This episode features Dr Rachel Grisham and Dr Kathleen Moore discussing the historical challenges associated with treating low-grade serous ovarian cancer and the recent transformational approved targeted therapy combination regimen of avutometinib and defactinib for KRAS-mutant LGSOC.
In this episode, Dr Rachel Grisham and Dr Kathleen Moore discuss newly approved treatments for low-grade serous ovarian cancer (LGSOC) and how recent research has transformed the therapeutic landscape for these patients, including:
Presenters:
Rachel Grisham, MD
Section Head of Ovarian Cancer
Memorial Sloan Kettering Cancer Center
Director Gynecologic Medical Oncology, MSKCC Westchester
New York, New York
Kathleen N. Moore, MD, MS, FASCO
Deputy Director and Cancer Therapeutics Co-Lead
Stephenson Cancer Center at the University of Oklahoma
Professor
Department of OB/Gyn
ASCO BOD
Oklahoma City, Oklahoma
This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.
Dr. Grisham: It is so great to be here today, talking with my good friend and colleague, Dr. Katie Moore, about , Newly Approved Treatments for Low-Grade Serous Ovarian Cancer.
I wanted to start by talking about what makes low-grade serous ovarian cancer unique. Historically, we have treated it the same way as high-grade serous ovarian cancer. But that probably was not really the right thing to be doing. How do you think about your patients with low-grade serous ovarian cancer differently than your patients with high-grade serous ovarian cancer?
Dr. Moore: This is a distinct group of tumors. We should not even call it ovary cancer. It is really a distinct group of tumors. How are these tumors different than the typical high-grade serous ovarian cancer? You can see low-grade serous ovarian cancer in women of any age. But the medians tend to be about a decade younger as compared to high-grade serous.
The truly distinguishing thing is the molecular phenotype of these tumors. In high-grade serous ovarian cancer, these are ubiquitously associated with TP53, either loss of function mutations or other deleterious mutations for TP53.
A true low-grade serous does not have TP53. It does often have MAP kinase alterations most commonly are alterations in RAS. If you want to even get more common, it is KRAS of a variety of subtypes. There is other RAS you can see.
You can find BRAF mutations, you can find BRAF V600E. There is some other lesser common mutations as well in that MAP kinase pathway. Low-grade serous is likely driven by endocrine pathways. That feeds into how we think about therapeutic strategies for this population.
Dr. Grisham: That is a great point that you make about low-grade serous ovarian cancer too, that if you look hard enough you will find like ER positivity in almost all of the patients and PR positivity in more than 60% of the patients.
Dr. Moore: If I have a confirmed low-grade serous tumor, I am going to use endocrine therapy combinations all the time. We do not need to test. I know it is there.
Dr. Grisham: We really do understand now that low-grade serous ovarian cancer is a completely different disease. We understand the molecular drivers so much better. It is really pivotal that we now have our first FDA-approved drug combination specifically for low-grade serous ovarian cancer. I know that that you did a lot of work towards that approval and that it is so important not only to have these drugs available for our patients now, but really the precedent that it set, because I see so many other pharmaceutical companies now getting interested in low-grade serous, and new concepts being developed.
It is really a new era of treatment for our patients with low-grade serous ovarian cancer hopefully, where we are seeing more and more clinical trials open specifically for these patients and specifically treating them based on their molecular profile and the unique features of this disease.
Dr. Moore: It just took a long time. But probably the maintenance options in the frontline therapeutic options really tailored to those molecular differences will help move outcomes forward in a more positive way, in a more rapid way for these different groups.
Many people doubted that we could do phase III clinical trials in low-grade serous epithelial ovarian cancer. We did and we have done several actually. Just shows the power of clinical trials and also the willingness of our patients to participate in clinical trials designed for them.
RAMP 201 Trial
Dr. Grisham: Let us talk about the clinical trial that led to the approval of avutometinib and defactinib for patients with low-grade serous ovarian cancer harboring a KRAS mutation. This was the RAMP 201 study, of course, a phase II study that looked at initially avutometinib versus avutometinib in combination with defactinib and then expansion cohort, where all patients received avutometinib and defactinib for recurrent low-grade serous ovarian cancer.
Enrolled patients who had recurrent measurable disease who had received at least one prior platinum-based therapy. Interestingly, these patients were allowed to have received a prior single-agent MEK inhibitor before they went on study.
