Verastem, Inc. (VSTM) Earnings Call Transcript & Summary

Good afternoon, and welcome to the Verastem Oncology RAMP 201 Update Conference Call. My name is Gary, and I will be your conference operator today. As a reminder, this call is being recorded. [Operator Instructions] I would now like to turn the call over to Julissa Viana, Vice President of Corporate Communications and Investor Relations.

Thank you, Gary. Good afternoon, and thank you for joining today's conference call to discuss the mature RAMP 201 data for the investigational combination of Avutometinib plus Defactinib in recurrent low-grade serous ovarian cancer. During this call, we will also provide a regulatory update regarding our rolling NDA submission. We issued a press release earlier today on the RAMP 201 abstract presented at the IGCS, which is available on Verastem's website along with the slide presentation that we will reference on our call. Before we begin, I would like to remind you that any statements made during this call that are not historical are considered to be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these statements and as a result of the various important factors, including those discussed in the Risk Factors section of the company's most recent annual report on Form 10-K and the current report on Form 8-K filed this morning as well as other reports filed with the SEC. Any forward-looking statements represent Verastem's views as of today. On today's call, we have from Verastem's management team, Daniel Paterson, President and Chief Executive Officer, who will provide opening remarks. Dr. John Hayslip, Chief Medical Officer, who will take us through the primary analysis of the mature RAMP 201 data. Mike Crowther, Chief Commercial and Strategy Officer, will follow with a review of the market opportunity and our preparations ahead of an anticipated launch in 2025. In addition, we are joined by Dr. David O'Malley, Director and Professor Division of Genealogical Oncology at the Ohio University and the James Comprehensive Cancer Center and a RAMP 201 investigator and one of the authors of the IGCS presentation. At the end of the prepared remarks, we will open the call for Q&A where our management team and Dr. O'Malley will be available for questions. I will now turn the call over to Verastem's President and CEO, Dan Paterson. Dan?

Thank you, Julissa, and thank you all for joining this afternoon's call. John Hayslip and I say hello from Dublin, we're in Dublin attending the IGCS meeting. So if there are any technical problems, the team in Boston is ready to take in and back up for us. Today marks another significant day with meaningful progress for patients with recurrent grade serous ovarian cancer or LGSOC. It's not often that a team gets to potentially deliver a first-ever approval for a new treatment regimen in a setting where nothing has been approved before, and we're very excited about this. Earlier today, we announced updated data from our Phase II RAMP 201 clinical trial, and we presented additional data during an oral plenary session at the International Gynecologic Cancer Society Annual Meeting in Dublin. We also provided regulatory updates following our latest interactions with the FDA. We have a robust set of updates to share today, and we're pleased with the progress we've made thus far as we continue to work towards bringing the unique mechanism provided by the combination of Avutometinib and Defactinib to patients. To summarize our news today. Now with a minimum of 12 months of follow-up, the mature RAMP 201 data, evaluating the combination of Avutometinib and Defactinib in patients with recurrent LGSOC, shows durable efficacy across various measures in heavily pretreated patients. While John will walk us through the specific details of the results of the study, I want to highlight some compelling data from the study. There was an overall response rate of 31% with a 44% ORR in KRAS mutant and 17% in KRAS wild type. 82% of all patients experienced tumor shrinkage and the duration of treatment was 14.5 months across all patients, 18.3 months in KRAS mutant and 10.17 months in KRAS wild type. We also observed 12.9 months meeting PFS with 22 months in the KRAS mutant patients and 12.8 months in KRAS wild-type patients. The discontinuation rate due to adverse events of 10% was consistent with the previous updates on the data. These results are truly incredible if you consider that the majority of these patients were heavily pretreated. All had prior chemotherapy, the majority also had prior hormonal therapy with about half having received prior bevacizumab and many had received prior MEK inhibitors before entering the study. When you consider the historical trial data with other treatments, which had started around 2013, in these studies, the patients received on average 2 prior treatments, did not receive prior mex and very few received prior bev. The standard of care in recurrent LGSOC of chemotherapy hormonal therapy has historically demonstrated low response rates between 6% and 13% with a PFS below 12 months and high discontinuation rates due to toxicity. Press released earlier today, we provided a regulatory update on our rolling new drug application with the FDA. In a recent Type A meeting held with the FDA, we aligned with the agency on moving forward and completing the NDA for adult patients with recurrent KRAS-mutant LGSOC who received at least one prior systemic therapy. Based on the mature data from RAMP 201 trial, the submission also included the FRAME study, which was the first study conducted with the combination of LGSOC and is a key supportive study in our regulatory package. While we continue to believe the RAMP 201 data in patients with current KRAS wild-type LGSOC are compelling and could potentially represent a meaningful advantage over available therapy, prior studies either included very few LGSOC patients, did not stratify the KRAS status, did not measure KRAS status in all patients and/or did not look for response by KRAS status as a prespecified endpoint, making cross-trial comparisons difficult. The plan we aligned on with the FDA provides a straightforward path for this NDA and an opportunity to bring a new treatment to patients with recurrent KRAS-mutant LGSOC in mid-2025. We previously guided towards completion of the NDA by the end of the year. I'm happy to report that we're on track to complete the submission later this month. We're filing for accelerated approval and plan to request priority review. We believe that the best thing for patients with LGSOC is to make sure that this therapy is available for prescribing by their physicians as soon as possible. I want to acknowledge for a moment that we're excited about the data from RAMP 201. The team and I have had a number of opportunities to discuss the study results with world experts in the treatment of LGSOC, and what we are hearing universally is that there is enthusiasm for this new treatment option across the entire recurrent LGSOC population regardless of KRAS status. It's important to recognize that KRAS wild-type LGSOC has a worse prognosis than KRAS mutant LGSOC. This is the opposite of what we've seen in a number of other cancers. Patients with KRAS-mutant LGSOC live on average for 12 years with their disease versus only 7 years for patients with KRAS wild-type LGSOC. It's just harder to treat regardless of the treatment chosen. We believe the data are very strong and demonstrate that responses are possible in patients who have seen the majority of available treatments previously. We're committed to making the combination available to patients with KRAS wild type, including continuing to pursue a path for regulatory approval. We plan to use the Phase III confirmatory study, RAMP 301, which continues to enroll all comers and will serve as the confirmatory study for the initial indication to also provide additional data to the FDA to support a potential expansion of the regulatory indication to include KRAS wild type patients. In parallel, we look to submit the full RAMP 201 data set to the NCCN for their consideration for their guidelines, which is critically important for reimbursement in the United States. Nothing has significantly changed when you look at the market opportunity for recurrent LGSOC, as Mike will review. We continue to work hard to achieve launch readiness with the plans of being fully prepared in early 2025, with an efficiently scaled commercial model that maximize our market opportunity. With these updates in hand, we've aligned with the FDA that there's clear regulatory path forward for recurrent KRAS-mutant LGSOC based on the strength of the data set in RAMP 201 and FRAME. Both our clinical and regulatory progress under validate and position us well to deliver the first ever FDA-approved treatment specifically for recurrent KRAS-mutant LGSOC to patients in 2025 pending approval. I'd now like to turn it over to John Hayslip to take us through the primary analysis of the mature RAMP 201 data. John?

