know, we look at the first-generation PARP inhibitors and what was approved and acceptable, I guess, to patients, physicians, and the FDA. I think 20-25% is very reasonable. I think 30% even borderline. You know, ultimately to me, it's also about the response rate that you're seeing, right? And it's the therapeutic index rather than just being focused on the toxicity. It's also about how much benefit one can achieve. And as Maria was saying earlier, you know, anemia is not a difficult one to manage ultimately, right? And, you know, so anyway, to give you a number, Joe, I think maybe 25-30%. Okay. Well, thank you. That, that's helpful. And then, and then maybe my quick follow-up, I was wondering if you could elaborate on the platinum sensitivity status for, for the patients with gynecological cancers and whether they were all resistant, refractory, and then wonder if there's any evidence preclinically that platinum resistance drives some cross-resistance to the mechanism of this combination. And I guess the, you know, reference PARPs again, I guess that's what I'm thinking of, how platinum status there was, was predictive of response. Thanks. So regarding the patient population, I don't remember the numbers, but out of these gynecological malignancies, everybody was treated with platinum. However, with the resistance, majority were resistant because you cannot be sensitive to get on a phase 1 trial. That's the reality, because you have to exhaust all available therapies to even get on a phase 1 trial eligibility. The patient, in addition, had PARP inhibitors, those who, as I said, and bevacizumab and ADCs and all possible other things. These were very heavily treated patients. We do not believe that platinum has any relevance to platinum status, sensitivity status, has any relevance to the mechanism of action. Because as you remember, these are CCNE patients or FBXW7 who may or may not have lesser sensitivity. This is actually very controversial, the sensitivity to chemotherapy in these patients. So the answer is no. ... Okay, got it. Thanks for taking my question. The next question comes from Charles Zhu with Guggenheim. Please go ahead. Hi, this is Edward on for Charles. Maybe just a question on the patients with late-onset anemia over greater than 6 weeks. Is there any frequency of that type of patient? And then is there anything in the baseline characteristics or anything else that you can kind of give some incremental color on those types of patients, like you did for the under 6 weeks with the preexisting anemia? Thank you. Thank you. So if you look at these patients, in average cycle 4 or 5. There was a patient with anemia in cycle 7, and never had anemia and then got grade three anemia. Remember, there is no grade 4 anemia. It is very important to say that. Grade 3 anemia is drop in hemoglobin below 8. And for patients with advanced cancers, those patients are used to the lower level of hemoglobin, so the anemia is not grade 3 anemia, even, you know, if you have hemoglobin 7.8. Some of these patients did not require any intervention, just a break in therapy, and the anemia recovers. The problem with these patients is that they will have some toxicity eventually from continuous dosing, weekly dosing of ATR and PKMYT1 inhibitor. And I believe that if it is just that anemia, it's a very manageable and also easily recognizable side effect that you can measure with just simple CBC. Now, what we did in camonsertib trial, and this is accepted for publication and should appear, you know, any week now, we developed a nomogram how to manage anemia for those patients on camonsertib. And the nomogram is saying that the physician should evaluate anemia, reticulocytes and hemoglobin for the first two, three weeks, two, three cycles, sorry, of the therapy. And this directs them to dose modification so that this grade 3 anemia doesn't occur. So we are going to eliminate, at least in camonsertib. So we are trying to do the same observation, but it took us a lot of patients with camonsertib to observe it and to test it. So we don't have enough patients, and we only have, I mean, only 40% of these patients have anemia, so it's hard to develop nomogram with these type of numbers. But that's the plan. And it is a simple physician and patient friendly nomogram that will be predictive of the anemia so that the physician knows how to- what to do with the dose, to avoid the grade 3 anemia. Next question? The next question comes from Tim Chiang with Capital One. Please go ahead. Hi, thanks. Dr. Yap, if you're still on, I just wanted to ask you, I mean, obviously, a lot of the questions are on anemia side effects. You obviously treat a lot of patients. You know, how do you typically deal with higher incidence of anemia? Do you basically pull down the dose? And also, you know, what are your thoughts, you know, providing advice to Repare, going forward? I think it's everything that Maria's already said. You know, typically, when we do see anemia in patients, we would just simply give patients a drug holiday. That's exactly what, you know, Repare are doing, right now in terms of the optimization of the schedule that was described, you know, during the talk, in terms of introducing a drug holiday. So that's being assessed currently, in terms of the optimization of the schedule. So, you know, I guess what's exciting is that we're seeing very robust, anti-tumor activity with RECIST, multiple RECIST responses. And so now it's just about getting the... Just fixing the