Dr. Oladapo Yeku :
Welcome to The ASCO Post Roundtable on Targeted Treatment Options for Platinum-Resistant Ovarian Cancer. I'm Dr. Oladapo Yeku, Director of Translational Research and a medical gynecologic oncologist at the Massachusetts General Hospital in Boston. I'm here today with two of my esteemed colleagues, and we'll start off with Dr. Musa.
Dr. Fernanda Musa:
I'm Dr. Fernanda Musa. I'm a gynecologic oncologist at Providence Swedish Cancer Institute in Seattle, Washington. Thank you for having me here.
Dr. Oladapo Yeku :
And I'm also joined by Dr. Liu.
Dr. Ying Liu:
Thank you. I'm Dr. Ying Liu. I'm a gynecologic medical oncologist here at Memorial Sloan Kettering Cancer Center in New York City, where I lead our inherited gynecologic cancer program.
Dr. Oladapo Yeku :
So today we'll be discussing the treatment and management of platinum-resistant ovarian cancer with three patient cases. Our first installment will focus on the treatment of high-grade platinum-resistant ovarian cancer that is folate receptor alpha positive.
We'll start with the case of A.T., who is a 65-year-old patient with a history of FIGO stage IIIC, BRCA wild-type, HRD-proficient, high-grade serous ovarian cancer. She underwent upfront cytoreductive surgery, to no gross residual disease, and this was followed by six cycles of adjuvant carboplatin and paclitaxel. She developed platinum-sensitive recurrent disease, and was subsequently treated with carboplatin liposomal doxorubicin and bevacizumab. Unfortunately, after six cycles of treatment, she developed progressive disease radiographically. And I leave that a little bit vague in terms of when after she developed progressive disease, because that might reflect different patterns in our management; I'll come back to that momentarily. She's here today to establish care for platinum-resistant disease.
Now we'll go very quickly over the rest of our medical record. She has a history of peripheral neuropathy, essential hypertension, and type II diabetes. She also stresses that she's had a history of multifocal pneumonia twice, with one episode leading to an ICU stay.
She was not intubated, but she was on vasopressors. In addition to her staging surgery, she's also had a cholecystectomy. Both of her parents died from natural causes, and she has a sister with emphysema, and she also makes sure that she stresses that with you. She has three children, all in good health. She's widowed, lives alone, and makes another point to mention that she works as an editor and has to drive long distances to work every day, and really in this way values her independence. So the first point I wanted to bring up is, is there any additional testing that we would normally get when we see cases like this of patients who either join our practice at this point, or we've been taking care of them and now we've reached this therapeutic decision point? And I'll start off with Dr. Musa to get some of your thoughts.
Dr. Fernanda Musa:
Yeah, I think that for anybody that comes in with a recurrent ovarian cancer, I want to have all the information in order to make personalized decisions. So I would like to have some next generation sequencing available. And I would also like to know what the folate expression, folate receptor 1 expression is. I would also like to know whether the patient expresses HER2, at the bare minimum that's what I would get.
Dr. Oladapo Yeku :
Thank you so much. Dr. Musa. Dr. Liu?
Dr. Ying Liu:
Absolutely. It's great to hear what you all are doing and to find that it's very consistent. I will say this case is all too common, right? 50% of our patients are going to be BRCA wild-type HR proficient, and I think this patient was treated very appropriately. You didn't ask us, but I would not have given this patient a PARP inhibitor or bevacizumab upfront in maintenance, given that she's at stage IIIC, had an optimal surgery and was HR proficient.
And then unfortunately it sounds like she had a platinum-sensitive recurrence. The fact that she's progressing very soon, if not on her platinum-based chemotherapy, is a pretty poor prognostic indicator. So that definitely makes me want to think about options outside of your traditional platinum-based chemotherapy. Our workflow is to do simultaneous germline and somatic testing upfront, with diagnosis on the upfront tissue. And then if the BRCA1/2 testing in both the germline and the tumor is negative, then we will reflex HRD testing. And so we do get that data at the initial diagnosis, but I completely agree with Dr. Musa at recurrence, I do want additional data if it's not already available.
I do want to know the folate receptor alpha status, HER2, and I know a lot of the commercial tests these days are bundling in tumor sequencing with these IHC markers, and so that's a very convenient way to do it all. But I'm interested to hear if you all are doing this upfront at diagnosis, or if you're waiting for recurrence.
Dr. Oladapo Yeku :
Dr. Musa?
Dr. Fernanda Musa:
I like to do it upfront. I don't like to wait on recurrence. Sometimes we can't, right? We see these patients and they have progressive disease, and soon after they'll develop effusions and need to get treated immediately. So sometimes we don't have the 3 weeks in recurrence to wait. I do want to ask you, and I am curious whether you retest in recurrence, and I think we'll get to that a little bit later about whether these tests change over time.
