Welcome to today's webinar, which is discussing a newly opened Phase III study for low-grade serous ovarian cancer. This webinar is supported in part by VeriSTEM. During our webinar today, we will be sharing information about a potential clinical trial for your patients. The RAMP 301 trial is evaluating the novel combination of avutumetinib and dafactinib versus investigators' choice of therapy in patients with recurrent low-grade serous ovarian cancer. I'm Rachel Grisham. I'm the section head of ovarian cancer for Memorial Sloan Kettering Cancer Center in New York, USA, and the director of gynecologic medical oncology at MSKCC Westchester. I'm joined today by my esteemed colleague and friend, Dr. Susanna Banerjee, who will introduce herself. Thank you very much, Dr. Grisham. So I'm Susanna Banerjee. I'm a medical oncologist at the Royal Marsden NHS Foundation Trust in London and a professor in women's cancers at the Institute of Cancer Research. I'm really looking forward to this webinar, and it's such an exciting time for progressing treatments for women with low-grade serous ovarian cancer. It really is. Thanks so much, Dr. Banerjee. Just a couple housekeeping items before we start. Please know that a recording of this webinar will be available on IGCS Education 360 Learning Portal within one business day. We encourage you to submit questions via the Q&A feature at the bottom of your screen, and we'll do our best to address as many of them as possible during our talk or at the end. But for now, let's get into it. So during the course of this study, we're joined by myself, who is the global lead of RAMP 301, and Dr. Susanna Banerjee, who is the global lead of RAMP 201. We'll be discussing both interim results from RAMP 201 and a newly opened phase 3 study called RAMP 301. But to start, we wanted to review a case to kind of get some background on how we think about patients with newly diagnosed low-grade serous ovarian cancer and what we do for those patients who have recurrent disease. So our first case is regarding a patient named Monica, who is a 35-year-old woman who presents with three months of abdominal bloating. She was referred to GI by her primary care physician, and colonoscopy revealed extrinsic compression of her colon. CT scan shows bilateral adnexal masses, omental infiltration, and pelvic ascites. Her CA125 was elevated to 2,300. She was seen by a gynecologic oncologist and underwent a primary debulking surgery that resulted in a complete gross resection. Her genital pathology was consistent with stage 3c low-grade serous ovarian cancer. So for a patient like this, Dr. Banerjee, who's had a complete gross resection for stage 3c low-grade serous ovarian cancer, what would you be thinking about in talking to her about initial adjuvant therapy? Thanks Dr. Grisham. I think this is such a challenging case with young patients that we see with this disease, which isn't as common as high-grade serous ovarian cancer. So the first thing I would do when I'm counseling a patient with this disease is highlight what the diagnosis is, and also give a little bit of a background of the lack of prospective clinical trials in this setting regarding the value or magnitude of benefit of chemotherapy and what that chemotherapy entails, and also other treatments. So I think that's really important as it helps aid decision-making. In this situation with advanced disease, I would be recommending adjuvant chemotherapy in the form of carboplatin in combination with paclitaxel. And one of the questions is also about the value of bevacizumab, and I'm sure we'll discuss this later, Dr. Grisham, but there is some retrospective or subgroup analysis data regarding the role of bevacizumab in the first-line setting, and I'd consider carboplatin with paclitaxel and bevacizumab. But I acknowledge that there's more than one right answer here. Yeah, for sure. And thank you, Dr. Banerjee, for highlighting the importance of discussing with our patients what their histologic diagnosis means and how low-grade serosevere and cancer differs from high-grade serosevere and cancer, both in the clinical presentation, oftentimes with younger patients, a younger median age of diagnosis, lower response rates to chemotherapy, and then also the molecular differences, which we'll discuss later on in our discussion of targeted therapies. And I think it's really important, like you said, that we don't necessarily have right now one standard of care for patients with newly diagnosed advanced low-grade serosevere and cancer. And, in fact, there's an ongoing, not the study that we're here to primarily talk about today, but I have to mention an ongoing international phase III study, NRG GY019, that is randomizing patients with newly