Hello, my name is Wendell Naumann. I'm at the Levine Cancer Institute in Charlotte, North Carolina. I'm at the International Gynecologic Cancer Society meeting in Seoul, South Korea. And we had a very interesting presentation on the safety and efficacy in the RAMP-201 trial. I'm joined by Rachel Grisham from Morristown Kettering, who presented this data. And thank you for joining us, Rachel. Thank you, Wendell. Happy to be here. Yeah. So tell me a little bit about the RAMP-201 trial and the data that you presented today. Thank you. Yes. Today we presented interim results from the RAMP-201 study of avutimetinib and defactinib in patients with recurrent low-grade serous ovarian cancer. So this phase two study enrolls patients with measurable recurrent low-grade serous ovarian cancer who've had at least one prior line of platinum-based chemotherapy and are allowed unlimited additional lines of therapy thereafter, including up to one prior line of MEK inhibitor therapy. During parts A and B of the RAMP-201 study, patients were initially randomized to treatment with avutimetinib alone or avutimetinib in combination with defactinib. Now avutimetinib is a dual MEK-RAF inhibitor, and defactinib is a FAC inhibitor. Both of these drugs are oral agents. During part A and B, the initial go-forward decision was made based on whether better efficacy was seen with the combination of avutimetinib and defactinib or with avutimetinib alone. Those results were presented earlier this year at the ASCO annual meeting by Dr. Susanna Banerjee and showed unprecedented response rates for the combination of avutimetinib and defactinib, a 45% response rate for the overall population, 29% in the KRAS wild-type population, and 60% response rate in the KRAS mutant population. After that go-forward decision was made, all subsequent patients enrolled to the RAMP-201 study received the combination of avutimetinib and defactinib. At the conference here today, we presented interim results updating on the efficacy based on number of prior lines of therapy received prior to study entry and also safety data based on number of prior lines of therapy. These results showed that the efficacy was almost identical for those patients who were less heavily pretreated or more heavily pretreated, with about a 45% response rate in both groups. Similarly, when we looked at safety and tolerability, we saw that the regimen was quite tolerable both in the less heavily pretreated and more heavily pretreated patient populations, with the rate of grade 3 adverse events being very low with the exception of elevated blood CpK, which is a class effect of MEK inhibitors and is generally asymptomatic. We found these results incredibly encouraging that the combination of avutimetinib and defactinib is efficacious and safe even in our most heavily pretreated patients. That's very exciting data. Obviously, this is a very high unmet need. These patients are difficult to treat, obviously. They don't respond to chemotherapy like the high-grade serious cancers. So it's really interesting to see that kind of response. I guess the first question I have would be, how do you sequence, when you see these patients, how do you sequence their treatment and how do you see these drugs playing a role if they were to be approved? Obviously, the response rates to this combination is outstanding, regardless of how many treatment lines they've had. Yeah. Thank you. My practice actually has a very large population of women with low-grade serious ovarian cancer, since that's what my research focuses on. And it's been historically so challenging to find agents that are effective for these women. So generally, in the first-line setting for my patients with newly diagnosed advanced low-grade serious ovarian cancer, I discuss with them GY019 and the option for after surgical debulking to go on to GY019, where women are randomized to treatment with platinum taxane chemotherapy followed by letrozole or letrozole alone. For those patients that opt not to enroll to that clinical trial, I generally recommend platinum taxane chemotherapy followed by letrozole maintenance. Now, in the second-line setting, honestly, my first choice is clinical trial. So when I have a clinical trial available for these patients, like RAMP201, that's going to be my first choice for second-line therapy, because response rates to chemotherapy and endocrine therapy are generally less than 15% in the recurrent setting. In terms of third-line therapy, or if a clinical trial is not available, I think about whether the patient might be more likely to respond to endocrine therapy or chemotherapy. So generally, low-grade serious ovarian cancer has a binomial age distribution. There's a proportion of patients that are diagnosed at a younger age and patients that are diagnosed more at the age that's typical of high-grade serious ovarian cancer. Those patients that are diagnosed at a later age are more likely to have MAP kinase alterations and are more likely to be sensitive to endocrine therapy and are more likely to have that typical more indolent low-grade serious ovarian cancer. That's the patient where I'm more likely to consider an endocrine therapy, like letrozole as a