Dr. Kathleen Moore:
Welcome to The ASCO Post Roundtable Overcoming Platinum-Resistance in Ovarian Cancer: New Strategies and Novel Treatments. I'm Dr. Kathleen Moore from the Stephenson Cancer Center, and I'm joined by two of my colleagues that I'll have introduce themselves, starting with Dr. Fuh.
Dr. Katherine Fuh:
Hi, I am Katherine Fuh. I'm a gynecologic oncologist at the University of California San Francisco, also the Director of Translational and Basic Research and looking forward to reviewing these cases with you all today.
Dr. Moore:
And Dr. Pothuri.
Dr. Bhavana Pothuri:
Hi, I'm Bhavana Pothuri, a gynecologic oncologist at NYU Langone. I serve as the Clinical Trials Office Medical Director here, and I am really pleased to be joining my friends and colleagues for this exciting discussion.
Dr. Moore:
Yes, I'm so glad to have you. Thank you for joining us. We're going to be discussing the treatment and management of platinum-resistant ovarian cancer with three different patient case studies that we're going to go to. Each of them is individual, and this first one is going to focus on a patient who was originally diagnosed with stage IV high-grade endometrioid ovarian cancer and has progressed on a platinum. So a little detail about her just to put her into context, she's now 75. At the time of her diagnosis in 2020, as I said previously, she was stage IV high-grade endometrioid.
She received neoadjuvant chemotherapy with paclitaxel and carboplatin for three cycles, underwent interval cytoreductive surgery that was very successful. She was rendered what we call no gross residuals, so nothing visible at the end of that surgery, which is our goal. And then received three additional cycles of paclitaxel and carboplatin, in which case she was completed with chemo and went on to niraparib maintenance for a year, at which point she was found to have a progression of disease.
Of note, she did have germline testing sent at her diagnosis once her diagnosis was confirmed and she was found to be BRCA wild-type. At the time of recurrence, which was again, a year after her last platinum, she received carboplatin and pegylated liposomal doxorubicin with the addition of bevacizumab for three cycles, and then had her first CT scan for disease assessment and unfortunately was found to have progression of disease and so now would be considered platinum-resistant.
So I'm going to stop there and we'll pretend that she's presenting to each of my friends at their centers that are on each coast. I didn't do that on purpose, but West Coast and East Coast are represented. And I just want to start broadly with you both, not necessarily about this patient, but when you have a patient that's sent to you for referral or a new patient that you're seeing and she comes in with platinum-resistant consult for therapy, what are you thinking about? What does that even mean? What are the considerations and how are you thinking about that patient in terms of questions you want to ask or things you want to know? I'll start with you, Dr. Pothuri.
Dr. Pothuri:
Yeah, thank you. I think the first thing I think about in terms of a patient who comes in with platinum-resistant disease is, how long has it been since their last platinum? So really looking at that platinum-free interval, and they do differently if they're less than 3 months vs 3 to 12 or more than 12 months. So I want to really get a feel for when did they progress. And then I want to know how did they tolerate their treatments? What kind of residual toxicities do they have? They've now just recently came off the carbo PLD and we're on niraparib, so how are their counts? These are some of the things that I'm thinking about.
And then of course, I want to know what histology. In this case, this was an endometrioid cancer, so keeping in mind that endometrioid cancers and high-grade serous cancers may not be the same as a low-grade cancer or a clear cell. So I think understanding what histologic subtype you're treating, and then of course I want to understand the molecular signature of this patient. And then maybe Katherine can talk a little bit about that.
Dr. Fuh:
Certainly, I have to think about the clinical factors, then we always ask, "Well, what about the molecular testing?" Now we know that there's actually some molecular testing that can be associated with response to treatment. And so that would be additional workup is did they have tumor testing? In the sense of not just mutational status, but also immunohistochemistry so we can really understand and pair these types of treatments to their testing.
Dr. Moore:
And we'll talk about this a little bit. This patient just had germline testing. Like a lot of our patients just come in... Thank goodness. So that's a good thing to do so I don't want to downplay that. Please germline test every patient. And that's what she had, but she hadn't had her tumor sent at-diagnosis for anything and now she's presenting, and it's been a couple years. Well, a little less than a couple years, but it's been a good period of time since her initial surgery. You just talked, Katherine, about wanting to send some immunohistochemistry and other testing. Do you send it off the archival tissue? Do you get a new biopsy? Does it matter? How do you think about that?