Thank you, Dan. RAMP 201 trial, a study of various Avutometinib in combination with Defactinib has enrolled over 200 women with LGSOC either recurrent or progressing after prior systemic therapy, making it one of the largest clinical studies for patients with LGSOC in the past decade. During the course of our research, we have been fortunate to meet with people like Amanda who are willing to share their experiences living with recurrent LGSOC. At just 26 years old, Amanda was faced with a rare... [Technical Difficulty]

So I think we might have lost the connection. So here to continue the conversation is Jon Pachter, our Chief Scientific Officer.

What we're saying is at just 26 years old, Amanda was faced with a rare ovarian cancer diagnosis. After initial treatment, a while later, she went on to experience a cancer recurrence. And as she shares, she was thinking not only about needing to endure treatment again, but was even concerned if there were still treatment options available. Amanda is not alone in her experience with LGSOC. In the United States, 1 to 2,000 women each year are diagnosed with recurrent LGSOC, and an estimated 6 to 8,000 women are living with recurrence. LGSOC often impacts younger women, often as young as their early 20s. And unfortunately, most patients experience recurrence despite initial treatments. The standard of care currently, which largely consists of endocrine and chemotherapies, offers low response rates and many patients discontinue these treatments due to toxicities. As there are currently no therapies specifically approved for LGSOC, treatment options are largely informed by clinical guidelines such as the NCCN guidelines that Dan mentioned earlier. An important point to remember as we discuss the RAMP 201 results, it is understood by LGSOC experts that LGSOC without any changes in the KRAS gene, that is to say KRAS wild type, is typically more challenging to control than LGSOC with the KRAS mutation. This is perhaps the most clearly seen in how the median survival estimates have varied for patients based upon tumor KRAS status. To understand why this combination offers a unique approach, we should spend a moment to review the biology of LGSOC. It's estimated that 70% of LGSOC tumors are driven by RES/MAP kinase pathway associated mutations shown on the left side of the image. Specifically, about 30% of all LGSOC cancers are KRAS mutation positive. Avutometinib acts as a RAF/MEK clamp potently inhibiting the activity of MEK while also blocking the compensatory reactivation of MEK by upstream RAF. This is important because reactivation of MEK by RAF is thought to be one of the resistance mechanisms to earlier generations of MEK-only inhibitors. [indiscernible] kinase or FAK, is at the top of a key resistance pathway activated in response to MAP kinase inhibition, a key resistance pathway to the MEK-only inhibitors. Together, the Avutometinib and Defactinib combination was designed to provide more complete blockade of the signaling that drives the growth and resistance of RAS/MAP kinase pathway dependent tumors, with the objective to deliver deeper and more durable tumor responses.