Dr. Oladapo Yeku :
That’s a great point because we all practice at different sites—and for example, at least in my practice, once or twice patients have come to me with results from an establishment that I didn't recognize, or a new testing company, and I'm not sure how they validated their assay, what they did. And I'm sure this is not uncommon when you guys get external referrals as well. So how often do you repeat it?
Just if folate was already available and ready to go, do you just say, "Well, this is Ventana or close enough, I'm going to use it." Or do you say, "You know what we have in-house testing, or I prefer to use Foundation or something else," and then you go with that? I guess all variations of the same thing. I'll start with Dr. Liu, because I know you guys do in-house NGS testing.
Dr. Ying Liu:
Folate receptor alpha testing is quite complicated, as you guys all know. I often use the case study of mirvetuximab trials and approvals for the fellows, to teach them lessons about clinical trial design.
In FORWARD 1, we all know that that study did not meet statistical significance, but there was a signal in the population with high folate receptor alpha expression, which sort of led to the subsequent studies in that population. But how to measure it has been a bit of a headache, because even after mirvetuximab was finally approved after SORAYA, we had trouble getting the Ventana assay, which is why we did develop our in-house assay. And I think now, with kind of the evolving changes around what level of folate receptor expression is enough for mirvetuximab, what level is enough for mirvetuximab plus bevacizumab? We've had to adapt the way we are reporting it.
And I've been looking at reports in different ways and I've been retesting a lot of my patients, because traditionally we were only reporting high levels, which meant 2 or 3+ expression of greater than or equal to 75%, but now we need to know if it's greater than or equal to 50%. And I would argue we really should just know what the percentage is. Because I imagine this is an evolving space, so we are retesting. Anecdotally I've also seen that depending on which specimen you test, you may have different levels of expression. I don't know if you guys have experienced this, but I feel like sometimes the primary debulking specimens are usually very good. Sometimes after neoadjuvant chemotherapy, the specimens are a little bit sparser. And if a patient does undergo a secondary debulking, if we get a biopsy to confirm recurrence, I will test, do IHC for folate receptor alpha on that, because it's a pretty easy and quick test.
Dr. Oladapo Yeku :
Absolutely, and I agree, and I think down to 25%, we really do need to know what the folate receptor expression as opposed to positive negative has been reported before. Dr. Musa, in your practice, I know you got patients from all over, do you just go by your in index of suspicion if you don't know the vendor, or do just always have a policy that you follow in your practice?
Dr. Fernanda Musa:
I think for folate, most of what I see is Ventana. So I don't think for folate there's a lot of variation. I will be very honest with you, I view testing as access, and I would only retest somebody who is below the cutoff that I needed to reach a cutoff. And so yeah, if they've hit that cut off and I have the ability to use, I will not look again.
Dr. Oladapo Yeku :
Absolutely. And again, going back a little bit to how we test patients, depending on what tools we have, we all know that germline testing is mandatory, that's proper standard of care during diagnosis. And there are some assays that already have several things bundled into it, even though that's not ... you're not looking for folate testing a new diagnosis, but sometimes we get that data. But for some sites we have to acknowledge that for some places, it's clinical genetics, they're only looking for BRCA1/2 and other HRD-related genes, and then they do some stage testing after that. I guess the key thing that we're all getting to is that we make sure on recurrence in the platinum resistance setting, we thoroughly evaluate patients for targeted therapy of some sort. So we test this patient, or we get data that we trust and we see that the folate receptor expression is 85%. And then the question then comes to when do we use mirvetuximab? And this is where maybe we might think differently, if the patient is progressing right after six cycles in the platinum ... after being platinum sensitive, or if this was a few months later they're resistant but maybe a little bit further out. I'll start with Dr. Musa for this one as well.
Dr. Fernanda Musa:
Yeah, I think holistically, the data that we've always been taught is that every subsequent line of therapy has a lower response rate and lower PFS, right? And so we start looking at these patients who are progressing on their chemotherapy or who are platinum resistant, and expecting response rates in the teens with progression-free survival of a few months. And then comes this phase III clinical trial called MIRASOL that doubled that. And also highlighted how ineffective chemotherapy is in the setting, to me. So I would have to have a very strong reason not to use mirvetuximab in a patient who meets my bar for folate receptor alpha expression, given that the alternatives are, in my view, inferior
Dr. Oladapo Yeku:
Dr. Liu, what do you think?
