Dr. Kathleen Moore:
Welcome to the ASCO Post Roundtable Series on Overcoming Platinum Resistance in Ovarian Cancer. I'm Dr. Kathleen Moore, Deputy Director at the Stephenson Cancer Center. Joining me today are two of my colleagues and great friends, and I will allow each of them to introduce themselves, and I'll start with Dr. Pothuri.
Dr. Bhavana Pothuri:
Hi, I'm Bhavana Pothuri. I'm a gynecologic oncologist at NYU Langone. I also serve as the CTO Medical Director here, and I'm really excited to have this conversation with two of my great friends.
Dr. Moore:
And Dr. Fuh.
Dr. Katherine Fuh:
And I'm Katherine Fuh, I'm a GYN-oncologist at the University of California, San Francisco, and I serve as the Director of Translational and Basic Research in gynecology, and also looking forward to this conversation.
Dr. Moore:
Awesome. Welcome to both of you, and thank you for participating. Today we'll be discussing the treatment and management of platinum-resistant ovarian cancer with three patient case studies. This is case three, our final installment, which will focus on a patient with stage IIIC high-grade serous ovarian cancer after progression on platinum-based therapy and on a PARP inhibitor. So, we changed it up on you a little bit.
Just to give you a little context about this patient, she was 72 at the time of her diagnosis. Now she's a little older. Diagnosed in 2019 with stage IIIC high-grade serous ovarian cancer. She was treated with neoadjuvant chemotherapy with paclitaxel, carboplatin, and bevacizumab, given in cycles one and two; had a surgery that was successful; had some little bit of residual disease, but overall successful; and then received additional paclitaxel, carboplatin and bevacizumab, starting a cycle after completing her interval surgery; and then went onto bevacizumab maintenance and received the whole 15 cycles of bevacizumab, which is about a year after her last chemo, and then was done. It was stopped. And so, we kept an eye on her, entered her into close follow-up.
And about 24 months after her last platinum, she had a bump in her CA-125 and was sent for imaging, and was found to have new, small, but they were there, metastases in her liver. Now, we do know she had molecular profiling sent, or just some molecular profiling sent at diagnosis, so we know she's BRCA wild-type, germline and somatic, and we know that her tumor is classified as homologous recombination deficient.
Now, at the time of recurrence, she was treated with carboplatin and pegylated liposomal doxorubicin for six cycles, and she had a partial response. Then she was treated with maintenance olaparib, and made it about 12 months on that before she had a clinical progression. And so, she was put back on monotherapy carboplatin. Got the first two cycles with stable disease, another two cycles, CT scan unfortunately shows progression.
And so, as I mentioned, she's progressed. We imaged her, and her liver metastases, that's really her main site of disease, are getting bigger. No bowel obstruction, no ascites, mercifully, and pretty good performance status for the amount of therapy she had. Still performance status 1.
And now she's waiting in your office, three lines of platinum. What are you going to order for her and what are you looking for in terms of deciding what therapy best suits her next? And I'll start with Dr. Pothuri.
Dr. Pothuri:
Yeah. So, I would want to get immunohistochemistry testing for FRα as well as HER2, given that we now have treatment options that are biomarker directed for both of these.
In addition, I would do tumor testing, and I would look for some of the more rare findings, like NTRK, RET, and then I'm also looking at MSI, TMB, and then other biomarkers such as CCNE amplification and ARID1A mutations.
Dr. Moore:
Yeah. Anything else you'd be looking for, Dr. Fuh?
Dr. Fuh:
I think we can... It's rare, but the TP53 Y220C mutation, in particular, can be paired to a treatment. So, I'd also look for that one, too.
Dr. Moore:
Yeah. And then, I'm going to stay with you for a second. So, she was diagnosed in '19, has had quite a bit of therapy since then, and now I'm going to send all these new tests. What are your considerations for testing now? Are you re-biopsying? Are you using archival samples? How are you thinking about tissue here?
Dr. Fuh:
Yeah, I agree with you. I think a lot of times it's thinking about when they were diagnosed, and as you said, 2019, and then has had platinum, and then PARP, bevacizumab, and progressed on that.