Dr. Fuh:
Yeah, I would say in general, I think we're still really trying to understand if it matters. And in some cases it does matter actually, to have the testing done in the most recent time. So if it's an opportunity to be able to biopsy at the recurrence and it's a location that's feasible, I think that would make sense in terms of the patient also feeling like that's something they'd like to do. But if baseline tumor is available and that's all that's available, I think that we've also been able to identify ways to pair treatments with molecular signatures and targets at the baseline, too. So truly it's a conversation that if the baseline is not available and the recurrence is at a site that is easily biopsied and then the patient is agreeable to it, then that would be certainly one consideration to do that.
Dr. Moore:
Yeah, I think we're learning a lot from other solid tumors where we do see some temporal, maybe, migration or it could be combination of temporal and spatial because our patients have metastases in so many places. I guess, would you agree that... I don't think at this point we can say, "You must re-biopsy," if you have good archival tissue. If you don't have archival tissue, I think you must re-biopsy so you know what you're treating. But if you do, I don't know that we have clear dogma that says you must re-biopsy at this point.
Dr. Fuh:
Exactly. These studies are certainly ongoing in terms of trying to do that paired collection of baseline and at the time of recurrence. And then we think about recurrence, location of recurrence also. So I think we're getting close to trying to figure out if it is necessary to re-biopsy. I think some of us in our guts feels like it would make sense to biopsy the tumor at the time of recurrence because that is what we're dealing with at that time. So if that's possible, it would be ideal.
Dr. Moore:
We'll go back to the case. So she recurred by CA-125, got an imaging, so she had her imaging after her third cycle, and she had some peritoneal disease, not a lot, no bowel obstruction. She does not have ascites, which is nice for when that happens, but she does have big lymph nodes in the mediastinum, so not resectable. Good performance status, she's performance status 1, and now she's sitting there and wants to know what you're going to do. So you mentioned wanting to send testing. What does that mean? I'll go back to Dr. Pothuri. And I'm asking one more question. What are you going to send? What are you looking for? And are you going to hold her therapy till you get it back? Is it that important or is it a nice thing for plan... I guess we'll be on plan D at that point. How are you thinking about things?
Dr. Pothuri:
Yeah, that's a good question. So typically what we do is we do our tumor testing upfront and so I have all those results at the time of the relapse. And in the ideal world, I agree with Katherine that I would like to re-biopsy if feasible. But in addition, we also do FRα upfront, we do HER2, and MSI testing is part of the NGS panel. And so I'm looking for other therapies that I can utilize based on these biomarkers. And so I think it's important to have this, and in addition, I'm looking at CCNE1, TP53, I'm looking for the NTRK. Those are really rare, but they're very actionable with medicines that really can control disease. As well as RET. So these are some of the things I'm looking for. And then in terms of IHC, I'm doing the HER2 and the FRα at this point.
Dr. Moore:
Dr. Fuh, anything else that you'd be looking for or wanting to find?
Dr. Fuh:
Yeah, I think you definitely have hit the main targets. I think for endometrioid and clear cell, maybe ARID1A, especially if there's some clinical trials that's ongoing right now that's ARID1A specific.
Dr. Moore:
So we sent tissue testing for both next-generation sequencing and immunohistochemistry. We already knew she was germline BRCA wild-type type, but it's confirmed somatic BRCA wild-type now as well. She's HRD-test negative, she's FRα-medium expressing. In this case, our folate receptor was 40% 2+ and HER2 was zero, so IHC was zero and no amplification, obviously. So from a standard of care standpoint, things that are FDA approved, nothing links to a particular therapy. From an NCCN standpoint, the FRα-medium is a two-way listing for the combination of mirvetuximab and bevacizumab, which is any FRα-expressing tumor. It doesn't necessarily have to be high.
And for trials, her profile list right now really doesn't have a clear link, although there's a number of trials open for FRα-targeting agents irrespective of being high or low. So that would be one potential link, but nothing like an NTRK, something that is a clear link. So knowing that, that biomarker profile and she's otherwise a healthy person, what are your considerations for her? Two prior lines of therapy, progressed on a platinum, she has had prior bevacizumab and progressed during prior platinum. What are her standard-of-care options? Let's start with that, and we'll start with you. Dr. Fuh.
Dr. Fuh:
Standard-of-care options, we can certainly think about chemotherapy options. She's had prior bevacizumab, but we can really still think about mirvetuximab and bevacizumab as an option, too. And so I think that in her case, she's the ones that we need to create more therapies and treatments and clinical trials, those certainly would be critical in her case to identify that. But in terms of standard of care, I would say either cytotoxic chemotherapies or considering mirvetuximab plus bevacizumab even though she's had prior bevacizumab.