The patients were initially randomized to either receive avutometinib, which is a novel RAF/MEK clamp, as a single-agent at a higher dose, four milligrams twice a week, or that drug at its standard dose 3.2 milligrams twice a week. These are pill therapies in combination with the oral FAK inhibitor, defactinib, which was given twice a day. For all patients on this study, they take these oral therapies three weeks on and one week off.
During that initial randomized portion, it was found that the combination of avutometinib with defactinib was more efficacious than single-agent avutometinib and had singular toxicity profile. Then in the expansion phase, additional patients were enrolled to that combination.
We had previously had concerns about these studies for low-grade serous ovarian cancer being able to enroll efficiently. But this study, of course, enrolled very well and was able to enroll above the projected rate, which was so wonderful and so great for our patients to be able to get these results so quickly.
This study, of course, showed overall a response rate of 31%. Then specifically in those patients who had a KRAS mutation, there was a confirmed response rate of 44%. This was really meaningful for our patients, where traditionally chemotherapy and endocrine therapy will have response rates less than 15% in the recurrent setting.
Something that was really meaningful too was the duration that patients remained on treatment. For those patients with a KRAS mutation, the median progression-free survival was 22 months. For those patients that responded, these were responses that had just endured. The median duration of response was over 31 months. That is really remarkable.
These very promising results from this phase II study actually led to accelerated FDA-approval of avutometinib and defactinib specifically for patients with KRAS-mutant low-grade serous ovarian cancer.
Now, for the KRAS wild-type patients, there was still responses in that population. For those patients, the response rate was 17%, which is similar to what we have seen with prior studies looking at low-grade serous ovarian cancer, where we see that KRAS is a prognostic marker and our patients that are KRAS wild-type tend to have lower responses both to standard of care therapy and to MEK inhibitors.
Given that this was a study that did not have a control arm, the accelerated approval was really based on that remarkably high response rate of 44% in those patients who specifically did have a KRAS mutation.
RAMP 301 Trial
Then, of course, while we now do have this accelerated approval, there is the ongoing phase III study, the RAMP 301 study, which similarly enrolls patients with recurrent low-grade serous ovarian cancer who have had at least one prior line of chemotherapy. That study does randomize the patients to either the investigational arm of avutometinib and defactinib, or the control arm of standard of care chemotherapy or endocrine therapy.
That study is almost completed accrual and we are just getting some additional information at the time of interim analysis about if more patients will be added or not. But that study has also accrued very well throughout the world. This study is going to give us a lot more information about the KRAS wild-type patients and what their responses to these drugs versus standard of care chemotherapy or endocrine therapy.
So hopefully we will be able to see those results soon.
Another interesting result of the RAMP study was specifically looking at those patients who had received prior MEK inhibitors before going on to this study and seeing that many of those patients responded as well, which is really interesting because one might have been concerned that we would not see responses in those patients, but really this dual blockade of the MAP kinase pathway and also an inhibition of the FAK pathway does seem to have a distinct mechanism of action that can overcome patients who have resistance to prior single-agent MEK inhibitors.
It is so exciting to now have these drugs commercially available specifically for our patients that have a KRAS mutation, while awaiting the results of the phase III study that may potentially expand this indication as well.
Dr. Moore: Now the onus is on us to make sure that we communicate that broadly to our communities who are going to be seeing these patients so that they can use this combination most effectively, and hopefully get the same outcomes that the study showed.
Dr. Grisham: Yes. It can be so overwhelming with all these. I mean, it is so wonderful that we have so many new drugs and new classes of drugs being approved. But to keep up with the dose, the schedule, how to prescribe each of these drugs and then, of course, the toxicity monitoring of each of these drugs. These drugs, specifically avutometinib and defactinib are pill therapies. The avutometinib is taken twice a week, three weeks on, one week off. The defactinib is taken twice a day, three weeks on, one week off. They come and when prescribed as a co-pack so that patients received both pills bottles and a pill diary explaining to them how to take those pills.
But it is so important that we are able to support our patients to make sure that they understand that dosing schedule. Also that they understand how to prevent toxicity. The most common side effects that we oftentimes see with these drugs can include acneiform rash oftentimes in sun exposed area. It is very important to try to use sun precautions.
Most of my patients I use prophylactic antibiotics with minocycline or doxycycline to help prevent acneiform rash. It is so helpful.
