What’s the Latest in Low-Grade Serous Ovarian Cancer?

February 23, 2023

Low-grade serous ovarian cancer behaves differently than other ovarian cancers, which has treatment implications. Join Dr. Rachel Grisham, Section Head of Ovarian Cancer and Director of Gynecologic Medical Oncology at Memorial Sloan Kettering Cancer Center (MSKCC), as she discusses low-grade serous ovarian cancer treatment and any recent advances. Bring all of your questions to this program geared toward your specific concerns!

Key takeaways from webinar viewers:

  • This is an exciting time for low-grade serous ovarian cancer research.
  • Information on MEK inhibitors and how they work.
  • Mutations and how they affect treatment choices.
  • The reasons surgery is considered more often with low-grade serous ovarian cancer.
  • Information on CA-125 usefulness and limits when it comes to low-grade serous ovarian cancer.

00:00:00:00 - 00:00:53:09
Unknown
Hi, everyone. I'm just going to give a little bit longer to let people continue to join and then we'll get started. Hello and welcome to the webinar. What's the latest? And low grade serous ovarian cancer? I'm Maggie Nicholas Alexander, the senior director of Gynecologic Cancer Patient Support and Education at Share. Please use the chat to let us know where you're joining us from today before the presentation begins.

00:00:53:14 - 00:01:29:13
Unknown
I'd like to tell you a little bit about share Shares, a national nonprofit that supports, educates and empowers anyone who has been diagnosed with women's cancers and provides outreach to the general public about signs and symptoms because no one should have to face breast, ovarian, uterine, cervical or metastatic breast cancer alone. For more information about upcoming webinars, support groups and our helplines, please visit our website at Share Cancer Support.

00:01:29:13 - 00:02:00:19
Unknown
DOT or all participants will be muted during the presentation. Once Dr. Gresham finishes presenting, we will begin the Q&A discussion. Feel free to ask any questions through the Q&A section at the bottom of your screen. Remember that Dr. Gresham is unable to give specific medical advice, so please keep your questions. General in nature. We also have closed captioning available.

00:02:00:21 - 00:02:26:14
Unknown
You can enable this feature by clicking the live transcript button on the bottom of the screen and selecting the subtitle option. This webinar is being recorded and will be on the share website soon. Now I'd like to hand it over to the day's speaker, Dr. Gresham, to introduce ourselves. We're so excited to have you here today. Thanks so much, Maggie.

00:02:26:14 - 00:03:03:00
Unknown
It's my pleasure being here and thank you so much for the introduction. My name is Rachel Grisham and I'm the section head for ovarian cancer at Memorial Sloan-Kettering Cancer Center here in New York. And also the director of gynecologic medical oncology at MSK, KCC, West Chester. My research for the past 12 years has focused on low grade serous ovarian cancer, a disease that I'm passionate about, and that luckily we are really starting to make large strides in in helping to better understand how this disease develops and trying to better target it to have better outcomes for our patients.

00:03:03:02 - 00:03:31:22
Unknown
So today I'm going to give an overview about some of the recent insights we've gained over the past decade and how this is our changing our treatment of this disease right now and hopefully further changing it in the future through ongoing clinical trials. Just going to start my screen share here. There we go. And that and thanks for everybody for putting your locations in.

00:03:31:22 - 00:03:56:12
Unknown
In the chat I recognize some names there, so it's nice to see some members of our Sloan-Kettering community joining the call today. So just to start with, when I talk today, I'm going to be speaking about low grade serous ovarian cancer. And we say ovarian cancer for short. But when we say that we're really talking about ovarian fallopian tube and primary peritoneal cancer.

00:03:56:14 - 00:04:17:10
Unknown
Now, unlike high grade serous ovarian cancer, where we believe the vast majority of cases actually originate from the fallopian tube, we do feel that most cases of low grade serous ovarian cancer are actually arising from the ovarian epithelial tissue, though there is some emerging data showing that more cases may be, again, in the fallopian tube than we realize.

00:04:17:12 - 00:04:56:01
Unknown
But regardless, when I say ovarian cancer, I'm referring to ovarian fallopian tube and primary peritoneal cancer. Now, when we think about the different types of epithelial ovarian cancer, of course, there's the most common type, high grade serous ovarian cancer, high grade serous ovarian cancer accounts for about 70% of ovarian cancer cases. High grade serous ovarian cancer is the type that's most commonly associated with the BRCA one or BRCA two mutation, with about 20% of patients with high grade serous ovarian cancer being found to have a germline or somatic bracket mutation.

00:04:56:03 - 00:05:27:21
Unknown
Now, that type of cancer is almost always found to have a P53 mutation within the tumor tissue itself. And then we have these rarer types of ovarian cancer, including low grade serous ovarian cancer, which I'm going to speak about today. Low grade serous ovarian cancer accounts for less than 10% of cases of ovarian cancer. Unlike high grade serous ovarian cancer, low grade serous ovarian cancer oftentimes arises from something called serous borderline disease.

00:05:27:23 - 00:05:52:00
Unknown
Patients who are diagnosed have serious, borderline disease, have this pre malignant lesion that can make them more likely to later develop low grade serous ovarian cancer. Some patients with serious borderline disease who have it resected will never have it come back. Others will have it come back as serious borderline disease again or others will eventually progress to low grade serous ovarian cancer.

00:05:52:02 - 00:06:26:12
Unknown
When we look at low grade serous ovarian cancer tumors, the most common alterations we find are those affecting the mount kinase pathway. That's something we're going to talk about quite a bit today. So more on that later. Other common types of rare ovarian cancers include clear cell, ovarian cancer and endometrial ovarian cancer. Now, these are both grouped within the ovarian cancer family, but for many patients, they're actually arising from endometriosis that has itself fallen on to the ovary fallopian tube or primary peritoneum.