Thank you Dr. Pachter. I believe we're back from Dublin. Thank you very much. So turning now, the RAMP 201 study was a 4-part registration-directed, randomized, open-label Phase II trial to evaluate Avutometinib alone and in combination with Defactinib in patients with recurrent LGSOC. A few points to orient you to the study and the results we'll walk through today. In Part A, patient for randomized 1:1 to Avutometinib as a single medicine dosed at 4 milligrams by mouth twice weekly for 3 weeks, followed by a 1-week rest period. That's a 4-week cycle, for Avutometinib, 3.2 milligrams by mouth. And Defactinib, 200 milligrams twice daily for 4 weeks, followed by a 1-week rest period. Again, that's a 4-week treatment cycle. Randomization was stratified to achieve equal numbers of KRAS mutant KRAS wild-type patients in each regimen. After full enrollment in Part A, which was approximately 32 patients per arm, Part B was open and expand into enrollment at the same 2 doses [indiscernible] KRAS status up to an additional 72 patients. The combination treatment of Avutometinib and Defactinib were identified as the go-forward regimen for further study in Part C. Subsequently, a low dose of Avutometinib 1.6 milligrams was evaluated in combination with Defactinib the same dose, 200 milligrams twice a day to see if a lower starting dose may provide similar efficacy with less Avutometinib. The RAMP 201 study has included over 200 women with recurrent LGSOC. I'd like to take a moment to sincerely thank the patients, their families and supporters, the countless health care providers who have all joined in this tremendous collective effort. We'd like to thank Professor Susana Banerjee, the global lead principal investigator of the study, who presented some of these results earlier today at the IGCS Annual Meeting. We'd like to also thank all of the RAMP 201 investigators for their contributions. Lastly, I'd like to thank specifically Dr. O'Malley for taking time out of his busy schedule here at the IGCS meeting to join us on this call today, as RAMP 201 investigator and author in the presentation, I know he'll be able to share his extensive experience with the trial and also provide his perspective on Avutometinib and Defactinib in recurrent LGSOC. But first, let's review the key results. For the combination of Avutometinib and Defactinib, we saw an overall response rate of 31% across all the patients. Further stratifying by KRAS data, we observed 44% response rate in KRAS mutation patients and 17% in KRAS wild type. 81% of responding patients remained in response at 6 months with 87% in KRAS positive and 63% in KRAS wild type. The median progression free survival is 12.9 months for all patients, 22 months in KRAS positive and 12.8 months in KRAS wild type. As we've observed previously, Avutometinib, Defactinib combination is well tolerated, allowing for prolonged treatment and only a 10% discontinuation rate due to adverse events. I will also review the results from the lower dose combination and Avutometinib as a single agent. Patients in both of those groups have seen benefit from these approaches to treatment. However, the best response rates and the lowest rates of discontinuation due to adverse events have been seen in the 3.2 milligram combination dose of Avutometinib with Defactinib, and that is where we plant to focus our ongoing efforts. Now thinking about the results of the study, it's critical to understand the type of patients who enrolled. These patients... [Technical Difficulty]