Dr. Moore:
Yeah, so the mirvetuximab plus bevacizumab data comes from a study called FORWARD II. It was about 90 patients and it evaluated the combination with response rates in the platinum-resistant setting about 50%, which is similar to what we see in AURELIA with weekly paclitaxel and bevacizumab, about 50% response rate. Now, both of those were mostly bevacizumab-naive, not entirely. In fact, FORWARD II had quite a few patients with prior bevacizumab, but we know we can use bevacizumab after bevacizumab. So those would be her options. Dr. Pothuri, we maybe want to capitalize on the folate. What about weekly paclitaxel though, or what about her standard chemo options? Are they all equal? How do you think about somebody, maybe she was folate zero and all you have are chemo. How do you think about your chemotherapy options?
Dr. Pothuri:
Yeah, I don't think they're all the same and I think the data supports that weekly paclitaxel is our most active agent in the platinum-resistant disease. And your other therapies like liposomal doxorubicin or topotecan have much lower response rates, between 5% and 10%. Whereas we're seeing almost a 30% response rate with weekly paclitaxel. So I do put the weekly paclitaxel into a separate category and usually prioritize utilizing that agent over the others if I'm doing standard of care.
Dr. Moore:
Right. So for this patient, it was a real patient, she was offered just what you both said, weekly paclitaxel. I think that the NCCN Guideliness hadn't been updated yet for the folate/bevacizumab because it just got to be category 2A recommendation, where we have more assurance about getting covered. But she was offered weekly paclitaxel. To your point, Dr. Pothuri, it is our most active chemotherapy and then the others are all after that vs clinical trial with a novel antibody-drug conjugate. And she proceeded on clinical trial to antibody-drug conjugate targeting CDH6 and actually remains on that therapy currently. So I think we can say is getting clinical benefit.
So in this case, for the key clinical takeaways, I think we went through them. The first is that platinum-resistant isn't platinum-resistant. There's a number of parameters that we have to consider at the time of recurrence in addition to the platinum-free interval greater than or less than 6 months. And this includes the things you both mentioned. Molecular subtype, histology, the absolute treatment-free interval, number of prior therapies, and what did they do on their last therapy? Did they respond to the platinum, did they respond to the PARP, or did they just stable disease and then eventually progress? All of those are coming into play and help us make better decisions.
You also both mentioned testing. So tissue is required. It's really imperative that we get tissue. We know you can just have a diagnosis based on cytology, but having a tissue block core biopsies is really key to allow for thorough biomarker evaluation to really assess eligibility for emerging approved therapies like we just talked about and we'll talk about more in this series, HER2 and folate when others are coming, but also all the other things. MSI, all the things we want to consider to make sure we're individualizing therapy to our best ability for patients.
And then apart from clinical trials, mirvetuximab soravtansine and weekly paclitaxel, not given together, just separate, are the most active medications in this setting. I think to date. We have more coming, but to date, these are our two most active with or without bevacizumab, both of them. Mirvetuximab with a 42% response rate in platinum-resistant, one to three prior. Weekly paclitaxel is 30%, irrespective of line of therapy. Both of those increase to maybe 50-ish percent with BEV. PLD, GEM, TOPO, response rates are less than 10% so there's a real gradation that we've not really acknowledged before.
And I think you guys both mentioned this at the beginning about residual toxicities and frailty, but these are platinum-resistant tumors and we are responding, we are doing better and patients are living longer, but it is still a terminal disease in this setting. I hate to say that out loud. And so shared decision-making about goals of care, assessment of symptoms, schedule, what someone's willing to tolerate from a side effect profile is critically important so patients feel engaged in decision-making in this setting.
I wanted to ask if you had a closeout on this particular case, Dr. Pothuri.
Dr. Pothuri:
Yeah, I just wanted to just highlight what you said, Katie, the importance of clinical trials here. And you offered her the standard of care, but she opted to go on the clinical trial and she's been on this for a year. That's incredible. And so I just can't stress how important it is, especially as we try to bring new therapeutic opportunities for our patients, really, really important. And our standard of care options are always there so I always think about a clinical trial first. I have my ask-me-about-clinical-trials pin that I wear, and so I really try to prioritize the trials. Obviously it is a shared decision, but I think it's also just the trials that you have open and how you are able to convey that message to the patient.
Dr. Moore:
Thank you for that. I totally agree. Dr. Fuh, any last comments on case one from you?
Dr. Fuh:
No, I agree. I think that the way that it was approached and the way we think about it is very typical of how we do it, and so it's good to really share this with everyone.
Dr. Moore:
This brings us to the end of this case. Please see the other segments for further discussion about the latest research in platinum-resistant ovarian cancer, or visit ASCOPost.com.