So, for her, I would probably discuss, if it's in a location that's safe, to consider re-biopsying and seeing... We don't really have the data yet to say whether in this situation we should re-biopsy, but at the same time, it feels like it would make sense because she has developed some resistance to some treatments. And perhaps that tumor's going to look somewhat different than the baseline.
Dr. Moore:
Yeah. I think this is one of the places where we just don't know yet if we have to re-biopsy or not. If I have a lot of archival tissue, can I just send that again, or do I need to re-biopsy?
In this particular patient, because her disease, when it recurred and still is in the liver, as opposed to multiple different sites of metastases where you can maybe have more spatial heterogeneity, I opted not to re-biopsy her. But maybe that's a mistake. That's completely my making things up.
But sometimes when they have lots of new spots, I do re-biopsy, but then I just wonder if what I'm getting is maybe just that spot and not all the other spots. So, there's this concept of temporal and spatial heterogeneity, and ovary cancer is a complicated one when you're biopsying one thing, and asking a question of whether or not a therapy is going to help. Either you miss something that might be important, or you identify something that's only important to that lymph node, and then everything else grows.
So, this is an area where we really don't know. I think you have to just do what you said is make clinical judgment and go from there. But certainly, if you don't have tissue, then it necessitates a biopsy if it's safe.
Dr. Fuh:
Exactly.
Dr. Pothuri:
I think if we had better ctDNA options that would help. It would address some of these tumor heterogeneity questions as well. But unfortunately, we're not quite there yet for ovarian cancer.
Dr. Moore:
Yeah, I agree. I think we're getting there, though. At ESMO last year, Dr. Vicky Makker presented some of the exploratory biomarker work from the DESTINY-PanTumor study, where they tried to look at at least amplification of HER-2 and compare it back to the tissue. And Stephanie Lheureux has looked at this as well in her, that's called the EVOLVE study, where she did biopsies and looked at CCNE1 in the tissue and then on amplification.
And both of those examples, they were able to identify on ctDNA amplification, but they missed some that was in the tissue. And so, you wonder whether or not which one's correct. Are you missing some, or you measured it in the archival specimen, and it's gone?
So, I agree. I think we're getting there. I think we're going to get there where we can do serum markers for some of these HER2, maybe hopefully CCNE1. Fully, that work is a part of the ongoing studies, so we'll know more about circulating folate I think in the near future. But I agree with you, we're not there yet, though. So, tissue for us for ovary is still the best way. The liquid biopsies for ovary sometimes is the best you can do if you don't have tissue. And I do send those. But the ideal is tissue for now, I think.
That's actually a great point, because I think sometimes people send the circulating tests, which aren't quite there yet for our tumor. But hopefully we'll get there.
But back to this case. So, she's very interesting, and she's also a wonderful patient. She is BRCA wild-type, both germline and somatic. HRD-positive, at least historically, was at one point. FRα-medium expression. HER2 2+. She actually has a TP53 Y22OC, and she's HLA-0201.
So, she's got a bunch of things that are now both standard of care, very recently with trastuzumab deruxtecan. That wasn't the case when we sent this. But as of March of this year, that is now approved. I think March or this year. So, standard of care today would be trastuzumab deruxtecan for her. NCCN, her FRα expression links her to rituximab and bevacizumab as a 2A. She has a number of trials, HLA-201, the TB53, et cetera.
So, this patient's now sitting in front of you with all of these potential options. She got a lot of options, which is nice to have. Three prior lines, three prior platinums, prior bevacizumab, and prior PARP. She progressed on her prior PARP and progressed on her prior platinum. So, on both of those.
I'll start with you, Dr. Fuh. Because we're seeing more of these patients now, because we're using so much PARP in the frontline. So, they've progressed on a PARP, sometimes after PARP, so we don't even know what that means. And then, maybe they get another platinum, and they progress on the platinum.
Is there overlap with resistance mechanisms? And at this point, do you think about those patients and their tumors differently, and maybe make different selections if they have progressed on or after a PARP, if at all? How is that feeding into how you think about best options for a patient?
Dr. Fuh:
Yes. No, it's true that those who progressed after PARP, and the mechanism for PARP inhibitor resistance and platinum, there are some crossovers. Certainly there are unique resistance mechanisms, but there are plenty that are together. And seeing her other options, too. I think that also weighs into the context of what she can receive.