anemia, and we certainly think that, the schedule will make a difference. And again, what's great is that no other toxicities that were high-grade, that we're dealing, that we have to deal with, you know? So, we're certainly hoping that the dose optimization will help and, and, you know, allow this to be a drug with a wide therapeutic index. Maybe just one quick follow-up for Maria. Maria, you highlighted that, you know, you do have a rapid, or you have a subset of patients that rapidly developed anemia here. Is there any way to eliminate some of those patients as you enroll more patients? Yes, so, definitely, yes. So if you, who are the patients? So these are the patients who enter this trial with hemoglobin median of 10.7, which is already grade two anemia, and they are heavily pretreated. We are not going to do our late-stage trials in this population. So, our goal for the eventual late-stage trials is second, third line at the most. We may be even more ambitious, but those patients do tend to have a better marrow reserve. Remember, you are going here to patients who all receive carboplatin that beats up your progenitor cells for erythrocytes. So the capability of the marrow to produce red cells is very, very diminished. So those patients, if they have any other injury from a new drug, even minimal, they go down. If you have a patient who has normal marrow or efficient marrow, these patients can deal with the injury by producing more young red cells, and the anemia never happens. So these are probably the patients, the 35% of patients who never had anemia. So it's really the... Not necessarily the drug. It is the type of patients you are addressing with your drug. And we unfortunately have to test our drugs first in phase 1 study, and the toxicities in the phase 1 studies are always worse than the, or usually worse, than the toxicities in your ultimate studies. Okay, thanks. It's very helpful. Our next question comes from David Martin with Bloom Burton. Please go ahead. Thanks for taking my question. Most of them have been answered. Good. But the question I have is, you're working with two drugs that are not FDA approved. What's the regulatory path? Like, I'm used to adding a new drug to an existing drug that is approved, and that's a pretty standard path. Is there anything different about what you'll need to do given this situation? We are definitely not going to comment on our regulatory strategy, unfortunately, as you would clearly understand. But we do have a plan, so, we do have a plan. Okay. Watch this space, David, and Maria alluded a couple of times to a point next year where we can, we expect be in a position to more clearly define the path forward. I think it would be reasonable to expect at that time, we would also be willing to comment on a regulatory strategy. Yeah. Okay. And I do have one other quick follow-up question. As far as the patients coming in who have grade 2 anemia already, is there any way you can reduce those patients in the current trial, or do you have to wait until the next stage? We can by increasing the eligibility to patients who have anemia grade 1 only, but this is very unfair to patients in a phase 1 setting. Because, you know, FDA has very clearly telling us that these patients deserve new treatments. And in addition, what we can do is we can eliminate eligibility for patients who are just transfused, because some of these patients were transfused, let's say, 2 weeks ago, and therefore, the hemoglobin is 11, but it's really because they were transfused. So we are now planning to ask for patients who did not have transfusion recently, like, for example, 4 weeks, because this will tell you that the marrow is truly functional. If you are coming to a trial with a recent transfusion, then the hemoglobin value is spurious after the transfusion. We cannot, you know, the patient is eligible because the hemoglobin is 11. But really, the hemoglobin is 11 because of recent transfusion. So that these are simple things that we can do, but we can do based on our learning. So now we learned, so now we will act on it. So these are all the things that are easy to do. So you will do those, or these are things you could do? Uh, we- For this trial. We will do... We will do this. Okay, thank you. Yeah. I think just given the lateness of time, we've gone over by a bit, and it already started late on a Friday night. I just want to thank you all for great questions. Extend our heartfelt gratitude to Dr. Yap for his participation today and his leadership, clinically, in this and so much of our important work. I'd also like to thank all the patients who are so courageous, their families and physicians, investigators, and other caregivers who participate in the studies. Without them, we could not possibly be here today. I'd also like to send a really special thank you to the entire Repare team. We have an expanded group who have really taken up the leadership as our clinical efforts expanded across a wider footprint under Maria's leadership, and we could not do this without them. And we're excited about the great new people who've come on more recently to help us drive and advance our mission to be the leading precision oncology biotech focused on novel synthetic lethality medicines that meaningfully improve the lives of people living with cancers. This concludes our call. Thanks for taking the time with us this evening. The conference has now concluded. Thank you for attending today's presentation. You may all now disconnect.