00:06:26:14 - 00:07:03:03
Unknown
These clear selling endometrial ovarian cancers are the ones that are most likely to be m.r deficient or associated with Lynch syndrome. They're also more common comment about to be found alterations affecting the map. The PI3 kinase pathway within these tumors such as PIK three C-A mutations or P ten loss. This is a molecular profile similar to endometrial cancer and so many of our novel targeted drugs targeting these tumors are similar to drugs that we're using in clinical trials for endometrial cancer.

00:07:03:05 - 00:07:30:10
Unknown
Finally, Mucin as carcinoma is another rare form of ovarian cancer. And this one is really tricky because a lot of cases that we initially believed to be Mucinex ovarian cancer are actually occult GI primaries, meaning that they're cancers that actually originated somewhere in the GI tract, such as from the appendix or the pancreas or the small intestine, and then metastasized to the ovary.

00:07:30:12 - 00:07:57:19
Unknown
So whenever somebody is diagnosed with Mucinex ovarian cancer, it is always very important that they've had a complete workup to make sure that they do not have a separate GI cancer. That's truly the source because that can affect how the cancer is treated. When we think about chemotherapy, the type of ovarian cancer listed here that's most sensitive to chemotherapy is high grade serous ovarian cancer.

00:07:57:21 - 00:08:23:13
Unknown
And we generally think about low grade serous ovarian cancer as being less sensitive to chemotherapy. However, that does not mean that chemotherapy does not work for low grade serous ovarian cancer. Chemotherapy has been shown in multiple different clinical trials to have activity in low grade serous ovarian cancer, but not as high of response rates as what we see in high grade serous ovarian cancer.

00:08:23:15 - 00:08:49:13
Unknown
But today, we're focusing specifically on those patients that have low grade serous ovarian cancer. So as I mentioned, this is a unique disease. Histologically It looks different underneath the microscope molecularly It has a completely different mutation profile than what we see with high grade zero ovarian cancer or these other rare types of ovarian cancer like Mucinex or Clear cell.

00:08:49:15 - 00:09:28:11
Unknown
And clinically it behaves differently. Also, oftentimes these tumors are slower growing than high grade serous ovarian cancer. However, they have a significant impact on patients lives. And unfortunately, this type of cancer is oftentimes diagnosed at an advanced stage. So therefore, even though these tumors are slower growing, they still have a significant impact on our patients life. And again, while we consider these tumors to be relatively chemo resistant, they do have responses to chemotherapy, but generally not as robust as that which we see in high grade serous ovarian cancer.

00:09:28:13 - 00:09:55:15
Unknown
When we look at the number of mutations that are commonly found in cancers, ovarian cancer falls right about in the middle of the spectrum amongst different types of solid tumors. Now, when we look specifically at serious borderline and low grade serous ovarian cancer, we see that in comparison to other types of epithelial ovarian cancer, the mutation burden is relatively low.

00:09:55:17 - 00:10:30:07
Unknown
So we oftentimes find very small numbers of actionable mutations in patients with low grade serous ovarian cancer. We consider it to be a relatively stable, genomically stable disease. This is important for several different reasons. One reason is that when we think about those MSI high tumors or what we also call microsatellite instability, those tumors that are most sensitive to immunotherapy, these patients with low grade serous ovarian cancer are unlikely to be those MSA high tumors.

00:10:30:13 - 00:10:56:18
Unknown
They're unlikely to have MMR deficiency. And so we really need to look for other targets outside of immunotherapy right now to help us treat these tumors. It's also important because of this relative genomic stability, we generally, over time do not see a large number of changes in the mutation profile of these tumors over the course of a patient's life with this disease.

00:10:56:20 - 00:11:25:20
Unknown
This is in different than some other types of tumors, such as lung cancer, where the mutation profile might change very quickly In low grade serous ovarian cancer, oftentimes the mutation profile remains relatively stable over time. So if we do find an actionable alteration in a patient's tumor, even if that tissue is from 12 months or two years ago, it's likely that that tissue still has that alteration.

00:11:25:22 - 00:12:06:09
Unknown
Now, when we first started looking at patients of serious, borderline and low grade serous ovarian cancer, we oftentimes grouped these patients together because of the rarity of this disease. Going to get up for a second and move because my light just went off. We like to conserve energy here. Excuse that interruption. So one of our first forays into trying to describe the molecular profile of Cirrus borderline and low grade Cirrus ovarian cancer depended on using something called sequencing and Sanger sequencing to try to identify hotspot mutations in patients with serious borderline and low grade zero severity in cancer.

00:12:06:11 - 00:12:42:03
Unknown
And what these initial studies found was a high rate of Krass and B 600 e BRAF mutations, particularly in patients with serious borderline disease. In fact, we found that those patients with serious borderline disease that had this P 600 BRAF mutation were less likely to present with advanced age disease, less likely to progress to low grade severe severity in cancer, and unlikely to ever be treated with chemotherapy during the course of their life.

00:12:42:05 - 00:13:11:18
Unknown
This led us to believe that presence of ab6 hundred E mutation likely was prognostic of improved outcomes for patients with serious borderline disease. Similar studies have also been conducted at Johns Hopkins and MD Anderson, which found similar findings that these patients that have a, B 600 E BRAF mutation generally do better, and if it's found in serious borderline disease, are less likely to progress to low grade serous ovarian cancer.

00:13:11:20 - 00:13:32:20
Unknown
This is important because for our patients with serious borderline disease, of course they want to know how likely is it that this will return as low grade serous ovarian cancer? What can we know to help to predict what the future will be? So this is one tool that can help us now in this case, this mutation was identified by a sequencing.

00:13:32:22 - 00:13:57:21
Unknown
However, since this time we've developed a IHT assay that can be used on the tumor tissue itself to relatively quickly determine if patients have this mutation in their tumor cells, and that we now perform this as a standard of care in all of our patients with newly diagnosed serious borderline disease to try to provide some prognostic information for our patients.