diagnosed low-grade serosevere and cancer that have undergone debulking surgery to chemotherapy with carboplatin and paclitaxel followed by letrozole versus letrozole alone, trying to tease out the relative benefit of the chemotherapy in this setting when we really aren't sure how much it's adding to the letrozole alone. However, that being said, with that still being an ongoing clinical trial, I do discuss the option of that clinical trial with my patients with newly diagnosed disease and the option of being randomized to chemotherapy followed by letrozole versus letrozole alone. But similar to your approach, in a patient who is not comfortable with going on to a clinical trial, I do still consider my standard of care to be platinum taxane chemotherapy followed by letrozole maintenance therapy. We asked this same question to many of the participants in the webinar today to see what their practices were across the globe. It seems like the majority of our participants do favor carboplatin and paclitaxel chemotherapy in the adjuvant setting right now, but with 17% of patients preferring endocrine therapy alone. So, still not just one answer here, still more to be learned in the frontline adjuvant setting and hopefully the ongoing phase 3 study looking at carbotaxel versus letrozole alone will help us answer that question. Now, for this patient who has newly diagnosed advanced low-grade serosevere in cancer, would you be doing molecular testing now at the time of diagnosis, Dr. Banerjee? So, I think it's also what I'd like to do and what I'm able to do within the NHS setting that I work in in London. So, I think we're learning a lot more about the biology and the relevance of mutations in low-grade serous ovarian carcinoma. But in terms of germline testing, a lot of our patients, thanks to the awareness of ovarian cancer and treatments, are aware of BRCA mutations potentially being linked to ovarian cancer and driving the disease. So often patients, including those with low-grade serous ovarian cancer, ask me about this in clinic and although the rates of low-grade serous ovarian cancer patients harbouring a germline BRCA mutation is minimal or may be questioned, there are reports of germline BRCA mutations. We also need to ensure that the histology is correct and I'd always be reviewing that in any case, but in particular if there was a germline BRCA mutation associated with diagnosis of low-grade serous ovarian cancer. So, BRCA testing does come up and again it depends on the wording of the availability of testing, for example serous or whether it's high-grade. In terms of tumour NGS, I would very much like to do this for all my patients if possible, but I appreciate in the context of first line and also arguably in the recurrent disease and low-grade serous ovarian cancer, it doesn't directly, outside of the context of clinical trials, aid or direct decision making for treatment, but I think it's really important aspiration that if it's possible to do NGS, it's important to do. Also thinking ahead for the patient in front of us, should they relapse, what potential options may be in or out of the context of clinical trials and also to aid clinical trial directions. Yeah, thank you. Yeah, this is one thing that's oftentimes a little bit easier in the United States because here oftentimes for our newly diagnosed patients, both germline and tumour NGS sequencing are covered by insurance under the premise of looking for a BRCA mutation, which of course could be either germline or somatic. As you said, the rate of BRCA mutations in patients with low-grade serous ovarian cancer is similar to that of the general population, and we therefore do not believe this to generally be a BRCA-associated disease, but that same panel testing that we use to look for BRCA alterations can also show us on the tumour NGS sequencing whether the patient has a MAP kinase pathway alteration, which is oftentimes what we're really interested in here with about a third of patients having a KRAS mutation and about 68% of patients having a V600E BRAF mutation. And oftentimes I like to have those results up front if possible just because we're always thinking about what our plan is going to be if this cancer does recur and thinking about next-line options. When a patient comes to see me who has not initially had tumour somatic testing done and has recurrent disease, I usually do order it at that time. So for this patient, Monica, she was treated with six cycles of IV carboplatin and paclitaxel chemotherapy, and at completion of chemotherapy, her CA125 had normalized to 17, and her CAT scan showed no evidence of disease. She initiated treatment with letrozole. After four months on letrozole, her CA125 increased to 55. She had a