Hi. This is Jon Pachter filling in again. These patients were, on average, among the most intensely pretreated patients that we have seen in studies of LGSOC. Late, Mike will review some historical studies in which the average typical patient may have received 2 prior lines of therapy. In this study, the average patient received 3 prior combinations of treatment. RAMP 201 did not cap the number of prior therapies and we saw patients with as many as 9 prior lines. The number of prior regimens, and what treatments make up those regimens, has continued to evolve with time compared to historical studies. The vast majority of patients on this study have received both prior platinum-based chemotherapy and endocrine therapy. Also rather uniquely compared to historical studies, over half of all patients in this study received prior bevacizumab and 22% of patients received prior MEK-only inhibitor therapy. As I said, this is a quite different study from historical studies of LGSOC and the relatively high rate of previous bevacizumab is also a key difference from what was seen in the FRAME study, the Phase I study for the combination of Avutometinib and Defactinib. Turning now to the efficacy findings. We are excited to see deepening responses from the Avutometinib and Defactinib combination compared to the data we shared in May of 2024, with ORRs improving overall and in both KRAS mutant and in KRAS wild-type subgroups. As a reminder, a confirmed response requires a 30% reduction or greater in tumor sizes and must be confirmed over multiple sets of images. The confirmed response rate by blinded independent central review was 31% for all patients with 44% response rate for patients with KRAS mutation and 17% for patients without KRAS mutation. Importantly, the responses are relevant because they're durable. The median duration of response was 31 months in all patients. At 6 months, 81% of responding patients remain in response and that rate is 87% for those with KRAS mutation and 63% for those with -- that were KRAS wild-type. At 1 year, the rate of differentiation of -- sorry, the rate of duration of response is still at 72%. In this study, the median time to response was 3.7 months, ranging from as brisk as 1.7 months to as long as 19.2 months until the formal response criteria were first fulfilled. These long-lasting responses are important for patients with recurrent LGSOC who currently often cycle through treatments that offer low rates of response and high rates of discontinuation due to toxicities. We've heard from LGSOC physicians who have seen this waterfall plot how enthusiastic they are to offer the RAMP 301 trial to patients based on these results from RAMP 201. This waterfall plot represents the individual experience of each patient enrolled to the combination at the proposed dose and schedule. A key takeaway from these results, 82% of patients treated with the Avutometinib and Defactinib combination had a reduction in their tumors, as you can see. As you can see by the colors, regardless of the mutation status of their tumor, reductions were seen across the majority of patients. While we recognize that subgroup analyses are exploratory in their nature, they're also important because they help put the results in context with other data and also might help navigate future treatment decisions in areas for additional research. In oncology, it's a common expectation that the more lines of treatment previously given, the more resistant the cancer may become. In this study, we see patients responding regardless of the number of prior therapies. But you can appreciate that patients who have received fewer previous lines of treatment showed a higher response rate. Likewise, with or without prior bevacizumab use, we see both patients -- both groups of patients responding, but those patients with no prior bevacizumab showed higher response rates. When looking at prior MEK inhibitor use, we see a 33% response rate in patients with no prior MEK inhibitor treatment compared to a 24% response rate with prior MEK inhibitors. But most importantly, across all these different subgroups, patients are responding. We plan to look further into these and other subgroup details to be shared at future medical meetings. While responses are exciting, living free of cancer progression is key. Overall, the combination achieved a median PFS of 12.9 months, which is remarkable considering the lines of previous treatment that many of these patients had received. Looking specifically at the PFS by mutation status, patients with a KRAS mutation had a median PFS of 22 months, approaching 2 years. And for KRAS wild-type, a median PFS of 12.8 months or more than a year. To put these findings in context, I noted previously that LGSOC without a KRAS mutation, wild-type was seen to be more quickly progressive and fatal in previous studies. Similarly, in RAMP-201, the rates of response and the duration of PFS trends better for patients with a KRAS mutation in their tumors, yet patients without KRAS mutations have also achieved responses. And most impressively, the median PFS is greater than a year even for these patients. Safety and tolerability are also important, especially considering the durations of response observed for this combination and the high rates of discontinuation that patients face with the currently available treatments. The Avutometinib and Defactinib combination continues to demonstrate a consistent and well-tolerated profile with only a 10% discontinuation rate due to adverse events and no new safety signals have been identified. While low-grade adverse events are common, severe reactions are generally uncommon, and they are typically manageable by temporary interruption of treatment. Overall, discontinuations due to adverse events were only 10% and about 1/3 of those have been an artifact of the initial study design because initially, patients who experienced Grade 4 CPK elevations or creatine phosphokinase elevations, were directed to discontinue the study. However, as the study progressed, it was noted that these appeared largely without symptoms or consequence, and the FDA agreed that we could amend the protocol and allow patients with CPK elevations to remain on the study with appropriate guidelines for treatment interruption or reduction. After we made this update, no further patients discontinued the study due to blood CPK levels and no significant consequences from these abnormal tests such as rhabdomyolysis, have yet to be seen. In RAMP 201, when relevant adverse events occur, we first guided physicians to temporarily interrupt the treatment, and 80% of patients use the treatment pause during the study. That said, most patients were able to resume treatment and did so at the previous dose and more than half of the time, no reduction in dose was needed. About 1/3 of patients use the dose reduction at some time on the study. All in, the tolerability of the regimen is generally favorable. And when we account for the dose interruptions or reductions, the overall dose intensity compared to the planned dose was approximately 80%. So importantly, no deaths have been related to study treatment. Before we provide an update regarding other arms of the trial because the combination regimen will be the focus of the program going forward, we'd like to pause here and ask Dr. O'Malley to share his experience in the RAMP 201 trial and how he views these data compared to his other experiences in LGSOC. Dr. O'Malley?

Well, thank you. And hopefully, you guys can -- everybody can hear us from Dublin here. So I think it is good that you paused on this slide with regards to the experience because what's really interesting that the other MEK inhibitors, and I was involved in both GOG 21 as well as MILO is that toxicity with -- even with the combination of the dual blockade seems to be markedly better. Typically, with MEK inhibitors, I would expect about 1/3 discontinuation rate. And it's -- as you see here, less than about -- right about 10% discontinuation rate. So -- and with those, about 1/3 of them were from the CPK and as you just heard, elevations, CPK elevations is 1/3 of those. And now we've worked through the dosing through the CPK elevations, which do not have -- we've not seen to have clinical significance. Most importantly, there's a waterfall plot. And you really look at that in about 85% of patients have disease regression. To me, that's the most impressive aspect really beyond the overall response rate so that almost all patients are getting clinical regression of their disease. I'm not a big fan of clinical benefit rate just because somebody has [indiscernible] for one stand, that, to me, is not a beneficial. But having disease regression [ logically ] in patients who have symptoms, it's so very important. So obviously, we're very excited to have these findings in the public domain and showing the justification for 301. So overall, very excited about these results and the possibility in the future of the 301 study.