00:13:57:23 - 00:14:52:03
Unknown
So now, as I mentioned, these earlier studies that we did that first started to describe the mutation prevalence in serious, borderline and low grade serous ovarian cancer, We're focused on relatively limited sequencing platforms. So in this case, sequencing, which looked at hotspot mutations, mutations that have been well-characterized, and then also Sanger sequencing. Now, since that time, our understanding of tumor sequencing has really evolved quite a bit and allowed us to make much deeper insights not only into how the disease functions across the large greater population, but also in order to be able to tell patients specifically more about their tumors and what treatments they may be more likely to respond to.

00:14:52:04 - 00:15:22:08
Unknown
So I mentioned these mutations like KRAS mutation and BRAF V 600 E mutation. These are mutations in a pathway called the map kinase pathway. So the map kinase pathway is a cell signaling pathway that when activated leads to cell growth and prevention of cell death. So when this pathway is activated in a cancer cell, this light switch is turned on.

00:15:22:10 - 00:16:05:01
Unknown
That makes that cell just keep reproducing and not die. So if you can target that pathway and inhibited and turn it off, you can then allow for cell death of these cancers cells, which is what we want. So oftentimes, since we know that we have activation of this map kinase pathway in patients with low grade C or Siberian cancer through cross mutations or other alterations affecting this pathway, it can help us to better determine what type of drugs we should be using to try to inhibit this disease.

00:16:05:02 - 00:16:39:00
Unknown
So one of the very first clinical trials that tried to leverage this information that we have about there being mapk kinase alterations in low grade Sierra Siberian cancer was Georgi 239 So this was a study of an early generation MEK inhibitor called cell. You mentioned EB and this study enrolled patients with recurrent low grade serous ovarian cancer who had measurable disease, meaning at least one centimeter tumor nodule or 1.5 in the smallest dimension.

00:16:39:00 - 00:17:04:17
Unknown
If it was a malignant lymph node. Patients who enrolled to the study were treated with this oral MEK inhibitor cell. You met to NAB and remained on treatment for as long as it was working or unless they developed bad toxicity. So we, as we say, until progression of disease or intolerable toxicity. And that study found that amongst those patients treated on that study, there was a 15% response rate.

00:17:04:17 - 00:17:36:10
Unknown
So eight out of 52 patients had what we call a resist response, which means 30% tumor shrinkage or more. And at the time this was considered to be a really good response rate, since historically the response rate to chemotherapy or hormonal therapies like aromatase inhibitors is generally considered to be less than 15%. Now, it's really important when we do a clinical trial to try to gain as much as possible from it.

00:17:36:12 - 00:17:55:13
Unknown
Every single patient that enrolls on to a clinical trial is making a huge sacrifice. As some of you may know, as you might have participated in clinical trials. Being on a study always, almost always requires more work than if you were receiving standard of care therapy. You usually have to come in for extra visits, have extra blood drawn.

00:17:55:13 - 00:18:33:22
Unknown
You might have CAT scans done more frequently. There might be tumor biopsies that are performed. And so the and the benefit of that is that this information is collected in a prospective way that allows for it to be very reliable information that we can then use to not just get the primary outcomes of the study, but we want to be able to use that information to get as much useful information as we can to empower patients to know about their disease and to be able to find pathways forward for new ideas, for better treatments for the disease.

00:18:34:00 - 00:19:10:08
Unknown
So although this was a relatively small study, we wanted to make sure that we were learning everything possible from those patients that had committed their time to enroll to the study. So one patient that was treated on that study was treated here at Memorial Sloan Kettering Cancer Center. And it was a woman who had been diagnosed with low grade serious of brain cancer several years earlier, had gone through multiple different surgeries, chemotherapy, intraperitoneal chemotherapy, endocrine therapy, and ultimately enrolled to the study, started the cellular medicine, and had a complete response.

00:19:10:08 - 00:19:33:21
Unknown
So after multiple prior lines of therapy before she went on this study, she went on this study and her cancer became so small that we couldn't see it. And that was more than 14 years ago. And she remains on the clinical trial. She's still taking that same drug. The study ended years ago, of course, but the drug company continues to provide the drug because she continues to respond.

00:19:33:21 - 00:19:59:06
Unknown
So this was a patient that we call an extreme responder, a patient that's had fantastic outcomes from treatment of the targeted drug. And so we want to know why did she have fantastic outcomes and how can we help to figure out who those patients are that are most likely to have these really strong responses to MEK inhibitors so that we can get this drug to those patients?

00:19:59:08 - 00:20:37:11
Unknown
So what we did with the patient's consent, of course, was look at her archival tumor and used a newer type of sequencing to evaluate this tumor tissue called next generation sequencing, which since that time has now become a standard of care. But back at this time was something we were still doing in a research laboratory and identified through that sequencing a deletion in a gene called MAPP two to K-1, and we were then able to use structural modeling to predict how that gene mutation was affecting the shape of the protein that it codes.

00:20:37:11 - 00:21:40:07
Unknown
For now, this was important because it allowed us to predict how this altered protein may potentially make a cancer cell likely to keep growing. And based on this formation, we felt that this alteration was leading to activation of the map kinase pathway and triggering phosphorylation of a protein called erk. So we subject gently developed cell cultures that had this same alteration and showed that the cells that had this alteration grew much more quickly and more strongly than cells that did not have the alteration, meaning it was oncogenic and showed in these plots that the cells that had this alteration had higher levels of this possible erk, that the erk was phosphorylated and then also showed

00:21:40:09 - 00:22:12:18
Unknown
that you could inhibit this pathway by treating with MEK inhibitor. So this was a great way for us to learn about how this alteration might make patients with low grade serous ovarian cancer more sensitive to treatment with MEK inhibitors. Now this sequencing, which now is called here at our institution, Ms. K impact is now a standard of care option for all patients and we can use this information in so many different ways.

00:22:12:18 - 00:22:36:16
Unknown
Here at Sloan-Kettering, we offer this sequencing to all of our patients with newly diagnosed or recurrent ovarian cancer, and this allows both patients to know if they have a mutation. And then also we can put this information into a database which can then be triggered to let us know if there's a clinical trial available that targets an alteration that a patient has.