repeat CT scan at that time that unfortunately showed peritoneal carcinomatosis and a 2 cm by 2 cm enlarged periaortic node as well as pelvic ascites. She was evaluated by a gynecologic oncologist and found to not be appropriate for secondary debulking. So in this patient with recurrent low-grade serous ovarian cancer, how do you think about treatment here in the second-line setting, especially for a patient like this who's had, unfortunately, a pretty quick recurrence after her initial chemotherapy? So I think this is really disappointing, having had not only chemotherapy but also endocrine treatment, letrozole, in such a short time frame. So I'd like to have an option that isn't chemotherapy or indeed endocrine therapy, and that's where the option of targeting the MAP kinase pathway, so a MEK inhibitor or indeed a clinical trial would be my preferred approaches. So we do know that from the clinical trials, I'm sure we'll discuss, that there are patients who progress on platinum-based chemotherapy, indeed endocrine therapy, who can respond as well as have a prolonged progression-free survival with targeted approaches such as MEK inhibitors. So that would be my preferred approach, whether that's accessing within an ongoing clinical trial, whether it's looking at combinations, for example, of MEK inhibitions or along that pathway of MAP kinase inhibitors, or indeed accessing clinical practice of a MEK inhibitor. So in England, within the NHS, although there isn't drug approval, tremetinib is reimbursed within the NHS based on the log study and GOG and UK study of tremetinib versus standard of care treatment, which is chemotherapy or endocrine therapy in recurrent low-grade serious ovarian cancer. So either tremetinib, for example, or a clinical trial, ideally of MAP kinase inhibitor pathway drugs would be my preference. Yeah, beautifully said. Yeah, I agree. For a patient like this that progressed so quickly on chemotherapy, obviously we're not going to go back to platinum-based chemotherapy. We've just progressed on endocrine therapy. To go back to your earlier comment, this is a patient where I might consider bevacizumab in combination with chemotherapy or bevacizumab alone based on the retrospective data, both out of Sloan Kettering and MD Anderson, showing relatively good response rates in the recurrent setting, though not tested in a prospective fashion. But this is definitely a patient where I'm going to be looking for a clinical trial and be pretty excited to put them on a clinical trial if there's one available. In the absence of a clinical trial, I would definitely be thinking about a MEK inhibitor like tremetinib, which is compendium listed. In the United States, we consider both tremetinib, which is 2A and binimetinib, which is 2B listed. Oftentimes, my patients are a little concerned about the side effect profile of a continuous MEK inhibitor given every day, as tremetinib or binimetinib are in this setting. We asked this question to our respondents as well, and so regarding second-line treatment for low-grade serosuvarian cancer, about 36% of people said chemotherapy, 39% endocrine therapy. Interestingly, only about 8% said MEK inhibitor. I think that was in part due to access to MEK inhibitor in different parts of the world where it's not necessarily accessible, and then also due to concerns about the toxicity of single-agent MEK inhibitor and the continuous dosing. But definitely, we do need better options in this setting because when the participants were asked what the biggest challenge is for treating these patients with recurrent low-grade serosuvarian cancer, 58% of people said limited efficacious options. So that's really what we're faced with, kind of choosing between the best of two or three bad options because we really need more effective treatment strategies for these patients with recurrent disease. But luckily, there are some very exciting clinical trials in low-grade serosuvarian cancer. So glad to have Dr. Banerjee here today to give us some background on this novel combination of abutometinib and dafactinib and really go over these top-line results of the recently presented results of RAMP-201 and how we're going to be building on the results of that study for a Phase III study for patients with low-grade serosuvarian cancer that is opening around the globe right now. So Dr. Banerjee, please take it away. Thanks, Dr. Christian. So I think the first thing is, it's great now that the gynae oncology community and trialists globally are working together to push forward in treatments for rare gynecological cancers. And that's so incredibly important, working within the academic groups and also with industry and our sponsors for many studies. And for example, with the