But thinking about how she has progressed on a PARP inhibitor and the platinum, I do put her in a different category. I do think about putting it in her where I wouldn't consider trying platinum again in her, and then really focusing on her biomarker-directed therapy. We know from a post hoc analysis from PAOLA-1 that there is, perhaps, after progressing PARP inhibitor, the response to platinum is lower. And so, luckily for her, she has some options.
Dr. Moore:
Yeah. How about you, Dr. Pothuri? How are you thinking about her?
Dr. Pothuri:
Yeah, I completely agree with Katherine. And when someone progresses on a PARP inhibitor, or while on platinum, I tend not to want to re-utilize platinum in those patients, just because of the platinum resistance that has likely developed, and I try to utilize other therapies in this setting.
Dr. Moore:
And I mentioned... I actually misspoke, so I'm going to clarify. I'm going to correct myself. She's HER-2 2+, which is NCCN listed, but the FDA approval is in 3+. I want to just come back and clarify that comment. It is a 2A NCCN for 2+, 3+, but standard of care for her would really be mostly chemotherapies. And then NCCN, she has both rituximab with bevacizumab, and trastuzumab deruxtecan on her NCCN listed list.
So, I'll stay with you, Dr. Pothuri, and I'll come back to Dr. Fuh. You have those two. Those are your two options. How are you going to pick, and what's the... We talked about rituximab already. What's the data that justifies adding trastuzumab deruxtecan to this list?
Dr. Pothuri:
Yeah. The DESTINY-PanTumor study really looked at different tumor cohorts, and ovary was one of them. It's a small cohort, 40 patients, but certainly significant efficacy that was noted.
And honestly, the HER2 ADCs are kind of one of my favorite new drugs to really utilize, given how efficacious they are and how well tolerated they are from a patient standpoint.
But I do think that we have to be mindful of the pneumonitis that is a risk, the ILD or pneumonitis, and I think something that we all, as GYN-oncologists, had to learn is that with this drug, even with a grade one asymptomatic ILD or pneumonitis, when you're using these drugs, you do have to hold drug and wait for it to resolve before you can continue. We have seen some very significant and progressive ILD pneumonitis that can even be fatal, so just a word of caution on that.
Dr. Moore:
Right. How about you, Dr. Fuh? You're looking at her, you can use two NCCN 2A category therapies, or all the chemos that are out there. Just another patient with a lot of options in front of her. How are you going to pick? What's your sense of activity and best choice for her?
Dr. Fuh:
Yeah, no, this is a tough one. We know as Bhavana mentioned with the PanTumor DESTINY, 40% response rate with the 2+ HER2 IHC expression, which is what she has, and her folate receptor is about 40%. We could consider doing rituximab and bevacizumab as well, too, for her.
So, I think sequencing wise, we just talk to her about that she has great options, and certainly we can try, start with one, and then if she were to progress, so we can have the next one. And actually seeing what other side effects she's had from the platinum or from PARP inhibitors might help guide, also, in terms of myelosuppression or anything of that sort, that might also lead us to do one vs the other.
Dr. Moore:
Right, exactly. And with mirvetuximab there's the eyedrops, which patients do great with, but they don't like it. They're not like, "Oh, I'm so glad I have to use these eyedrops." There's some patients that are just like, "No, not doing that." This patient actually has two biomarkers.
And beyond the point of this ASCO Post Roundtable, but something I think we're all really interested in, this patient has two biomarkers. And we're like, "Why would you use this for this reason? Or I might use this for this reason," but we don't really know how to sequence with these overlapping IHC findings on these tumors. And with the panoply of ADCs that are coming into play, we're going to have to figure it out because otherwise we're going to be guessing, and I think we can do better than guess. But we don't know yet. So, it comes down to shared decision making with the patient for these, you can't say on-label, but at least on-compendium options.
And then she does have multiple clinical trial options, and she is one that has this TP53 Y220C. We've never been able to target TP53, so this is really exciting to have this medication. It's PC14586. It has a funny name called rezatapopt, which is hard to say.