00:22:36:18 - 00:23:12:00
Unknown
There are also other commercially available assays that can be used at other institutions such as foundation medicine and others that also use similar sequencing platforms and are available to the too much of the population worldwide. Now, that's one example of an alteration that we found of in an extreme outlier. But there are other alterations that we've found in patients with low grade serous ovarian cancer as well, such as this patient who was treated on a clinical trial.

00:23:12:00 - 00:23:56:22
Unknown
We were running with the MEK inhibitor in weekly Taxol and had an extreme response and subsequent, well, they threw deep sequencing of her tumor tissue and other analysis. We found her to have a novel BRAF fusion that had not previously been identified. But then when we went through our archival database of other patients with low grade serous ovarian cancer tumors, we were actually able to find a whole slew of different alterations affecting the map kinase pathway that we had not previously been looking for when we were just looking for these hotspot mutations like Cross or BRAF, allowing us to better understand the extent to which this pathway is altered in patients with this disease.

00:23:57:00 - 00:24:21:11
Unknown
So it's good to understand why a cancer is forming and and what makes it grow. But the reason we really want to understand that is so we can target it and treat patients and have good responses. So the next two clinical trials were our big forays into trying to treat patients with low grade serous ovarian cancer with MEK inhibitors and on a large scale to to see how effective they were.

00:24:21:13 - 00:24:49:12
Unknown
So I'm going to describe two different studies. The first one is called the Milo Study Our Milo and got over 11 study, which was open across the world in multiple different countries. The study initiated in 2013 and closed in 2016. It enrolled 341 patients and thus far has been the largest prospective clinical trial ever performed in low grade serous ovarian cancer.

00:24:49:14 - 00:25:11:21
Unknown
So this study enrolled patients with recurrent or persistent low grade serous ovarian cancer and patients that had at least one prior line of chemo, but they couldn't have had more than three prior lines of chemo. And then patients were randomized to either treatment with a single agent been imatinib. This one is called excuse me, a single agent MEK inhibitor.

00:25:11:21 - 00:25:48:07
Unknown
This one is called been imatinib or two treatment with physician's choice of chemotherapy where the physician and patient would choose together which chemotherapy was most appropriate for that patient. And the choices could have been percolated like the symbol doxorubicin, which is also called Doxil Paclitaxel or Topol can. So this study unfortunately closed in 2016 when an interim data analysis showed that the PFC analysis had crossed the predefined futility boundary, meaning that the PFC was similar between the two arms.

00:25:48:09 - 00:26:24:04
Unknown
But again, even though that study closed early, we want to learn as much as possible from this study. You know, over 300 patients sacrificed their time to enroll on this study. And we want to make sure that we're obtaining as much information as possible from this study that was performed. So because this study was performed across the world, we had the advantage that the patients that were enrolled to this study were somewhat more diverse population than what we've enrolled to with our patients that have been limited to our studies, that have been limited to the United States population.

00:26:24:04 - 00:27:11:00
Unknown
And overall, over 100 patients donated their tumor tissue when they enrolled to this study to allow for it to undergo sequencing to look for alterations using this next generation sequencing. In this study, it was done using a platform called Foundation Medicine, which is a commercially available platform, and it found that amongst patients who had a cross mutation, one of those mutations that affects the map kinase pathway for those patients that were treated with the MEK inhibitor have been imatinib the progression free survival, meaning the time that the patient stayed on treatment before their cancer progressed was significantly longer if the patient had a cross mutation.

00:27:11:02 - 00:27:50:01
Unknown
So for those patients that had a cross mutation at 17.7 months versus 10.8 months for those patients that did not have a cross mutation or what we call cross wildtype, meaning not mutated. Now for the patients that were treated with physician's choice of chemotherapy, there was also a nonsignificant trend towards longer pafs in those patients with the cross mutation 14.6 months versus 11.5 months, indicating that having a cross mutation appears to be a prognosis stick, that patients that have the cross mutation, no matter what they're treated with, might do a little bit better.

00:27:50:03 - 00:28:20:10
Unknown
But amongst those patients that are treated with the MEK inhibitor, those with the most robust responses were those with the cross mutation. Though it's important to note that there was activity seen both in patients with and without a cross mutation amongst those in that primary popular publication. We also showed that the response rate for patients with a cross mutation was 44% versus 19% in those patients that were cross wildtype.

00:28:20:11 - 00:28:45:07
Unknown
And again, when we're talking about response rate here, this is using that resist criteria that's used in clinical trials. So a response means 30% shrinkage or more. So amongst those patients that had a cross mutation, they were treated with the MEK inhibitor, 44% of them had 30% shrinkage or more. And and amongst those that did not have a cross mutation, cross Wildtype, 19% of them had a 30% shrinkage or more.

00:28:45:09 - 00:29:25:12
Unknown
So still a good a good response rate, but but more robust in those patients that have a cross mutation. We did a further analysis of this looking at map kinase alterations in general. So not just cross mutations also and ROS mutations and BRAF mutations and if one mutations so other alterations in this same pathway and found pretty much the same effect across alterations affecting this pathway where we see this same trend towards improved response rate in those patients that have a map kinase alteration versus those that do not.

00:29:25:14 - 00:29:53:02
Unknown
But again, with responses both in those patients with a map kinase alteration and without meaning that we think that this alteration is prognostic, but it's not predictive. It doesn't tell us, you should get a mack inhibitor and you shouldn't because both populations of people, those that are that have a mutation in or wildtype can derive benefit and have responses, but it can give us prognostic information.

00:29:53:04 - 00:30:20:07
Unknown
So another study that was ongoing at the same time, Jujitsu 81, was a very similar study. So this study again, enrolled patients with recurrent low grade serous ovarian cancer who had measurable disease. The key difference here was that these patients were a more heavily pretreated population patients. Again, had to have had at least one prior line of chemo, but there wasn't a limit on how many lines after that they could have had.