GCIG. So I'm currently the co-chair of the Rare Cancers Committee in GCIG. And I think it's really important that we develop many more trials together in low-grade serosuvarian cancer and beyond. So what I'm going to share with you now is basically a hypothesis based on some preclinical work and an early phase study from our institution at the Royal Marsden Institute of Cancer Research. So avitamatinib is a first-in-class oral RAF-MEK clamp that basically inhibits MEK kinase activity, but also blocks this compensatory reactivation of MEK by upstream RAF that we know can happen with traditional MEK inhibitors. And then difactinib is a selective inhibitor of focal adhesion kinase or FAC. And that's been shown to be one of the pathways to mediate resistance to some of these treatments and other anti-cancer agents. So avitamatinib and difactinib showed a relatively high rate of responses and also durability of responses, specifically in recurrent low-grade serosuvarian cancer in the phase one academic sponsored FRAME study. And in this study, the response rate was around 46%, and median progression-free survival at that time was around 23 months. And this is very promising compared to what we've seen in practice and in randomized phase three trials of low-grade serosuvarian cancer, comparing it to responses that we see with chemotherapy, which can be less than 10%, and indeed endocrine therapy, either 0% with potentially tamoxifen and 13% or so with letrozole. So this led to the FDA breakthrough therapy designation, and importantly, the rationale for the NGOTO V60-GOG3052-RAMP201 study, so a true example of a collaboration between NGOTO and GOG. So this is the initial trial design, and the key points I want to highlight to you is that for recurrent low-grade serosuvarian cancer, patients need to have prior platinum-based chemotherapy, have measurable disease bioresist, and what's really interesting is that prior MEK inhibitor treatment, or indeed BRAF-directed therapy, is permitted. And we looked at the combination of avatamatinib and afectinib in either KRAS-mutated or KRAS-wild type populations, and also the RAF MEK inhibitor avatamatinib alone in either the KRAS-mutated or KRAS-wild type patient. Now these are studies with relatively low numbers in order to try and help direct us into which regimen to take forward in the next phases of the trial. So the primary endpoint was response rate. And the key part of part A was to really decide or help decide whether we take forward the combination or the monotherapy in this population of patients. So if we can move on to the next slide. Just want to highlight some aspects of the patient demographics in part A. So as you can see in either the monotherapy or combination is around 30 patients. And as I said, included KRAS mutated and also wild type. I want to highlight the median age, which is in the 50s. Again, showing that in this disease, in patients can be younger than what we see with some other histologies. And that the median number of prior systemic regimens was around three to four. You can see that some patients had prior MEK inhibitors. I saw up to 30% or so, prior bevacizumab and also prior hormonal therapy. And I think this really reflects what we see in clinical practice. So if we move on to the next slide, these are the key results from part A. And what we see is that the responses in terms of confirmed responses and unconfirmed responses at this point was 10% with avatamatinib with a combination it was clearly higher. So if we can move on to the next point of the slide, the response rate was 45% with the combination and 10% with monotherapy, that's confirmed responses. And what's really interesting is that responses were noted in three out of four patients who received prior MEK inhibitor therapy in the combination arm. And it was one out of 10 patients in the monotherapy arm. What's really interesting and important to note in clinical trials and also in counseling patients is that the median time to response was five and a half months. So if you have a patient where there isn't immediate shrinkage, that doesn't mean that those patients won't go on to have a response later on. And so I think that's an important point to make. So next slide, please. So here's a waterfall plot of the monotherapy and also the combination. I think it's really interesting to see that as well as the actual formal partial responses, that we do see that the majority of patients have a degree of tumor shrinkage. And what you see in the orange bars is the KRAS wild type and in the blue bars, the KRAS mutated and the stars indicate those patients at the time of data cutoff last year who was still on treatment. Next slide, please. I never get tired of looking at this