Dr. Kathleen Moore:
Welcome to The ASCO Post Roundtable on Overcoming Platinum Resistance in Ovarian Cancer: New Strategies and Novel Treatments. I'm Dr. Kathleen Moore, Deputy Director at the Stevenson Cancer Center in Oklahoma City, and I'm joined by two of my, honestly, very close friends and esteemed colleagues in GYN oncology, Drs. Pothuri and Fuh, and I'd like them to introduce themselves. I'll start with Dr. Fuh.
Dr. Katherine Fuh:
Hi, I'm Dr. Katherine Fuh. I'm a GYN oncologist at University of California San Francisco, also the Director of Translational Basic Research here, and really looking forward to these cases with you.
Dr. Moore:
I'm happy to have you. And Dr. Pothuri.
Dr. Bhavana Pothuri:
Yeah. Hi, I'm Bhavana Pothuri, I'm also a gynecologic oncologist at NYU Langone Health. I serve as the Clinical Trials Office Medical Director and I'm really excited to speak with both of you about this exciting topic.
Kathleen Moore:
Awesome. Let's just dive right into this. These are kind of short little segments, but packed with good information. Today we'll be discussing the treatment and management of platinum-resistant ovarian cancers with three patient case studies. Our second installment will focus on a patient with stage IIIC high-grade serous ovarian cancer who progressed after her last platinum-based treatment. Just to give you a little more context to this patient, she was 66 at the time of her diagnosis, was diagnosed as most of our patients are with advanced-stage disease, here stage IIIC, high-grade serous ovarian cancer, and this was back in 2019. She was treated with a primary cytoreductive surgery that was very successful, taken to no gross residual disease, followed by very much the standard of care, which is paclitaxel, carboplatin, and bevacizumab, followed by bevacizumab maintenance for a year, which is the amount of time, 15 cycles. So ended treatment, no evidence of disease, and was put into close surveillance.
She had her tumor sent and germline testing sent during her first therapy and is known to be BRCA wild-type and negative for any germline alterations and HRD test-negative. 18 months after her last platinum, so about 6 months after finishing her last bevacizumab, she was noted to have an elevated CA-125, underwent a CT scan, and found a recurrence in her abdomen. She was termed platinum-sensitive recurrence and was treated with, really, at our institution what we almost always use in the first recurrence, carboplatin and pegylated liposomal doxorubicin, and we restarted bevacizumab here for six cycles. She had a partial response and then continued the bevacizumab maintenance and recurred about 5 months into that maintenance. So recurrence less than 6 months.
She had imaging at that time. This was just found on a surveillance CT scan or a treatment-related CT scan, and found to have new liver metastases, but no bowel obstruction. A little bit of ascites though that was new, good performance status. And so now she's back. She was coming in for pre cycle six of her bevacizumab and she's got this new progression and is coming to see you for a treatment discussion. Are there any other tests that you want to order? The initial testing is 2019, and now she's here with this recurrence, platinum-resistant. What additional testing are you looking for? What are you going to order for her? I'll start with Dr. Fuh.
Dr. Fuh:
Since 2019, we now know that folate receptor immunohistochemistry and HER2 IHC are really important in our patient setting. So I would look for that. Also, 2019, I think we were ordering microsatellite instability, but I think that's something else to really make sure that that's been ordered as well. But really focusing on the folate receptor and the HER2 immunohistochemistry.
Dr. Moore:
Yeah, that's what I'd be looking for too. Dr. Pothuri, anything else that we're forgetting here that you'd be wanting to look for on the test that you send?
Dr. Pothuri:
I just would look for TMB because we have that tumor agnostic indication for immunotherapy, and then some of the more... The RET and the NTRK, which are highly actionable as well. Much more rare but very actionable. So I'd want to look at that in addition, as well as CCNE1 and TP53.
Dr. Moore:
Yeah, we're all trying this. We're all looking for things to match to trials for sure. Standard of care, we're looking for fully MSI and HER2. Just before we talk about what she had, you're all talking about this, so I'm presuming you're sending next-generation sequencing. So that's how we get many of those amplifications and mutations. For immunohistochemistry, how are you getting that? Are you doing it locally based on archival tissue? Are you getting it on a panel? How are you both getting all these IHC tests you just mentioned run?
Dr. Fuh:
For folate receptor, we do send it out. For HER2, we do do it in-house because they do it for the other tumor types like breast and gastric cancer. So that's how we have done it right now or are doing it right now.