00:30:20:13 - 00:30:50:07
Unknown
So about half of the patients that enrolled to the study that had three or more lines of therapy patients here were randomized to either treatment with a different MEK inhibitor in this time called trauma to NAB or standard of care therapy. And here it had those three chemo options that were available in the other study. Mylo So liposomal, doxorubicin, paclitaxel or topo can and two of the other options were endocrine or hormonal therapies.

00:30:50:07 - 00:31:14:16
Unknown
So Letrozole or Tamoxifen. So patients enrolled to this study, if they were randomized to standard of care, could have chosen in conjunction with a discussion with their physician to either be treated with chemotherapy or with a endocrine therapy like Letrozole or Tamoxifen. And patients remained on study again until either they progressed or had side effects that made them come off of study.

00:31:14:18 - 00:31:51:18
Unknown
So as I mentioned, this was a more heavily pretreated population, with half the patients having three or more prior lines of therapy before they enrolled to this study. But this study did meet its primary end point, and it showed a significant improvement in progression free survival for those patients that were treated with traumatic AFib versus those patients that were treated with the standard of care, chemotherapy or hormonal therapy and the difference in progression free survival was 13 months versus 7.2 months.

00:31:51:20 - 00:32:23:09
Unknown
So looking across both of these studies, what we see that is we gained a lot of important information. We gained information about what to expect with standard of care therapies because we didn't have a lot of good prospective information about that before these clinical trials were done. A lot of it was retrospective data and honestly, a lot of the retrospective data had predicted that the response rates to chemotherapy were going to be lower because there was a lot of retrospective data saying response rates to chemo would be 4% or lower.

00:32:23:09 - 00:33:00:23
Unknown
And so when we saw these higher response rates to chemotherapy, it somewhat affected our statistical design. But that was, you know, it's one of the challenges and in a rare tumor study is that you don't always have a lot of prior information. So this gave us important information about standard of care therapy. It gave us really important information about expected response rates to single agent MEK inhibitors and has given us important information about how tumor profiling, determining the molecular alterations in somebody's tumor can help us to predict how they are going to respond to a treatment.

00:33:01:01 - 00:33:24:17
Unknown
And so that's really important information. So looking across these two studies, one where in one study patients that had more prior chemo than in the other, and so the response rates to standard of care therapies ranged from 6 to 13% across these two studies. And then the response rate to single agent MEK inhibitor ranged from 16 to 26%.

00:33:24:19 - 00:33:51:14
Unknown
So that's good. We were we were happy to have a new option for our patients with low grade serous ovarian cancer. And so based on the response of these studies, traumatic fib and been imatinib are now included in the NCC guidelines, which is our National Comprehensive Cancer Network guidelines for what we feel are the appropriate or acceptable treatments for all different types of cancer.

00:33:51:14 - 00:34:18:11
Unknown
So we have NC ten guidelines for for all different types of of cancer. And so amongst the ovarian cancer guidelines, the low grade serous ovarian cancer guidelines now include trauma to never been imatinib as options for patients with low grade serous ovarian cancer. So, so great news that our patients have that option in the United States at least we still have challenges abroad, but we need better response rates.

00:34:18:11 - 00:34:41:22
Unknown
Right. That's that's good. That's some advancement, but it's not enough. So we need to find a way to have more patients responding and we need to have deeper responses because this isn't good enough yet. So our next generation of clinical trials is looking to see how can we improve upon these response rates that we see with single agent MEK inhibitors.

00:34:42:00 - 00:35:05:07
Unknown
And so this is a study that I'm very excited about. Now I'm going to talk a little bit about a Phase one study that was called the Frame Study. And then I'm going to talk about an ongoing Phase two study called the ramp to a one study I should note that I am the National PI of the ramp to one study and so have a would like that study to do well.

00:35:05:09 - 00:35:40:05
Unknown
So so I'm disclosing that information. So the the frame study was a phase one study that looked at a combination of a dual MEK inhibitor plus a FAK inhibitor with the idea of being trying to enhance the efficacy of a dual MEK BRAF inhibitor in patients that have cancers that are sensitive to MEK inhibitors. Now a dual MEK RAF inhibitor means that we're inhibiting both MEK.

00:35:40:05 - 00:36:18:18
Unknown
So MEK inhibitors, we just saw a couple examples of those traumatic then imatinib. So you mentioned those MEK inhibitors. There's another type of drug called a RAF inhibitor such as vemurafenib that inhibits RAF, which is another component of that MAPP kinase pathway. So a dual McGrath inhibitor is inhibiting with one drug, both MEK and RAF. So we've got a drug that's trying to hit two parts of that pathway and then a FAC inhibitor is the second drug to throw in there to try to prevent resistance from developing.

00:36:18:18 - 00:36:44:07
Unknown
So when you inhibit one pathway, we have other pathways that try to compensate for it and get around that pathway being inhibited. And so it's always important when giving a targeted drug to be predicting how that resistance is going to develop and then trying to inhibit that resistance from the beginning so that your drug works as long as possible.

00:36:44:07 - 00:37:13:02
Unknown
And you have a response as long as possible. So the supreme study, which was open to multiple different solid tumors, including low grade serous ovarian cancer among those patients with low grade serious ovarian cancer in this phase one study showed really promising results for this combination with patients, both with map kinase alterations and without map kinase alterations having really deep and durable responses.

00:37:13:04 - 00:37:45:01
Unknown
The other thing that was really interesting, which was seen in this initial frame study, was responses in patients who had been previously treated with MEK inhibitors. So this is a plot that shows best tumor response. So its amount of shrinkage for each one of these individual patients that was treated on this frame study. So, for example, this patient had about 70% shrinkage of their tumors and they have a cross mutation.

00:37:45:03 - 00:38:03:08
Unknown
So for each one of these individual patients, if they have these lines, these these crosshatch is going down their column, it means they had already been treated with a MEK inhibitor before. So they had either been treated with traumatic nerve or been imatinib or saw you mentioned them either on a clinical trial or through a standard of care treatment.