waterfall plot because it's for our patients with low-grade serosuvarian cancer, you know, this is like unheard of. And this is, you know, this is not biomarker selected. This is the KRAS wild type and the KRAS mutant patients. So yeah, it's so nice to see these results finally for patients with low-grade serosuvarian cancer. So we're going to see it again in a minute because it is a good waterfall plot. So, but hand in hand with efficacy and appreciate these early signals in a relatively small trial, it's really important to look at toxicities because as Dr. Grisham mentioned, as you mentioned earlier, one of the limiting factors has been the toxicity profile of MEK inhibitors and drugs like MEK inhibitors, which is different to chemotherapy. And that's also about how we as clinicians and also as trialists, counsel patients and manage some of the toxicities upfront, either prophylactically or early on when they occur. So the key points that I want to make here rather than going through all the toxicities, and if we can move forward with some of the aspects of the slides, is that dose reductions with the combination was 17%. And there were relatively low number of discontinuations due to adverse events in the combination arm. Overall, it was 12%. And around 5% were due to elevated CPK levels, which were not symptomatic. And the safety parts of this presentation was actually of larger numbers. So it's parts A and B. So around 80% or 80 patients in the combination arm. So if we look at the toxicities, we look at the combination, for example, and grade three toxicities, diarrhea was relatively low, around 3%. It was the CPK increase that was more notable at 18%. Fatigue, grade three, around 4%. And the acneiform rash that we're familiar with for grade three levels was under 3%. So important to look at how this evolves with more patients in these studies. But I think at least initial encouraging toxicity profile given the mechanism. So next slide, please. Yeah, and Dr. Banerjee, I would just emphasize that the dosing for abutametanib and defactanib. So in these studies, abutametanib, the oral MecGraf inhibitor is given twice a week, three weeks on, one week off. And the defactanib is given twice a day, three weeks on, one week off. And I think that intermittent dosing schedule that you used in this study is really partly to credit for this really tolerable toxicity profile. And I think, of course, haven't been compared head-to-head with other single agent Mec inhibitors, but I seem to find in my patients that this intermittent dosing works so much better for toxicity than continuous Mec inhibitor dosing. Well, great, great to hear that. So here again, this encouraging waterfall plots and what we've highlighted in the hashed lines is the previous treatment with Mec inhibitors here. So we looked at this a bit more deeply in terms of a presentation at a recent SGO, that what we saw was that there was similar response rates as well as safety profile in patients treated with one to three prior lines or indeed four or more prior lines. And just to highlight again that tumor regression was seen in many patients, so 86% of patients of the combination. And of those patients that had stable disease, the 13 patients with stable disease, 10 actually achieved tumor shrinkage and six of those had 15% or more of tumor regression. And what we have described is that some of the prior therapies that were used when the patient had stable disease, and some of them included Bevacizumab and also Mec inhibitors. So let's move on to the next slide. And what this shows you is a bit more detail on those four patients that had prior Mec inhibitor treatment. And as you can see, all four of those has some degree of tumor shrinkage, minus 24.9% through to in the 60s percent of tumor shrinkage. And the duration of prior Mec inhibitors ranged from around four months to over 70 months. And Mec inhibitor was the last line of therapy in two of those patients and two it wasn't. So I think there is some small numbers here, but interesting looking more deeply at the characteristics of the prior therapies for these patients. And they, as you can see, had a fair number of lines of therapy ranging from four to seven in this situation. And as I mentioned before, similar response rates according to number of lines of therapy in a small cohort of patients. So I just want to mention the rest of the RAMP201 study. I highlighted part A results of efficacy that we presented and some of the safety, including part B patients. So part C was a further expansion of the combination arm in KRAS mutated and KRAS wild type patients. And part D, which has completed enrollment, was looking at a lower dose of the avetamatinib in the combination arm. So we await