next-line of therapy or anastrozole or examestane. With my younger patients who might be less likely to have a MAP kinase alteration, I'm more likely to go to chemotherapy, such as liposomal doxorubicin. That's great. Yeah. So, I mean, these are difficult patients, and obviously we're very excited about having new options for these women. You know, in agents blocking the MAP kinase pathway, you know, there's a lot of compensatory change, and I know there's some science behind multiple blockades with this combination. Very often, those are not tolerable because of the importance of that pathway. What was your experience with the tolerability of this combination? Yeah. Thank you. And this is such an important consideration because sometimes I have patients who are on targeted therapy for low-grade serious ovarian cancer for years, which is wonderful, but we want that to be a tolerable and safe regimen for them. And so, as you said, it's been challenging in the past with MEK inhibitors and especially with MEK inhibitors given in combination with other drugs, that the typical class effects like rash, peripheral edema, GI toxicity can be quite difficult to tolerate long-term. Now, on this study, avutametanib and defactanib are given intermittently. Avutametanib is taken twice a week, three weeks on, one week off, and defactanib is taken twice a day, three weeks on, one week off. And I found with my patients treated with this combination that it really does help with the tolerability. Patients have time each cycle for their skin to recover from the rash, for the GI toxicity to resolve, and things don't really seem to elevate to the level as they do with continuous therapy. And I do have quite a few patients, actually, that have had really minimal skin toxicity and much less than I would usually expect with a MEK inhibitor alone. It's of course also incredibly important with targeted therapies to make sure that you're maximizing correct supportive care. And so for all patients that I start on a MEK inhibitor, whether on trial or not, I start them with actually a prophylactic oral antibiotic to help prevent the skin rash. We also talk about appropriate skin care, such as topical moisturizers and the use of sunscreen to prevent sun-associated rash. We also talk about management of GI toxicity, and then also can mitigate other things like peripheral edema with the use of diuretics. That's great. And I think that your point about how long these patients are on therapy, I mean, obviously with the initial data, we saw the median duration of response to be over two years. And that's phenomenal. For patients that are heavily pretreated, many of who have had MEK inhibitors and really don't have any good options. So that's really exciting. The other thing that caught my eye was the response rate in the KRAS mutated patients, obviously a very difficult MAP kinase agent or point to target with targeted therapy, with the exception of the G12C mutation. What do you think about that? And is there any strategy that you think of when we look at the wild type? Is there something else we can add to this that might be tolerable? Yeah. Thank you. Yeah, I think there's a couple of points there. So yes, G12C inhibitors are a very promising strategy for multiple different types of cancer. Although MAP kinase alterations are quite prevalent in low-grade serosuvarian cancer, G12C itself is actually not very common. So quite a niche population for this disease. What I find very encouraging when we look at the results from the RAMP 201 study is not just that exceptionally high response rate in the patients with a KRAS mutation, but also that really excellent response rate of 29% in the KRAS wild type patients. And this shows me that these are an effective class of medications for those patients that do not have a KRAS mutation. And I think this speaks to a couple of different things. One thing is that low-grade serosuvarian cancer tends to be driven by MAP kinase alterations, but these are not always easily identified for several different reasons. They can be less common alterations, like a MAP 2K1 alteration that might not always be found on standard panel sequencing. But also the sequencing can be difficult in these patients because of the somatitis calcifications and the poor DNA quality oftentimes in biopsy samples. What we're really finding is that this combination is active both in those patients with an identified biomarker and in those patients without one. The role of KRAS in low-grade serosuvarian cancer is complicated because we have found that MAP kinase alterations are a prognostic indicator. So patients that have a MAP kinase alteration with low-grade serosuvarian cancer tend to do better no matter what they're treated with. So I'd say as of right now, it's more of a prognostic indicator than a predictive indicator. And I think that there's a really good rationale for use of these targeted drugs in the entire population of patients with low-grade serosuvarian cancer. That's great. Again, I think I was a little bit surprised by the data that you showed that split the patients by less heavily pretreated versus more heavily pretreated. And the fact that the response rates are