Thank you, Dr. O'Malley. This is John Hayslip again. The RAMP 201 trial also enrolled 69 patients who received treatment with a higher dose of Avutometinib as a single therapy. These patients had baseline characteristics similar to the patients evaluated in the go-forward regimen. These patients also had a median of 3 prior lines of treatment. And comparable prior bevacizumab and MEK inhibitor use. Compared to the 31% response rate we observed regarding the doublet, patients receiving Avutometinib monotherapy had a response rate of 17%. We don't plan to study the monotherapy further in LGSOC. Also, this study tested a lower starting dose regimen of 1.6 milligrams of Avutometinib twice weekly with the same dose of Defactinib, 200 milligrams twice daily. The lower starting dose was found to be suboptimal based on pre-defined analyses. We will not be pursuing the low-dose regimen as the starting dose. Disease progression by the second scheduled imaging assessment, which occurred at month 4 of treatment was higher with the lower dose regimen than was seen in the selective combination regimen. Further supporting the proposed dose and schedule is optimized for most patients. Also presented at the IGCS meeting is a trial in progress poster for the ongoing and actively enrolling Phase III study, RAMP 301. The eligibility criteria are similar to RAMP 201. We welcome patients with either KRAS-positive or KRAS wild-type LGSOC. Patients may enroll regardless of the number of prior therapies, so long as they received at least one line of platinum-based chemotherapy. This is a randomized study and the comparator arm is based on the investigators' choice of treatment. Perhaps most importantly, to many physicians I've spoken with, patients who are initially random receive traditional therapy may cross over to Avutometinib and Defactinib combination if they experience disease progression confirmed by the Central Radiology Committee while receiving standard treatment. We are targeting full enrollment by the end of 2025. The trial will serve as the confirmatory trial for the initial KRAS mutant indication and has the potential to support a broader indication that it will be a randomized comparison against standard available therapy and enrollment is stratifies on KRAS status. With that, I'll hand the presentation over to Mike Crowther, Chief Commercial Officer. Mike?

Thank you, John. I'm going to walk you through how we see the combination of Avutometinib and Defactinib having the potential to change the treatment paradigm in recurrent LGSOC. I want to take a moment and walk you briefly through the patient experience in LGSOC. With no approved therapies, health care professionals use the NCCN guidelines to guide their treatment decisions. Often patients will start on chemotherapy but as symptoms progress an 80% of patients experience recurrences will often be provided with options like hormonal treatment, bevacizumab and maybe on occasion a MEK-only inhibitor. But with poor response rates and high discontinuation rates, patients will still unfortunately cycle through multiple lines of treatments while living with LGSOC. Recurrent LGSOC treatment options today were developed for other indications and have demonstrated poor effectiveness and high rates of discontinuation when used to manage LGSOC. I'm not going to go through this deep data in detail, nor can I make direct comparisons to RAMP 201 data, but this information highlights some important differences between the trials and underscore why better treatment options are needed. These studies started as early as 2013 when there was a limited use of bevacizumab. The analysis of KRAS status was done retrospectively, owning a subset of patients, so there's not a genuine understanding of the performance of these products in relation to KRAS mutational status. But it's this historical data that has been guiding treatment decisions for years, and we want a need to do more for patients with LGSOC. We believe that Avutometinib and Defactinib regimen truly has the potential to address the key treatment gaps identified and make a meaningful difference in the lives of patients with recurrent LGSOC. You've heard John walk through the compelling data of clinically meaningful rates, durable benefit, long progression-free survival and long durations of treatment, all with a low discontinuation rate due to AEs. With the mature RAMP 201 data in hand and a clear regulatory path forward, we feel that we are very well positioned to meaningfully support or change the existing treatment paradigm. As we have stated before, we believe that the overall LGSOC market represents a significant opportunity, and we anticipate high market penetration in recurrent KRAS-mutant LGSOC population given the lack of FDA-approved therapies. With a total estimated prevalent addressable opportunity of over $1.7 billion, we plan to fully address this population over the first 3 to 5 years following launch. And it's important to remember that patients cycle through therapies and do so relatively quickly in the prevalent setting. And recurrent LGSOC patients have a long overall survival of around 10 years providing opportunities for patients to experience and benefit from new therapies and stay on those treatments if efficacious and manageable. While our current focus from a regulatory perspective is on KRAS mutant patients, I'd like to remind everyone that treatment and reimbursement for recurrent LGSOC has been driven by NCCN guidelines for many years. We plan to submit these findings from our mature 201 trial, inclusive of the entire patient population for both publication and then NCCN consideration. You'll see here how the NCCN categories are broken out from left to right with general payer coverage correlating with each category and the corresponding recommendations and the clinical data that supported their inclusion and the category that they achieved. I know that I've already shown this slide, but I want to briefly show it again to reiterate the point that while the regulatory path will focus on the KRAS mutant initially, we will continue to try and address KRAS wild type by compliantly introducing, educating and promoting the product against the final label and the supporting evidence. Turning now to our prelaunch initiatives. We've been preparing an efficiently scaled model to deliver a best-in-class launch for a current KRAS mutant LGSOC. Our prelaunch initiatives center around 3 key areas, including a focus on key health care organizations and accounts where we see most patients being treated; a focus on patient education with disease awareness resources and other support programs; and lastly, a focus on GPOs and large affiliation practices to ensure inclusion in all relevant pathways and EMR systems. While this is a rare disease, it is one where there's a concentration of patients. Over 50% of the actively managed patients are concentrated in only 100 centers, giving us an opportunity to execute a very focused launch. We've been conducting extensive market preparation activities across all stakeholder groups. And among the outcomes that we're encouraged by is that of the patients themselves, the prevalent pool within which will be initially indicated. We have over 2,300 of those patients already engaged through our unbranded disease education website, giving us the opportunity to communicate directly with patients post approval. We expect the speed of adoption will be high. Most physicians indicate they'll adopt within the first 6 months of approval and a lot of physicians say that they'll reach out to their LGSOC patients. And if they're dis-satisfied with their current management, we'll offer them an active switch to the Avutometinib and Defactinib regimen upon approval. We'll naturally come to market with a broad set of access tools and programs to ensure both broad and early access to patients. Given the length of therapy we're anticipating, we'll also be making sure we have sufficient programs in place to support patients staying on therapy as long as possible as well as starting. In summary, the Avutometinib and Defactinib regimen have the potential to change the way Recurrent LGSOC is treated. Between 6,000 to 8,000 women suffer from this rare cancer today in the U.S. and there is great potential for high market penetration in the KRAS mutant population at launch. We've stated and shown the different ways in which the current available treatment options lead clear areas of unmet need that we believe the Avutometinib and Defactinib regimen can address. And with the disease managed by NCCN guidelines, we look forward to submitting our entire RAMP 201 data set for consideration. With our efficiently scaled launch model, we believe we can deliver a best-in-class launch for a current KRAS-mutant LGSOC and bring patients a treatment option that was developed specifically for their needs. And with that, I will hand to Dan for closing remarks.