Dr. Pothuri:
We do exactly the same.
Dr. Moore:
Okay. It's incorporated in a panel, so we send it out. Yeah, I think some people are doing it locally, though, and that's okay if you have that capability. So there's a myriad of ways you can get these results.
This patient, we did send her archival specimen for this sort of big panel testing, and we knew she was BRCA wild-tape by germlines, confirmed somatic. There's no BRCA somatic mutation. We already knew she was HRD-negative. That was reconfirmed on the panel that we sent. But she was found to be FRα-high. She had 100% of her cells staining 2+. She was HER2 0. We also send HLA testing, again, to link to some of the cellular therapies so we know if someone's eligible for clinical trials, and she has HLA-A*0201, which does open up doors for her to participate in clinical trials at our site in the future. So on her preamble on MyChart, that's all her positive things.
Standard of care for her would include all the chemotherapies that are on the NCCN plus now mirvetuximab because she's FRα-high, the NCCN would list mirvetuximab plus bevacizumab as a two-way listing. So if you wanted to use bevacizumab, you could do that. And then trials, as I mentioned, there's many things that she's eligible for that are not biomarker-linked. I want to emphasize that. But she is potentially eligible for consideration of these bispecifics and engineered T cells that are in clinical trials because of this HLA-A*0201.
So knowing that about her, two prior lines, prior bevacizumab, actually, twice, and she's progressed after responding to a platinum, what are your considerations? She's sitting in your office, what are your considerations for her for both standard of care and clinical trial options? I'll start with Dr. Fuh on this one.
Dr. Fuh:
I think I would definitely let her know about the clinical trials that are available. Standard of care will certainly still be there, but especially with HLA type-positive, that's very encouraging, so I would certainly talk to her about that. But then with 100% folate receptor expression, mirvetuximab, certainly in the setting with the MIRASOL results, would be another standard care that I would opt for her.
Dr. Moore:
Maybe some people haven't heard the results of MIRASOL, it's a very new confirmed approval by the FDA, just new in 2024. Can you just talk in 30 seconds snippet, what was the trial and what were the results that may get FDA approved?
Dr. Fuh:
Sure. In platinum-resistant setting, comparing mirvetuximab to investigator-initiated chemotherapy, and really showing that in that setting that the mirvetuximab was improved survival, both progression-free and overall survival. This is the first ever in platinum-resistant ovarian cancer to show an overall survival benefit. And it was really extensive. 16.5 months, I would say, compared to 12.75 months. I mean, that's just phenomenal for our patients.
Dr. Moore:
Yeah, agree. Dr. Pothuri, any thoughts on what else you'd be thinking about, if anything, for her in the standard of care clinical trial realm?
Dr. Pothuri:
This is a patient where you could consider reutilizing platinum. Her interval was 5 months, so certainly is NCCN listed. And as we're changing the way that we're thinking about platinum resistance, she didn't really progress while on platinum and had more than 3 months. So this is someone that I would consider. Although I agree with Katherine, that I would probably opt for mirvetuximab given the overall survival and PFS benefit that we see. I would consider adding bevacizumab to that based on the NCCN category 2A listing, given that she does have a little bit of ascites developing, and so I may consider that. And that response rate was also higher, although it was a much smaller phase II trial.
Dr. Moore:
Right. Yeah, I would say it was not placebo-controlled, it was a single-arm study, but it is NCCN and I think we have enough experience across ovarian cancer with bevacizumab plus whatever. There are risks, hypertension, bowel obstruction, bowel perforation, DVT. There are risks, and we always have to weigh risks and benefit. But on the flip side, I can't think of an example where we added bevacizumab to something other than weekly paclitaxel. Well, actually, weekly paclitaxel it worked as well. So whatever you add it to, it works better. So for most things that we just maybe are a little too blase about, because there is toxicity.
But I think you make a really good point, and this is a nuance. Actually, I think medical oncologists sort of get this a little bit better than those of us that grew up in a more GYN-ONC world where we're like, platinum-resistant, don't use platinum, and they're like, "You're responding to platinum and I stopped it and you grew back, I'm going to use platinum again until it stops working." So I've adopted that over time as well. Use platinum until platinum stops working or someone's allergic, which happens to our patients. So this would be a conversation between me and the patient. I think reuse of platinum vs mirvetuximab, but I would probably fall on the mirvetuximab side. Because you could use platinum again. She's still responding to the last platinum and mirvetuximab doesn't have overlapping mechanism. It's a microtubule taxol vs DNA damage with carboplatin. So this is where sequencing is the art of what we do. It's hard to run trials with sequencing, but she does have good options.