Dr. Moore: The skin toxicity has been especially bothersome for patients. They have this acneiform rash. It can be pretty pronounced with MEK inhibitor single-agent. They just do not want to walk around with this blistering rash on their face.
As this medication rolls out into the community and we get a bigger sense of the prevalence of these and incidence of these toxicities really comparing it to single-agent MEK will be.
I feel like it is either less common or less severe with this combination, which I find interesting. I do not know why we would be seeing less. We seem to be seeing less cardiac toxicity with the combination than with single-agent MEK. Would you agree with that statement?
Dr. Grisham: I do, yes, because, I mean, cardiac toxicity really has not been seen with avutometinib and defactinib thus far. So it has not been associated with decreased ejection fraction, which has been characterized for other single-agent MEK inhibitors like trametinib or binimetinib. We will see if any additional safety signals are identified during the phase III study. But thus far that has not been identified as a safety signal, which is reassuring.
I think it is a great point that you make about the rash. While the rash is usually the most significant side effect that is experienced, that it is more tolerable than what I have seen with single-agent MEK inhibitors.
Of course, with single-agent MEK inhibitors, we have that continuous dosing schedule. Here, the MEK/RAF inhibitors only taken twice a week. Then there is also that recovery week out of each four-week cycle. That intermittent dosing really prevents that cumulative toxicity that can really allow this rash to build up and become difficult to handle. We really see that in the clinical trial also because in the RAMP 201 phase II study, only 10% of patients discontinued treatment due to toxicity. In the prior study of trametinib in low-grade serous ovarian cancer, more than 30% of patients discontinued due to toxicity, even though the patients in the RAMP 201 study stayed on treatment longer.
It hopefully does show us that that these drugs are tolerable for our patients. It is hard for us to say specifically without a head-to-head comparison. Just looking at these experiences across trials and personal experience with treating patients in clinic, we are so used to dealing with different types of ocular toxicity now with ADCs. But these drugs do not require prophylactic eyedrops. They can cause fluid accumulation in the eyes, and therefore patients can develop vision changes, most commonly within the first week of starting treatment if that is going to occur.
These types of vision changes oftentimes resolve spontaneously without need for dose reduction or dose hold. But it is important that patients being treated with these drugs are monitored by an ophthalmologist and have a screening exam prior to starting the medications.
Dr. Moore: Patients are tolerating this better than single-agent MEK inhibitor. I also think we have learned a lot from the MILO study. The NCI-led what we call GOG 281, which were two big phase IIIs of MEK inhibitor monotherapy versus investigator's choice.
We all learned a lot about MEK inhibitors and the toxicities and how to manage things from those studies. I am a very different physician in terms of how I counsel patients, how I follow them, my mitigation strategies for rash, monitoring of ocular and cardiac events.
The goal is for these oral medications, if you get close to three more years of life on one therapy, and we still have other things we are developing. That is really a market improvement in anything we have developed in this disease ever. It is the singular development in low-grade serous ovarian cancer.
Dr. Grisham: Yes. I know it makes me even more excited about the future. How we could improve upon this even further? Yes, I have a patient who enrolled onto the 201 study early on, and soon after that delivered a child via surrogate. She has had almost a complete response on the study. That baby is three years old now, and she is still on the same treatment. She gets it by commercial supply now because the study has ended.
These are amazing things that we did not think were possible before. So it is so great to see this happening in real time.
We were saying that these drugs are specifically approved right now for patients who have a KRAS mutation. Could you talk to me a little bit about how you approach biomarker testing for your patients with low-grade serous ovarian cancer?
Dr. Moore: Sure. At our institution, we are pretty aggressive about molecular profiling right out of the gates, which I would not tell you is right or wrong at this point, but we like to know what we are dealing with from the beginning.
We are testing everyone for BRCA. I do not care if you are low grade. I am still going to test you for BRCA because I do not want to miss one. Then we are doing somatic testing. These are going to be all HRD test negative. Like this is not a disease where we are using PARP inhibitors at least as monotherapy maintenance.
The maintenance strategies here are very different. We are testing right out of the gate so we know what we are dealing with. Then we are using that information at our site where we do have clinical trials available to plan out sequencing and therapies already. I am going to just acknowledge we do not really know the right sequencing. Speaking of clinical trials, for NRG-GY019 a huge study.