00:38:03:09 - 00:38:33:03
Unknown
And despite having come off that treatment, in most cases for progression, they still responded had tumor shrinkage with this combination. So it's really exciting to think that this might be a possible post MEK progression option or for people that have never had a MEK inhibitor, perhaps potentially an option that is more active than MEK inhibitor alone. Right? Because we want the the best responses possible.

00:38:33:05 - 00:39:02:23
Unknown
And in many patients on that initial phase one study remain on treatment now. So based on the results of that study, the FDA in the United States granted breakthrough therapy designation to this dual MEK RAF inhibitor, 6766 in combination with two factor NAB for recurrent low grade serous ovarian cancer, which allowed for this pathway to try to expedite drug development of these drugs.

00:39:03:01 - 00:39:33:13
Unknown
You know, it can take so many years between the time that a drug looks promising in the lab until it becomes available to patients. And so we try to take advantage of these opportunities when possible to try to accelerate that process so that we can just try to get drugs to patients as quickly as possible, because nobody wants to be waiting around for years for a clinical trial process and then to be reviewing that clinical trial process for any longer than it has to.

00:39:33:15 - 00:40:04:09
Unknown
So that led to the development of this ongoing Phase two study. G 3052 and got to be 60, which is called the ramp to a one study. So this is a study looking at patients with recurrent low grade serous ovarian cancer with measurable disease. They're allowed to have had one prior line of MEK inhibitor and treating patients with either this dual mack RAF inhibitor, B 6766 or dual met inhibitor plus defect in EB.

00:40:04:11 - 00:40:32:06
Unknown
And looking at two different cohorts of patients, those patients with a cross mutation and those patients without a cross mutation to try to better learn about how response rates and progression free survival are in those two populations. Because we know from our prior experience on these other clinical trials that patients with a cross mutation might respond a little bit differently than patients without a cross mutation.

00:40:32:08 - 00:40:59:12
Unknown
And so some initial results from this study have been not presented yet, but released on the website for the company, which initially are showing good tumor shrinkage. Now again, these are just results that have been released by the company and have not been formally presented yet or published. And so we should wait for the presentation and publication before we draw any strong conclusions.

00:40:59:13 - 00:41:14:05
Unknown
But initial data looking very promising for seeing similar tumor shrinkage to what has previously been reported in the frame study, which I'm very excited about as this study continues.

00:41:14:07 - 00:41:58:12
Unknown
So just switching gears for a minute, I just wanted to say that, you know, for in studying rare diseases like this low grade serous ovarian cancer, we really need to come together and work together across the world to try to make these studies happen and to try to learn and gather information as quickly as possible. And so it's so important to have groups like this that bring patients and advocates and family members together to try to spread the information, to try to find out what clinical trials are available, to try to find out what's changing in the treatment of a disease and and just to really all work together, because we've all got the same

00:41:58:12 - 00:42:39:08
Unknown
goal here. And so one example of someone that beautifully, really brought people together is Jane Littman and her family, who worked with David Gershwin's in at MD Anderson Cancer Center to develop something called the ICI LLC, which is an international consortium of researchers who study low grade serous ovarian cancer. So this includes and physicians from across the globe who really just work together to try to make sure that we're furthering research and benefiting from each other's research and just trying to accelerate the process as much as possible.

00:42:39:10 - 00:43:16:00
Unknown
And through this group, we're working to develop a new clinical trial platform to hopefully bring more studies to low grade serious ovarian cancer patients quickly working on a potential patient registry, working on different projects to just try to bring our patients and physicians together. And this is across multiple different organizations from New Zealand and the Anderson Sloan-Kettering. Hopkins and I think is a really nice example of how we can come together within these rare diseases to just be all on the same team.

00:43:16:02 - 00:44:02:05
Unknown
And, you know, and I think that we've done that across a lot of other solid tumors. But we can do we can do better. And it's something that we just have to keep challenging ourselves to work together and collaborate and try to accelerate research. And so finally, I wanted to, of course, thank our wonderful patient advocates and everybody that worked so tirelessly, whether it be through spreading patient information, building websites, donating their time, donating resources, cycling for our Cycle for survival team, you know, doing all these different things that so much of our our our patients and families have committed their time and efforts to to try to help us to get better options for

00:44:02:05 - 00:44:31:10
Unknown
the future. So thank you. Thank you so much, Dr. Gresham. That was a great presentation. And so we're going to get started with the Q&A. You can still submit questions in the Q&A section at the bottom of your screen. We will try to get through all of the submitted questions, but we may not be able to due to time constraints.

00:44:31:11 - 00:45:00:05
Unknown
All right. So this person is asking, when should someone with low grade serious consider a second or third surgery? That's a great question. So, you know, I'm a medical oncologist, so I didn't talk too much about the surgery here. But that's a really important question because surgery is a much bigger part of low grade serous ovarian cancer than it is for high grade serous ovarian cancer.

00:45:00:07 - 00:45:25:13
Unknown
So in high grade serous ovarian cancer, often times patients just have their primary surgery. There's a select group that have a secondary debulking and a even smaller group that have a tertiary debulking. But almost it's it's pretty rare that we go past a tertiary debulking with high grade serous ovarian cancer. Now, low grade serous ovarian cancer is a disease where we never really stop considering surgery.

00:45:25:15 - 00:45:57:06
Unknown
It's something we always want to be weighing. And so it's always important that a patient with low grade serous ovarian cancer continue to be followed by their gynecologic oncology surgeon. So patients that follow with me, I'm a gynecologic medical oncologist, also follow with a gynecologic surgeon, and we work together each time that there is a symptomatic progression, we think about, is this something that would best be treated with systemic therapy or is surgery something we should be considering?

00:45:57:08 - 00:46:20:07
Unknown
And the reason it's so important is because of, you know, that being less sensitive to the chemotherapy is an important factor and we don't want our patients to develop obstructive symptoms if something is slowly growing over time and then has a risk of obstructing the bowel or bladder, and we can prevent that or significantly delay that from happening with surgery, it is something we should be considering.