those results. And I think this is, I wanted to thank everyone that's been committed to this study in terms of enrolling patients and those of you that also refer your patients to the trial centers so that we can try and push forward improving outcomes with new treatments to remove this disease. Thank you, Dr. Banerjee. And yeah, ever since we closed enrollment to 201, I've had a wait list of patients at my site waiting for the next generation of the avetamatinib and defactinib clinical trial. So of course, based on those incredibly promising response rates that you presented, as well as the relatively tolerable toxicity profile of this combination of avetamatinib and defactinib, there is now an international phase three study opening across the globe for patients with recurrent low-grade serosevere and cancer who are enrolled to have the option to be randomized to either this combination of avetamatinib and defactinib or to physician's choice of treatment with chemotherapy with pegylated liposomal doxorubicin, paclitaxel, topotecan, or endocrine therapy with letrozole or anastrozole. And very importantly, patients who do enroll to this study do have the option for crossover at time of progression if they're treated with investigator's choice. So really a fantastic option for so many of our patients with recurrent low-grade serosevere and cancer. So the RAMP301 study is currently open at sites in the United States and in Australia. It's opening in Europe now across multiple countries, also planned to open in Asia. So the rollout across the globe is just happening right now, but hopefully we'll have more sites opening every day so that we can bring this study to our patients with recurrent low-grade serosevere and cancer. Just to highlight the key inclusion criteria for this study, similarly to RAMP201, this is for patients who have confirmed low-grade serosevere or low-grade serous primary peritoneal cancer, who now have recurrent disease after having received at least one prior dose of platinum chemotherapy. Patients should have a known KRAS mutation status. You don't need to have a KRAS mutation, but before the patient goes on the study, we'd like to know whether they have a KRAS mutation or not. So if those results are already available, it's good to have those. If not, there's a mechanism through the study where those results can be obtained. Patients should have measurable disease per resist. They are allowed to have received a prior MEK inhibitor and are allowed to have received prior bevacizumab, though it's not required. And then patients are randomized one-to-one to either treatment with the combination of a butametinib and defactinib, which are these targeted pills that we've just seen fantastic results with and the results that Dr. Banerjee just showed us, versus physicians' choice of treatment with the option for crossover at time of progression. So we've included the clinicaltrials.gov identifier here at the bottom, but really excited for this study to now be opening up across the globe and bringing more options to our patients with recurrent low-grade serous ovarian cancer. I think we have one or two questions that came up in the chat. Dr. Banerjee, are you able to speak? Yeah, I'll tell you that. So one of them is, this would be a good question given what you commented on about NGS. So one of the questions is, what genes would you want covered in NGS or in your panel testing in low-grade serous ovarian cancer? Yeah, that's a great question. So of course, we're most commonly interested in the MAP kinase alterations. So with my next-generation sequencing platform, of course, I want to make sure that BRCA is covered because that's what's reimbursable for in the United States. But then along with that, we usually look for KRAS mutations and patients can have any of the KRAS mutations, really, within this disease. We look for V600 BRAF mutation. I also look for other MAP kinase alterations like NF1, NRAS. And then also, it's important to look for other potentially targetable alterations like CCNE1 amplification. Those are usually the key ones that I'm looking for. Are there others that you look for, Dr. Banerjee? I think they'd be the key ones. So I'd be interested, again, not necessarily for this pathway, but looking at ESR1 mutations, just thinking about endocrine therapy. And that leads me on, actually, onto one of the other questions, which was about ribocyclib and aromatase inhibitor treatment. So, you know, CDK4, 6 inhibition and AI. So, in particular, if there isn't access to MEK inhibitors or a clinical trial. And, you know, there have been very encouraging results in some of the trials so far. And we need so many options for our patients with low-grade serous ovarian