Dr. Ying Liu:
I completely agree. I think this patient would be ideal to start mirvetuximab, you know, in the MIRASOL study that Dr. Musa mentioned, patients had one to three prior lines, and this patient has very high folate receptor alpha expression. I guess the question would be do you continue the bevacizumab along with the mirvetuximab. So I would throw that back at you guys, Dr. Musa and Dr. Yeku, I don't know.
Dr. Fernanda Musa:
Dr. Yeku, I'm curious, would you continue her bevacizumab?
Dr. Oladapo Yeku :
I would not. And the reason for that is because her folate expression is just so high, that I think even though numerically there may be an improved overall survival ... overall response rate by adding bevacizumab, and we know bevacizumab always seems to give a median of 3 to 4 months whatever we add it to. I worry that in this recurrent setting, the cumulative toxicities might not necessarily outweigh the benefits. I think if the patient were closer to 25% or there about, we do have NCCN compendium listing to use that combination, perhaps to compensate for the lower folate receptor expression. But I think 85 and above 100%, I would probably give the patient a break from bevacizumab.
Now if you had ascites or maybe other compelling reasons, or they had no toxicity from bevacizumab, that would be a conversation with the patient weighing the toxicities and the benefits. But the trial really just studied monotherapy.
Dr. Fernanda Musa:
Thank you. Would it give you pause that she likes to drive at night, and-
Dr. Oladapo Yeku :
Yes. So that was going to be my next question, but before we do that then, because it seems that all of us are in agreement that we want to use mirvetuximab. So when do we give chemotherapy? Is anybody giving chemotherapy anymore? Under what circumstances in this scenario with the same folate receptor, would you say, "You know what, this feels like a weekly paclitaxel case, or this really feels like a topotecan case." Or is that even a thing?
Dr. Ying Liu:
I don't know if I'm giving much topotecan, but I do agree that toxicities really play a big role here. So if her neuropathy is pretty significant, and her quality of life with the driving is really important, I would reconsider mirvetuximab because you do see significant neuropathy, it can come on quickly, and even sometimes dose reductions don't alleviate symptoms that much. The other major toxicity is the ocular toxicity, which is definitely manageable and there are great patient resources and chemo calendars out there to help with the eye drops. But I do work with our ophthalmologists, the patients are seen every other cycle. And I do find that when they have toxicity doing holds and dose reductions, and sometimes using the eye drops more aggressively, especially the lubricating ones, it can be helpful to help combat those. But those are very real toxicities that we do see.
And I do still use chemotherapy. I think there is a role, a lot of these studies don't compare chemotherapy plus bevacizumab. We know that paclitaxel with bevacizumab has really good response rates. And so I think it does depend on the symptoms the patient is experiencing. And then what the toxicities you're most concerned about are.
Dr. Oladapo Yeku :
Do you disagree Dr. Musa, or do you have-
Dr. Fernanda Musa:
No, I wholeheartedly agree, and I agree as well about the ocular toxicity being very manageable. Chemotherapy to me has moved down the road a little bit. There are some regimens that are my tried and true Hail Marys, like the weekly taxane plus bevacizumab tends to be my last line.
But I have moved clinical trials up in mirvetuximab to standard of care in first line platinum-resistant, because the data is, in my opinion, good.
Dr. Oladapo Yeku :
Absolutely. And thank you so much for bringing up the ocular toxicity, Dr. Liu, because as we've seen the community, our patients are aware of these studies, and that's why I'd mentioned that this lady was an editor, she drives to work, and she has independence, and she's had these vague histories alluding to what's her risk for pneumonitis and lung inflammation. So I think having a template, or a prescribed way for how we discuss these toxicities are very helpful. And also reassuringly at the recent ESMO meeting, there was some data regarding quality of life with mirvetuximab that showed that patients make do, especially with early involvement of ophthalmology and or an optometrist, as we often do. So we'll conclude this case with some of the key takeaways that mirvetuximab soravtansine has demonstrated an overall survival advantage in patients with platinum-resistant ovarian cancer, who have received up to three prior lines of therapy, compared to investigators choice chemotherapy.
We agree that folate receptor testing should be performed on all patients with platinum-resistant ovarian cancer, if they haven't had testing before. And of course, depending on individual circumstances, testing may need to be repeated because of tumor heterogeneity. And reassuringly, because we have up to three lines, if there is a patient who needs urgent treatment with no available results, we still have an opportunity to expose them to this drug. And we do agree that ocular toxicities occur with mirvetuximab , it's something that we have a high vigilance for. And early management by an ophthalmologist, I think it is mandatory, I think it's part of the drug label.
But what also helps is educating patients by the proper use of the prophylactic eye drops, and sort of supporting them through the management of these toxicities as it affects their quality of life.
So this brings us to the end of our case. Please see the other segments for further discussion about the latest research in ovarian cancer, or visit ascopost.com.