Are there trials running right now, Dr. Pothuri? We have retrospective data on carboplatin in this setting, but are there any trials either in the past or currently that are evaluating re-treatment of carboplatin in a platinum-resistant setting?
Dr. Pothuri:
Yeah, there's the Olvi-Vec trial that is running that is utilizing carboplatin plus this agent. The phase II data was really quite impressive in terms of efficacy. So clearly there's something that you can also offer the patient in a clinical trial setting.
Dr. Moore:
Yeah, it's kind of exciting to be in a setting where you're actually studying prospectively reuse of platinum, which we've never done. I've been around for a bit now in the field and I haven't seen it, so I'm kind of excited about that. And then this is an intraperitoneal vaccinia vaccine that's given just one time with the carboplatin vs carboplatin doublet. Both arms get an effective therapy, kind of looking to see if it improves PFS and OS. So we'll see if it's positive. But even if it's not, which I hope it is, the idea that we're actually studying treatment of platinum and going to get some prospective data here, I think, will be potentially paradigm-changing in and of itself. So I'm excited about that.
Let me just tell you what happened with her. I think we were thinking the same, Dr. Pothuri, she got mirvetuximab and bevacizumab, and I added that because of the ascites, because I was worried. So I did both. She's still on that. But we are testing, because of the HLA-A*0201 and we're a clinical trial site, we are getting ready to send her tumor for something called MAGE-A4 testing to see if she potentially would be a candidate in the future for engineer T cells that target MAGE-A4-positive tumor cells in this setting of HLA positivity.
That's a study called SURPASS-3, which is a phase II that takes tumors that are the appropriate HLA type, and that's not a tumor, that's just what you're born with, and then MAGE-A4-positive tumors and randomizes them to get engineered T cells or engineered T-cells plus nivolumab, which again, I'm excited about, in full disclosure, because I'm the national PI, so I get to mention things, but I am generally excited about it anyway because this is the biggest study other than TILs of adoptive cellular therapy that's ever moved into gynecologic cancers, and so it's a completely novel way to look at solid tumors and I'm excited that we're going to get to see whether or not it's transformational in ovary as well.
For takeaways on this case, access to tissue is really critical. It's increasingly critical in ovarian cancer as we have more and more biomarker-directed therapies. So if we don't have archival tissue and diagnoses were made on cytology or the tissue has been exhausted and there is the opportunity to safely biopsy it again, that's a key point. We really think that's important so that all the biomarkers can be kept up to date and patients can have access to the most cutting-edge therapies. These must knows include germline or somatic like BRCA and other high-penetrance genes, IHC for HER2 fully and probably more are coming, and then MSI, MSS, and all the things that Dr. Pothuri mentioned that are on the next-gen sequencing, 1% to 2%. But if you find one of them that's game changing for that patient. If I ever find an NTRK, never found one, someday, maybe I will, I'm going to use the right drug.
I think it's an interesting conversation. Mirvetuximab is standard of care and clearly I used it, but consideration for reuse of platinum in the setting of platinum resistance should be a consideration, not a must, but a consideration for appropriate patients, especially when there was response to the penultimate platinum.
And then choice of recurrent platinum-resistant therapies should take into account the histology, molecular profile, immunohistochemistry profile, and all the things we've been talking about, residual toxicity, patient factors, patient desires and choices and priorities probably should be the number one thing I mentioned. All those should be taken into account as we move forward. Any last thoughts, Dr. Fuh? Any last thoughts on patient case two that you wanted to make?
Dr. Fuh:
Yeah, I think to your point about tissue being really important in our field and our treatment recommendations, and so I think sometimes when we're getting tissue, it's like, "Oh, one core, two cores," But sometimes we actually need multiple cores as we're thinking about this, because as you can tell, even with folate receptor, HER2, and the slew of other IHC markers that we might use later on, really getting the appropriate number of tissue cores or if that were the case vs laparoscopic biopsies are really going to be important and integral in our patient journey, I would say.
Dr. Moore:
Yep. It's much more tissue-driven than it's ever, ever been. I agree with you. All right. Well, this brings us to the end of this case number two. Please see the other segments for further discussion about the latest research in platinum-resistant ovarian cancer or visit ASCOpost.com. Thank you for joining us for case two.