Thank you, John, Mike and Dr. O'Malley for your perspective. As we've met with several other investigators, including physicians, at IDCS, they share your enthusiasm for the potential of Avutometinib and Defactinib in treating recurrent LGSOC. As we walk through today, our positive RAMP 201 data mature and continue to build our confidence and enthusiasm for potentially changing the way that recurrent LGSOC patients are treated. We remain laser focused on execution as we work hard to potentially bring the first FDA-approved treatment specifically for recurrent KRAS-mutant LGSOC in 2025. In closing, we are eager to keep executing against our milestones and further advancing our broader pipeline as we're preparing for a near term LGSOC launch. We're also working to prepare for potential expansion opportunities within large underserved patient populations. Our other RAMP trials and our G12D program all have important milestones in the near term and throughout 2025, which are outlined here. Verastem potential is yet to be unlocked, and we look forward to leveraging the positive momentum in LGSOC to further deliver meaningful treatments across other RAF/MAP pathway-driven cancers. As we transition to a commercial stage company, our commitment is to delivering novel treatment to improve outcomes for patients and that drives us every day here at Verastem. Lastly but importantly, we thank all of the patients and their families, investigators and the team members involved in [indiscernible]. With that, we'll now transition to Q&A. Operator?

[Operator Instructions] Our first question is from Pete Stavropoulos with Cantor Fitzgerald.

Congratulations on the data. I guess, the first question that I have, there was a decrease in the ORR observed between Part A data presented at ASCO in 2023, which were similar to the FRAME data and the maturing data that includes Part B and C patients. Can you just sort of help us understand why this may be the case? Is this a result of baseline characteristics of the patients enrolled in Part B and C were different compared to Part A and FRAME? And if Dr. O'Malley is on the line, I'd love to hear his perspective.

Thanks, Pete. Thanks for the question. As we look at both the historical studies, the Phase III studies that were done, the FRAME study, and interestingly, Part A, there was less bevacizumab usage in those cohorts than there were in Part B, C and D. Yes, B and C and we've shown patients who have prior bev don't do quite as well on the treatment as those who have not had prior bev, and that's the most likely experience. I don't know, John, if you have any other comments or Dr. O'Malley wants to add to that?

I would just say that in addition that, our work remains ongoing. Of course, we're laser focused with the completing the enrolling new drug application, and we'll continue to further evaluate the data in other ways and look at other subgroups and we'll bring those results forward as they emerge. I'll just pause, and Dr. O'Malley additional comments?