This mutation in ovary cancer is only about 3%, but if you don't know about it, you're not going to catch it on all of your NGS reports, so it's just one of those things you want to look for 220C, and then at least try to get that patient some information about the trial, because the response rates have been quite high for this particular biomarker. And it will be difficult to move forward because of the rarity, but could be the next BRCA for 3%. So, that's important.
And then you mentioned this, Katherine, she's FRα-medium, so that's NCCN listed but not labeled, and there's many new folate ADCs coming as well on clinical trials.
So, for this patient, what happened with her is that she progressed before trastuzumab deruxtecan was on NCCN compendium, so she received a similar agent that Dr. Pothuri and I both are involved with on a trial, and was on it for over a year, with a partial response, but had to discontinue because of just what you said, Bhavana. She had grade one pneumonitis that didn't go away within the study-prescribed hold parameters, and so she had to be discontinued because of that, but she was still in response, and we just sort of watched her for a bit of time.
And then she elected to participate on the Y22OC clinical trial, and then most recently she's been on a novel ADC for FRα on continuous clinical trials. So, this is at a clinical trial center, but she had two options off clinical trials as well that we just have to make sure everyone is aware of.
So, clinical takeaways for this case is a lot of unknowns that I think we just are all going to have to be very fluid with, potentially even changing our treatment algorithms as new data comes out.
But the impact of PARP on mechanisms of resistance is emerging and may impact treatment selections in the future. I think we just have to be ready and willing to pivot one way or the other based on those data.
And a lot of that's work that you're doing, Katherine, just looking at mechanisms and taking specimens back to the lab. This is really science-driven work that I think will impact what we do.
I said this in every case, tissue is key. We have to have tissue for patients with ovary cancer. Now it is not okay, if at all possible, to just have diagnoses based on cytology, and try to run all these diagnoses based off of blood or cytology. We really, really need tissue for all the biomarkers we've talked about.
And really understanding these new therapies as they're rolling out, they're kind of rapid, is really imperative to use these safely. And you mentioned this, Bhavana, the pneumonitis grade one. Most of us, it doesn't say that on the CT scan. What does it say?
Dr. Pothuri:
Nonspecific patchy opacities. Yeah, bilateral infiltrates.
Dr. Moore:
Clinically correlate-
Dr. Pothuri:
Right.
Dr. Moore:
Patient's like, "I feel great." And you're like, "Okay, cool. I'm going to keep treating." Doesn't say that's pneumonitis, but you've got to know it, and hold, and get it worked up. That's the biggest learning point. And then there'll be more as these medicines come out.
And then, early referral clinical trials. You made this point on one of the other cases, Dr. Pothuri, and it's just really key. I know everyone doesn't have access to trials at their site, but they... Ask us about clinical trials. Patients should ask. And there are trial centers hopefully relatively near to patients that have a wide variety of these biomarker-directed therapies, so we can really try and get patients the right drug at the right time in the right setting.
Any last thoughts from either of you on case three? She's a real patient. It's an increasingly common scenario. Lots of unknowns. Any comments on her?
Dr. Pothuri:
I just want to make two little comments. So, one, both of you mentioned that tissue is key, and so, as many more patients are getting neoadjuvant chemotherapy, I think really making sure you are able to get tissue, and if you can't get enough tissue through IR with core, bring those patients to the OR or send them to a GYN oncologist to get scoped and get tissue. So, I think I wanted to make that one point.
And then the second point I wanted to make is, and you alluded to this as well, Katie, again, the clinical trial option gave this patient a year. I mean, we've never had a year on therapy with our standard of care options. So, I can't just highlight that enough.
And this case was really interesting and cool to me because there were so many different targetable alterations, both standard of care as well as with clinical trials with the Y220C, the TP53 reactivator, and the HER-2 ADCs, and then the FRα medium and low expressors, where there are trial options. So, really just so many cool options.
Dr. Fuh:
And I would say with the folate receptor, the new trials, I mean, the folate receptor ADCs can differ by payload or by linkers, and so I think just thinking about that. Not each folate receptor ADC is not the same. And that's why there are definitely more options that we need for our patients' clinical trials, and to really add on to that.
Dr. Moore:
Absolutely. Well, we could probably talk for another hour, but 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. Thank you for joining us, and thank you to my colleagues for participating today.