Frontline, low-grade serous, resected, patients were randomized to chemo followed by letrozole versus letrozole. No chemo. That study is done and maturing. We are going to know a readout on that within the next few years. That may be the next big pivotal discovery in this disease is do we even need chemo?
Could you imagine that? Just go to letrozole in a resected tumor, and then you would have this as standard of care in a RAS-altered tumor. So I would want to know that right out of the gates so that as somebody started to grow back, maybe with something that is not biopsied, I can just put them on the right drug rather than waiting until there is something I can biopsy and then send next-gen sequencing. We do not think that there is temporal drift here. It is KRAS. We will learn over time if we repeat biopsy.
I think the really interesting question that you are trying to answer is whether or not this drug should be moved into frontline in those tumors that are not resectable. The expected response rate to frontline chemo in a patient who is deemed unresectable, which about half are, is only about 20%. It is very different than high-grade serous where you expect it to melt away and you can get somebody to a surgery after three cycles.
That paradigm has been applied to low-grade serous for forever. They get three cycles and then they never go to the operating room. We are on the cusp of rewriting that paradigm, a neoadjuvant study for this population using a CDK4/6 inhibitor and fulvestrant instead of chemo.
This idea of fitting low-grade serous into the same box as high-grade serous and applying the same surgical resection rules and timing probably does not serve our patients.
In a study called CHAMELEON, were removing this in the frontline. If I get a 40% or 50%, it is probably going to be higher in a not pretreated tumor. If I can get that tumor into response to you, your brilliant surgeons can get it resected and then de-escalate to some endocrine therapy. Could you imagine the potential change in outcome for that patient? We got to prove it.
I think that is really how you change the whole treatment paradigm for these patients who never get to the OR and they walk around with these abdomens full of calcified tumor for eight years because it never was resected. I really believe if you get this to resection earlier that patients will live longer, live better, less side effects.
Dr. Grisham: In the CHAMELEON study, we are looking at the combination of avutometinib and defactinib in combination with letrozole for patients with newly diagnosed low-grade serous ovarian cancer who are not appropriate for primary debulking surgery or who have had a suboptimal primary debulking surgery.
These patients who have really the most dismal prognosis, and the most morbid outcomes to try to now use these newly approved drugs to go straight to the upfront setting and really be able to try to improve outcomes for these patients. These drugs are also being looked at across other cancers with KRAS mutations as well, and within our gynecologic cancer community, mesonephric and mesonephric-like cancer, which have a very high rate of KRAS mutations.
Generally, patients with those diseases will have KRAS mutation. We have clinical trial going there. I know you have a study of these drugs in patients with any histology with KRAS mutation, I believe.
Dr. Moore: Right. It is for anybody but low-grade because low-grade we want you, of course, to go on this, the other study although now it can get standard of care. But any gynecologic cancer with KRAS or MAP kinase alteration can get avutometinib or defactinib, including mesonephric. We are really trying to figure out in whom this combination will work.
It is an intersection of the molecular alteration in the tumor type. We are still really trying to figure out how we target KRAS in gynecologic cancers. But this is a big step forward. I just want to come back to one thing you said is the prognostic significance of KRAS in this tumor is the reverse of what you would think.
Here, it is positively prognostic. Just coming back to the RAMP 201 KRAS wild-type response rate of 17%. KRAS wild-type actually does worse. We have never looked at this in a real prospective fashion that that negative prognostic factor of KRAS wild-type, this may be transformational in that group as well, which is something I had not considered.
When you do not have a control arm, you really cannot see what the other group is doing. RAMP 301 is going to be really critical to look at both groups versus the control arm and then make a decision of how to optimize this drug and others for our patients.
Dr. Grisham: That is great. There is one last thing that I wanted us to point out. I see so many patients in the community having their somatic testing done by liquid biopsy. I just want to point out that in low-grade serous ovarian cancer, it is a poor shedder. It is not a good way to identify a KRAS mutation for these patients.
When Dr. Moore and I are talking about KRAS mutations in these patients, we are talking about doing that testing specifically on the tumor tissue. It is so important for our patients with low-grade serous ovarian cancer and for any cancer where we do not have clear evidence on their level of tumor shedding that we do the actual somatic testing on the tumor tissue, because we do not want to be missing those patients that are potentially eligible for these drugs.