Yes. I think I've got asked this before. I'm really excited about the current data. I think as we look at this in a heavily pretreated population, 3 prior therapies Bev as well a fair amount of patients getting MEK inhibitors that this activity that we're seeing is, again, very exciting, very challenging patients to treat. So compare the FRAME study, I'm excited about the current data that we have and moving into the 301 study gives me a ton of confidence that this will be a treatment option in the future for our patients.

All right. Great. Also for the subgroup analysis, we showed a greater response rate, 4 patients that were treated earlier in the course of therapy with Avuto and Defactinib combo. Dr. O'Malley and also to the company, some of the KOLs that you've been, what is this sort -- does this impact the way you're thinking about where to actually place it? Can you possibly see moving it up earlier in line of therapy and possibly even used as a de-bulk -- before you debulk to shrink the tumor?

Don't get crazy on me. I think -- no. I mean you have an active -- an active agent, we're going to try to move it up. Now when we look at the current treatment paradigm, and this is a big change in our treatment, because we still utilize platinum-based doublets followed now by hormonal therapy, really anti-hormonal therapy with enrollment phase inhibitors. So I think at the -- moving forward, you're going to have the next line of therapy to be this combination is absolutely where we're going to be. Are we are going to wait to 3 or 4 prior lines? No, because your first lines are your platinum doublets followed by your hormonal therapy. And your second line will be the combination. So moving forward and trying to [indiscernible] epitaxel versus hormones, I think that will be something we'll look at in the future, particularly in a type of a [ MEK ] setting. This is me talking. This is -- they've never had a discussion with me. I want everybody to know that. But as a clinical investigator, obviously, I'm looking at those possibilities in the future, trying to get disease control, and hopefully cure more patients.

One last question, if you don't mind. Again, Dr. O'Malley since you're a practicing physician as well, can you just help us understand what are the more ovarian symptoms caused by the tumors in LGSOC? And like even if you don't cross that 30% threshold for ORR is there any benefit in just shrinking the tumor a bit?

I'm going to answer the second part of that. Absolutely, and that's why I emphasized that earlier. Disease regression is the key. And look at the waterfall plot, I forgot which slide back was. You're going to see about 86%, I think, was the official number of disease regression. What do I mean by that? Shrinkage of the tumor. Those disease -- those -- that waterfall plot going below the 0 curve, the 0 line. So as we look there, that is -- getting disease regression in a symptomatic patient is so important. So what are the symptoms patients have first part of your question? It's peritoneal disease, intra-abdominal disease. So pressure on other organs like bowels, the pelvis, the bladder, the rectum [indiscernible] urinary as well as bile function are usually the challenges that we have with patients that become symptomatic.

The next question is from Gregory Renza with RBC Capital.

Congrats on the data and the update. Maybe we could just start a bit with some of the discussions with FDA and very helpful. And as you mentioned, more of a straightforward path now following the recent meeting. Just curious if you could comment a bit on what some of the discussions were around the bar for duration of response when it comes to mutant versus wild type, maybe what the FDA you think may be looking for? I appreciate that it can be difficult to play back to us, but I just wanted to ask. And maybe for Dr. O'Malley just on a related topic, why does the KRAS wild type have that less favorable prognosis for LGSOC? And maybe at what point would you put these patients with KRAS wild-type on Avutometinib if it is, in fact, listed on the NCCN guideline?

So I'll let John speak to the duration of response question. In these discussions, you typically don't get a hard bar, it's a totality of the data. And I do think one of the challenges we had with wild type is there weren't directly comparable data sets. And when you look for an accelerated approval, arguably 17% is on the low end and without a good direct comparator, that becomes a hard discussion to have. And we felt very strongly that the best thing we could do for patients is get this drug ASAP, and we do believe that it will be used across the board based on what we've seen. John, I don't know if you want to say anything more about the duration.

Yes. The only thing I would add is, I think as we interact with the FDA, they think carefully about the measures of efficacy. They think carefully about the safety and tolerability. They also think and look at what are the available information that can allow them to be confident about what can the available therapies deliver for patients. And as Dan has highlighted, although there have been trials now it started over a decade ago, [indiscernible] line in the MILO trial, those are important studies, but they're now started over 10 years ago. Neither study evaluated KRAS incubation status in all patients. It's only a small set of patients. And so I think for those reasons, I think people would love to hear a single number that you need to beat. But the reality is that that's not how the agency approaches these questions. And what they communicated to us is in the KRAS mutation group, the data we currently have provide their view a clear path and given the overview of data that we've discussed, they sure -- they see an important therapy for patients. And so regarding the duration of response, we reviewed that with the agency and they're quite satisfied with what they've been used, and encourage us to go ahead and complete our enrolling submission. I think you also had a question for Dr. O'Malley, I'll turn it over to him. I think the question is, what would it take for you to use this in a wild type?