very similar. This is very different from what we see with chemotherapy, for example, where the results decline drastically with each cycle. So was that a surprise to you, and how do you see that information in terms of sequencing your agents? Yeah, I think it's super encouraging. Even though we see the response rate is similar both in the less heavily pretreated and more heavily pretreated patients, I still do try to prioritize my most efficacious agents earlier on also because these treatments are pills. And of course, I always hate it when a patient develops something like a bowel obstruction later on that would make them unable to tolerate an oral regimen if I've got an effective oral regimen that I can give to them earlier. And so I would still prioritize clinical trial enrollment in oral drugs earlier in the course of therapy when possible, just to make sure that patients remain a candidate for it. Yeah, I think that's a great point. Now tell us about the registration trial, the RAMP-301 trial. That's obviously, it's also known as NGOT-OV-81 and GOG-3097. Tell me about that trial and how long it's going to take to enroll. When do you expect the results of this trial? Yeah, so super exciting. So based on these very promising results of abutametanib and defactanib that have been seen in the RAMP-201 study, the decision has been made to move forward to a randomized phase three study, as you said, the RAMP-301 study. That study is set to open hopefully later this year, 2023. And that study is going to enroll women with recurrent low-grade serous ovarian cancer who've had at least one prior line of platinum-based chemotherapy. They're, again, allowed unlimited additional lines thereafter. And patients will be randomized one-to-one to either treatment with abutametanib and defactanib or physician's choice of chemotherapy or endocrine therapy. So that can include liposomal doxorubicin, weekly paclitaxel chemotherapy, topotekin chemotherapy, anastrozole, or letrozole. And those patients that are enrolled to the physician's choice arm will have the option for crossover at time of progression as long as they meet eligibility criteria. And so I think a really exciting option. That's a great design. Yeah. That's a great design. Yeah. I'm so excited to have that option for our patients. And so this is an international study. It will be opening in North America, Europe, Asia. And so we think it will actually enroll quite quickly because it's, in my opinion, the best option for many of our patients. And so really excited to get that study started. So just to emphasize, they will get this combination either initially or if they randomize the chemo option, they will be able to cross over. So it's a great option for people who don't have any other treatment options that really, particularly for low-grade serious. And as I recall, this trial allows people who've been previously treated with MEK inhibitors. That's correct. So there's really not any barrier to entering the trial as long as they have a good functional status and good GI status, as you pointed out. So. Yeah. Start screening your patients now. Yeah. So, yeah. Just a little bit to back up about the workup. You mentioned the different types of patients that you put on endocrine versus chemotherapy. What is your workup? Do you always get NGS sequencing on these patients? Do you think that's important? Do you think that's important to set expectations in terms of responding in these types of situations? I know there's some other treatments out there. What is your thought on that? I do. So, yeah, as a standard of care, I get germline and somatic sequencing on all of my patients at time of diagnosis. And that gives us information both prognostically and can be important for future clinical trial eligibility and consideration of also other targeted drugs. So, of course, there's a tissue agnostic indication for those patients that have a V600E BRAF mutation for treatment with MEK and RAF inhibitor. And so it's good to think about that option for that 6% to 8% of patients that have a V600E BRAF mutation in low-grade serosuvarian cancer. And of course, always looking for other clinical trial options as well. And so I do get that information at time of diagnosis. It's generally pretty rare for a patient's mutation profile with low-grade serosuvarian cancer to change over time. So I don't think it's necessarily essential to re-biopsy someone and re-sequence them at time of each recurrence. But I think it is really important to have that information at least once during their disease course. And there are some other trials out there. I just want to mention the GOG3051, the Bouquet trial, which is a trial based on that they do have to have a certain diagnostic test to get on that trial, but that's covered on the trial. So there are other options. But I think everybody who sees this data is just very excited about it because these patients are so hard to treat. And I want to thank you for this and for your insights into this trial. We look forward to seeing the data in the future. Thanks so much, Wendell. Thanks.

Dr. Rachel Grisham

RAMP-201 trial

avutimetinib

defactinib

recurrent low-grade serous ovarian cancer