cancer. So it's also about what's accessible. So perhaps you could comment, Dr. Christian, from the U.S. perspective about access and also your thoughts on endocrine combinations. Yeah, thank you. Yeah, so, of course, you know, Dr. Slomovitz presented at SGO last year the results of a GOG study in the recurrent setting for patients with low-grade serous ovarian cancer treated with a CDK4, 6 inhibitor in combination with an aromatase inhibitor. And then also interim results of a neoadjuvant pilot of CDK4, 6 inhibitor plus fulvestrant in patients with newly diagnosed low-grade serous ovarian cancer getting neoadjuvant therapy has been presented. And, of course, we have data about the toxicity profile and management of these drugs through our prior treatment of breast cancer patients. Thus far in the United States, this combination is not compendium listed. So I've not been able to have it available for my patients, but definitely something that I think definitely warrants further clinical trial exploration and is potentially an option for our patients in the future. Couple of other questions or clarifications. One of the aspects is about why patients with BRAF and NRAS mutations are not included. So just to clarify, they are included in RAMP-201 and RAMP-301. They would be, in terms of stratification, considered in the KRAS wild-type population, but they're certainly included. And in our analyses, we will be looking at outcomes according to MAP kinase pathway alterations. I don't know if you want to comment any more on that. Yeah, I just think it's such an important point because I know it does cause confusion when we say that we want to know if the patient has a KRAS mutation or not, but just exactly as you said, that's for stratification criteria, and it is not an eligibility criteria that a patient needs a KRAS mutation. So the RAMP-201 study, which has completed accrual, and the RAMP-301 study, which is opening around the globe right now, are open to patients with recurrent low-grade serosevere cancer, regardless of mutation status. You do not need a KRAS mutation. Great. Then some other questions. When will the trial open in Canada? Well, we know that it certainly will open. It will, it will. I'm afraid I'm not sure. I'm not sure if you know, Dr. Grisham, on specific timelines, but it is set to open. Exactly, yeah. I don't have the exact date, but yes, multiple sites in Canada will be opening. And we hope to open at the Royal Marsden in London, hopefully next week. Oh, exciting. Exciting. And then a question about the combination in high-grade serosovarian cancer. And you may want to comment, Dr. Grisham, on this. So it's in my experience, because this was the trials we did in the phase one were hypothesis-specific, and hence we targeted low-grade serosovarian cancer in terms of the gynae cohort. So I don't have experience of this in high-grade serosovarian cancer, but welcome your comments, Dr. Grisham. Yeah, much like you, I don't have experience for this combination in high-grade serosovarian cancer. There was a prior study of a single-agent MEK inhibitor, binimetinib, in combination with paclitaxel chemotherapy in patients with ovarian cancer. And that study enrolled patients with both high-grade and low-grade serosovarian cancer with the response rate in patients with high-grade serosovarian cancer being quite low. So generally, the MEK inhibitors have not been further pursued in high-grade serosovarian cancer. Great, I don't see any further questions. I'm pretty sure we've addressed them, but I think the key thing is really the excitement that I hope you can see that Dr. Grisham and I have about the studies in low-grade serosovarian cancer, where we have had limited effective options for far too long. And it's great that MEK inhibitors have come on the scene. And also, there's optimism about CDK4-6 inhibitors and combinations with endocrine treatments. We've got a long way to go, and we need to do a lot more translational work, looking for new targets, and also biomarkers for this disease. Okay, beautifully said. And yeah, and I just echo your enthusiasm that we're finally seeing positive studies, good results, really encouraging data in low-grade serosovarian cancer. And so, incredibly excited for the RAMP301 study to be opening across the globe now, and hoping to get many more sites up and running in just the next few months, including yours next week, so very exciting. Well, it's always great to see you, Dr. Banerjee. I'm sure I'll see you again very soon. And so, thank you so much for joining me today, and thank you everybody else for joining as well. Take care. Thank you.

Phase III study

RAMP301

low-grade serous ovarian cancer

avutumetinib

dafactinib

MEK inhibitors

NGS testing