00:46:20:09 - 00:46:50:13
Unknown
Of course, surgery comes with risks, no doubt. You know, risk of poor wound healing, bleeding, infection, fistula, all these things that can occur. But I would say for my patients with low grade serous ovarian cancer, we always consider surgery at time of first recurrence. We consider surgery if there's a potential obstructive event that could happen like a bowel obstruction or any time where the disease appears to be somewhat localized and it's grew in its growth.

00:46:50:13 - 00:47:25:13
Unknown
So I think it is important to continue that relationship with your surgeon and to to consider that more often than we would with high grade serous ovarian cancer. Great. Thank you. And this person is asking whether k 125 is less of a marker in recurrent disease for low grade serous. Yeah, it's another great question. Thank you. So yes it is so C 125 is less predictive in low grade serous ovarian cancer than it is in high grade serous ovarian cancer.

00:47:25:15 - 00:48:03:00
Unknown
This was found in a clinical trial with Amanda Theater, amongst other prior retrospective studies. And so, you know, we still look at it. I still measure it in my patients with low grade serous ovarian cancer. I think there's little downside to that. But here's the key thing, and this is something I've seen done what I feel is incorrect before, I would not monitor someone with low grade serous ovarian cancer with K 125 alone if somebody had advanced stage disease at time of diagnosis and has completed their adjuvant therapy and is now on follow up, there's some people with high grade serous a bone cancer that are followed with just 125 and then scan of C1

00:48:03:00 - 00:48:24:05
Unknown
25 elevated for someone with low grade serous ovarian cancer. I don't think the G1 25 is good enough to be able to make those decisions. And so for my patients who have advanced advanced low grade serous ovarian cancer at time of presentation, I will follow them with routine scans because I just don't think this year 125 is good enough to to drive those decisions.

00:48:24:07 - 00:48:50:07
Unknown
That makes sense. And sort of a question someone else was asking what what is sort of your opinion if the K 125 is rising, but you know, the scans and everything show no side shows that disease is stable. Yeah. You know, so the as we all know, year 125 can be affected by a lot of different things. Right?

00:48:50:07 - 00:49:15:16
Unknown
It can it's everybody has this year 125 value it doesn't go to zero there is some number in any patient that you measure it on whether they've ever had cancer or not. And as we just said, it's not as predictive in low grade serous ovarian cancer. So if some I really go by the scans more. So if somebody's scan is stable in this year, 125 is going up it.

00:49:15:18 - 00:49:44:15
Unknown
I generally feel that it's it's best to wait until there's a radiographic change before you change treatment, partly because we only have so many lines of therapy. And if there's all if there's no radiographic change, it's unlikely you're going to benefit somebody by quickly going through all of their available lines of therapy based on just see 125, you're more likely going to drive tumor resistance and limit their options for the future.

00:49:44:15 - 00:50:06:20
Unknown
And so I think it's best to wait until there's a radiographic change. Now, sometimes when this year 125 is going up, that is because there's more microscopic cells that are floating around. But luckily those microscopic cells are not the ones that are hurting us, Right? It's the ones that are big enough to see that are growing, that have the potential to cause harm.

00:50:06:22 - 00:50:31:17
Unknown
And so I think it's better that we reserve our change in treatment for when there is that tumor growth that we can see. great. Thank you for that. And so this person is asking about Anna's versus Kara's. And the question is, are treatments showing success, Kara, as also effective for interest because they feel that they hear more about Karev?

00:50:31:22 - 00:51:03:05
Unknown
Yeah. Yeah. No, it's a great question. Yeah. And it's been it's been kind of a hot topic, especially with the ramp to one study going on because it limits to the Cross mutant and cross wild type cohort. So having that as an inclusion criteria was was frustrating for some of our patients. When the cross wildtype cohort closed in, you need a cross mutation because the you know really and what we've learned from doing this map kinase alteration, an analysis from the MILO study is that we see the same trends across all map kinase alterations.

00:51:03:11 - 00:51:42:23
Unknown
So yes, I think that an interest mutation is likely just as predictive of response as a cross mutation. And so, you know, whether it's, you know, a BRAF mutation, an interest mutation to cross mutation, I think these are all good prognostic indicators. And so I would really group them together into the greater family map kinase alterations. But for various reasons, sometimes a clinical trial or something like that will limit to cross mutation is a separate topic would be that there's a separate class of drugs that specifically inhibits a certain type of cross mutation.

00:51:42:23 - 00:52:14:08
Unknown
Cross day graders, and that's being considered for some phase one clinical trials right now. And some of those might have spots open for low grade serous ovarian cancer patients. If it's a drug that's specifically a cross degrade or that, yes, you need to have a cross mutation. But when considering just the use of a drug like traumatic fib or been imatinib, I would consider cross in interest to both be similar prognostic.

00:52:14:09 - 00:52:41:12
Unknown
Right. Thank you. And we're getting some more questions about scans. And so this question is about whether there's a specific type of scan that better shows low grade serous growth. Yeah. You know, so so it can be a little tricky because with low grade serous ovarian cancer, we get these calcifications, right, that has the disease and you look at it under the microscope, it has these at the moment is calcifications.

00:52:41:14 - 00:53:05:21
Unknown
And then when you look at it, radiograph, it can also have these calcifications. In general. I feel the best scan for most patients with low grade serious ovarian cancer is a CAT scan. A CT scan. You know, there's sometimes because the low grade source of brain cancer is a bit slower growing, it may not be pet avid. And also PET scan is not the best way to evaluate for a change in size of lesions.

00:53:05:23 - 00:53:33:23
Unknown
And what we're really looking at for is to see if things are growing by millimeters or decreasing by millimeters. And a CAT scan is is generally our best way to see that. Definitely there's imperfections with any imaging modality. But and for some reason and for various reasons, we might use a different imaging modality such as if somebody has serious borderline disease and does not have cancer that's progressed to low grade serous ovarian cancer.

00:53:34:01 - 00:54:06:04
Unknown
We might follow that patient with ultrasounds or in certain cases MRI, because of course there's the risk of radiation and contrast over the course of somebody's life, particularly in somebody who's young and doesn't have a diagnosis of invasive cancer. But for somebody that has low grade serous ovarian cancer, generally, CAT scan is my preferred scan. Great. And then one other question about scans is just around the the frequency that people should typically be scanned.