Well, what would take and why they're harder to treat, I don't know that. I think as you look at the machinery and with the mechanism of action with regards to the more resistant, the cellular replication is probably the reason because we cannot interrupt the machinery and the repair mechanisms in the cell. And so when you have that mutated, then you can target it. Would I use this in a wild type mutation? Absolutely. I think as you look at the options, we're already using hormonal therapy in the first-line setting. So the best treatment for this is hormonal therapy. So we're already utilizing that. What else do I have in an unbelievably modest response rates with [indiscernible] with 0 response rate in total [indiscernible] we're looking at single-digit to 0% response rates in this. So I would absolutely use this in wild type. I look forward to the opportunity to have it earlier than that in our mutated patients. And obviously, the off-label utilization in practitioners' hands will be important as we often do. The most important thing that I want to just go back really quick to the regulatory question. One of the most important aspects that we were able to do here is to get the FDA to recognize low-grade serious ovarian cancer. We've really been talking to them for a decade to get them to understand, this is a completely different disease compared to high grade. And so that is the most important bar that they now realize. And the most important asset [indiscernible], besides obviously [indiscernible] concentrated, the amazing duration of response that will benefit the earlier approval.

I appreciate the color, Dr. O'Malley. Maybe just one back to you, Dan, just for one final question. And as we know, this submission is for the combination of 2 investigational drugs. Just curious if you could just comment about any of the considerations that we should be keeping in mind as to what makes that unique and how Verastem is navigating that?

Well, and again, I think one of the reasons we're so anxious to engage the agency early and really start the rolling NDA early even before the data was mature is this to full CMC [indiscernible], and so we've been in tight communication with them around that. Obviously, FDA guidance on novel, novel drug approval to the [indiscernible] agent really why we had Part A of the study. And so we've carefully gone through these things with FDA. And again, when you have 2 drugs, novel, novel when you get a clear signal that there's a path forward and that the [indiscernible] the potential might be harder, you choose the easy path forward, so you can make the drug available to patients. And then we will continue to work on broader regulatory approval. But if you -- as you've heard and you've heard about our plans through NCCN, we do believe it will be used, and we do believe it will be reimbursed, but we are committed to pursuing a regulatory path as well.

And an important point, this is O'Malley. I'm talking to -- those optimization has already been completed with the Cohort B that you heard for the first time here today. So not only do we have a relative contribution worked out. And I say we because these are drugs I've used a lot and I treat the -- patients are sitting in front of me. I have no connection to Verastem except I participated in the trial. So when I say we, I just mean drug investigators is that we have the dose optimization completed at this point as well as the relative contribution, 2 huge barriers to overcome approval.

The next question is from Michael Schmidt with Guggenheim.

Congrats on that data presentation. You have super interesting data, I think, especially the fact that response rate obviously seems to improve meaningfully in less heavily pretreated patients. And I think you mentioned there's potential earlier line use in clinical practice, perhaps, than what has been studied in the trial here. But have you looked at duration of treatment or PFS in less heavily preposed patients perhaps in the second or third line setting, what would that grow for the 12.9 months in the study?

Yes, John, do you want to speak to that?

Yes. Thanks for the question. So we are -- that work is ongoing, and we're evaluating different conferences and medical meetings to bring that work out. But in general, the observations that you're seeing are -- we see across various endpoints. But that work is ongoing, and we look forward to sharing that in more detail as it comes up.

Okay. And then couple of commercial questions just on the fact that the initial label presumably will be in the KRAS mutant setting, obviously, appreciating the potential for broader use. But can you talk about perhaps how common KRAS testing is in LGSOC clinical practice? And what if anything needs to be done to get a companion diagnostic approved as well?

So we had planned for a companion diagnostic, we've had a diagnostic partner for quite a while. And so we will have that in place. As far as adoption in the community, there's going to be education. And again, I think part of it will depend on physicians feel they need to know the answer to that and make a treatment decision. But there have been varying levels of adoption of new diagnostics as they become available. We probably saw that happened in lung cancer when we had [indiscernible] agents and other KRAS agents. I don't know, John, if any other comments you want to make?

Yes, I could just add that most of the patients who enrolled on our trials already had local analysis done, not all, but the majority have. And we have Dr. O'Malley with us, Dr. O'Malley, care to mention your experience?

Yes, across the world in the U.S. and in Europe basically to do the metastatic recurrent disease per the ASCO guidelines and [indiscernible], the recommendation is the next-generation [indiscernible]. So we have patients that are -- they're diagnosed, to make these treatment decisions outside of the diagnostic test. These are commercially available. It's part of our routine treatment paradigm with metastatic recurring disease.

Right. And then just from a modeling perspective, I was thinking about the potential launch next year pending approval by midyear. How should we think about the launch trajectory given absence of effectively -- effective approved other drugs. Would you expect a quick launch? Is there a potential pent-up demand even at that time point? Are you planning to avail an early access program perhaps for patients before approval? How should we think about the launch trajectory?