00:54:06:06 - 00:54:25:03
Unknown
Yeah, it depends of course, on your individual situation. Of course. And everybody's different and. You know, the best predictor of when I'm going to see somebody next scan should be is what their last scan looked like. And so you have to take into account what the scan looked like and whether they're in determinant findings or whether there's something we're watching.

00:54:25:05 - 00:54:48:02
Unknown
But in general. So I'm going to say as an example for somebody, let's say, who's had newly diagnosed low grade serous ovarian cancer, stage three and has completed their surgery and adjuvant therapy and is on follow up, I would generally do a CAT scan every six months, but it can vary from from person to person, of course. Great.

00:54:48:02 - 00:55:13:19
Unknown
Thank you. And so this person is asking whether there are any studies looking into check to mutation and its connection to low grades. There is. Yeah. I'm guessing that person maybe has a check two mutations because of course you want. And what do we do this when we do the sequencing You want to know, right? Because it is empowering to have these alterations.

00:55:13:21 - 00:55:33:21
Unknown
And so it's good to have that information and to be looking. We don't have a specific study that I know of in low grade serous ovarian cancer right now, but when somebody has a specific alteration, it's always good to be thinking about phase one studies also and talking to your provider about what phase one studies might be available.

00:55:33:23 - 00:55:57:15
Unknown
And if your site doesn't have phase one studies, you know, sometimes in your geographic region there might be a larger referral center that has a phase one center, because not every study for an ovarian cancer patient has to be an ovarian cancer study. Sometimes if you have a alteration of potential interest, you can be in a phase one study that's open to all different types of cancer.

00:55:57:17 - 00:56:23:04
Unknown
But with a drug that's targeting that alteration across different cancer types. And that's really the type of studies that first showed efficacy for MEK inhibitors in low grade serous ovarian cancer before we had that first study of. So you mentioned it, it was larger phase one studies that enrolled people with lots of different types of cancer and then found that the few patients that had low grade serous ovarian cancer were responding to these drugs.

00:56:23:06 - 00:57:00:06
Unknown
Great. Thank you. And speaking of MEK inhibitors, this person is saying that they have no identified mutations. Is a MEK inhibitor likely to be effective or should one try a combo of MEK plus other drugs? Yeah. Yeah. So it's a great question. And so I would say that while the alterations give us important information, one thing we should in the same way that I think it's really important that we not say chemo doesn't work in low grade serous ovarian cancer because it does.

00:57:00:06 - 00:57:23:21
Unknown
There's a good number of patients that have significant responses to chemo. We also shouldn't say MEK inhibitors don't work in patients without MAB kinase mutations because there's a good number of patients without MAB kinase mutations that have great responses. So, for example, that complete responder who I showed you the scans from, who's been on site, you know, for more than 15 years, she had like an alteration that's pretty hard to find.

00:57:23:21 - 00:57:45:19
Unknown
It's not like a regular cross mutation or BRAF mutation or anything like that. So it wouldn't show up on an and a lot of the type of sequencing that people have had done. And she had a complete response to MEK inhibitors. So we have a it's a disease that's driven alterations in the map kinase pathway and it's not always these hotspot mutations.

00:57:45:19 - 00:58:06:17
Unknown
It can be other alterations that aren't so easily found and so, yes, I would say that there is still a good chance of responding to a MEK inhibitor, even if you don't have an identifiable alteration. But at the same time, MEK and I don't even have time to talk about this. I'm sorry, but MEK inhibitors have potential toxicity, right?

00:58:06:17 - 00:58:39:16
Unknown
And so I should have even spoken more about that since we're talking MEK inhibitors so much. But they can cause ocular toxicity, they can cause skin toxicity, they can cause swelling, they can cause GI toxicity, decreased ejection fraction, all of these things. So if someone doesn't have an alteration and they're weighing two different options of a MEK inhibitor versus treatment with, let's say, Letrozole or fulvestrant or bevacizumab plus or also toxin, all of which are good options, they might choose to first go with one of the less toxic options.

00:58:39:18 - 00:59:08:11
Unknown
And so it can help us to decide about what's the best option for someone as an individual. Right. Thank you. And I'm looking at the time and we probably only are able to get through one more question. So I think just to wrap it up, I would ask you, what's your biggest takeaway for patients diagnosed with low grade serous ovarian cancer or something you're most excited about?

00:59:08:13 - 00:59:36:17
Unknown
Yeah, So I would say, you know, over the past 12 years, I really feel like we've learned so much more about this disease. We're finally completing prospective studies in this disease, We're completing international studies, We're gaining more information about what makes the cancer grow. We're learning what drugs can hit this cancer down. Finally, drug companies are interested in developing drugs for this disease, which is what we need to kind of further development.

00:59:36:17 - 01:00:00:17
Unknown
And so I think it's actually a really exciting time in research for low grade serous ovarian cancer. And I think we're going to keep making headways and keep making new discoveries and developments. And so I'm so appreciative of our patients who participate in these clinical trials that make this discovery possible. And, you know, I think we're all going to work together to get better outcomes for everyone.

01:00:00:19 - 01:00:32:03
Unknown
Right. Thank you so much, Dr. Gresham, for an extremely informative presentation and for answering all of these questions. And thank you to everyone who participated today and submitted these great questions. We really appreciate it. Make sure to check out shares, upcoming educational programs and support groups and follow us on social media as well. Please take a moment to fill out this survey.

01:00:32:03 - 01:00:57:03
Unknown
At the end of the webinar, the survey will show up in the browser when the webinar ends, and the link will also be sent in a follow up email. All surveys are anonymous and we really use that feedback. So please take the survey. And that concludes today's webinar. Thank you again, everyone, and thank you again, Dr. Gresham Thank you.

01:00:57:03 - 01:00:59:08
Unknown
Bye.

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