Dr. Oladapo Yeku:
Welcome to the ASCO Post Roundtable on Targeted Treatment Options for Platinum-Resistant Ovarian Cancer. I'm Dr. Oladapo Yeku, the Director of Translational Research at the Massachusetts General Hospital and a gynecologic medical oncologist. Joining me today are my two esteemed colleagues, Dr. Musa.
Dr. Fernanda Musa:
I'm Dr. Fernanda Musa. I'm a gynecologic oncologist at Providence Swedish Cancer Institute in Seattle, Washington, where I run clinical trials for gynecologic oncology.
Dr. Oladapo Yeku:
And Dr. Liu.
Dr. Ying Liu:
Hi, I'm Dr. Ying Liu. I'm a gynecologic medical oncologist here at Memorial Sloan Kettering Cancer in New York City where I lead our inherited gynecologic cancers program.
Dr. Oladapo Yeku:
Today we'll be discussing the treatment and management of platinum-resistant ovarian cancer with three patient cases. Our final installment will focus on the treatment of low-grade platinum-resistant ovarian cancer. So we start with the case of patient J.M.. She's a 75-year-old patient with a history of stage IIIB low-grade serous carcinoma. She underwent six cycles of adjuvant carboplatin and paclitaxel and did not receive any maintenance therapy as per records because her BRCA was wild-type and she was HRD proficient. Five months after her last cycle of adjuvant chemotherapy, she was evaluated in the emergency department for abdominal pain and was found to have peritoneal carcinomatosis and a 5-cm liver mass.
The rest of her medical history is as follows. She has type 2 diabetes, hyperlipidemia, anxiety, and fibromyalgia. And in addition to her staging surgery for her ovarian cancer, she's also had an appendectomy and cesarean section. She has no family history of malignancy. She's married, lives with her husband, is a retired librarian, and she has three children in good health. So the question that I have, I contemplate is at each of our sites, we all do things differently. And I'm curious, starting with Dr. Liu, do you or your site routinely test for hormone receptor expression levels for your low-grade serous carcinomas? And do you also do next-generation sequencing at the same time or do you only do it in recurrence?
Dr. Ying Liu:
Yeah. It's a good question. We do routinely test for ER and PR just because hormonal therapies are so important in low-grade serous ovarian cancer. And it's a very different cancer than high-grade serous. And actually this patient has some characteristics that are a little unusual of typical low-grade serous ovarian cancer. She's a little bit older. Usually we see this in younger women. It's not unusual that she's BRCA wild-type.
We do follow, for all of our ovarian cancer patients, we do parallel germline and tumor sequencing at diagnosis. So we have reported on our institutional findings that actually we don't see a lot of BRCA1 and 2 mutations in low-grade serous ovarian cancer, which makes a lot of sense given the different drivers. And so we would generally do all of that testing upfront. And for this patient, I think it's good because she's having recurrence 5 months after chemotherapy, which is also a little unusual for low-grade serous and speaks to maybe a more aggressive phenotype that we sometimes see in older patients and maybe KRAS wild-type low-grade serous ovarian cancers.
Dr. Oladapo Yeku:
Dr. Musa.
Dr. Fernanda Musa:
I completely agree with my colleague, Dr. Liu, but I want to backtrack and just say that I would look at this case of a recurrent low-grade serous ovarian cancer with the eyes of a surgeon first. And I think your liver metastasis here sealed the deal for me that she was not a candidate.
I think that were she a candidate, that probably would be my first response because it would alleviate her symptoms faster and it would, generally speaking, these are slow-growing diseases where surgery does help. Your case does not reflect a surgical candidate, and I think that's on purpose. I think testing is extremely important because KRAS mutations are actually really common in this population and it would really define my algorithm of what I would try next. So those were my two additions.
Dr. Oladapo Yeku:
Thank you. With histologies, some of these ovarian cancer histologies are probably more amenable to oligometastectomy when you get the opportunity to do so. Maybe followed up by systemic therapy or sometimes not depending on the overall clinical context. So that was a great clinical pearl Dr. Musa.
Dr. Ying Liu:
I will agree. Yeah. I actually think surgery is probably the best treatment for low-grade serous ovarian cancer. And we do have patients that have surgery and then long remissions, even decades. And so I do sort of think of this treatment paradigm very differently than high-grade serous, and surgery is definitely a very big tool, multiple surgeries. And then it's also I think sort of more how can I prolong the course for patients and how can I sort of maximize benefit but minimize side effects of surgery. Or it's not surgery, but therapies in general.
Dr. Oladapo Yeku:
So this particular patient didn't have any molecular indications for maintenance therapy. When do you guys use maintenance letrozole for you in the upfront setting? I left that there. I've seen it from colleagues. So I'm super curious what you guys do or in which patients, how do you select who you do that for? Who you let enjoy their chemo-free break?
Dr. Fernanda Musa:
I think that you can still enjoy your chemo-free break on letrozole with some arthritis management, especially in a post-menopausal woman. But I would say I use it very often. I had a recent clinical trial open that chemotherapy followed by letrozole vs letrozole alone enrolled several patients into this trial. So have been using hormonal management frequently with excellent success. It really works. I don't know this patient with the liver metastasis and carcinomatosis 5 months post chemo is that candidate. But in the patients who have indolent symptoms, low volume of disease, I do use hormonal therapy very often.
Dr. Oladapo Yeku:
Dr. Liu, what's your practice?
Dr. Ying Liu:
I agree. I would've probably discussed it with this patient. She's postmenopausal, I think she would've tolerated it very well. But even in some of my younger patients, depending on what type of surgery they've had, whether or not they have their ovaries still in or not, it's also a discussion there. But I think hormonal therapies can work very well in low-grade serous ovarian cancer, sometimes even better than chemotherapy. So it's definitely something I consider even upfront.
Dr. Oladapo Yeku:
Absolutely. I think when we draw that Venn diagram of histologies that are more chemotherapy or classical cytotoxic sensitive vs resistant, I think low-grade shifts a lot more towards the resistant side. So we do have modifying agents like hormonal therapy. That's kind of how I classify it intellectually with reasonable or manageable side effect profile. I think it's worth giving it a shot and giving the patient that chance with working with them on their symptoms. It's done very well for breast cancer.
And at that point, I think low-grade serous carcinoma I think represents an important histology for us because it's one of those where because of this relative responsiveness, lack of responsiveness to chemo, we've had to put patients in a lot of trials and that's why we've learned about all these evolutions and roles of hormonal therapy, both as maintenance or as definitive therapy in certain contexts. So I'm going to back into this, but who would you give chemotherapy to in the recurrent setting? So we've talked about cases where if your folate receptor, HER2 and we have established pathways for that. But for low-grade, who would ever get chemotherapy? Since we know hormones work and we have other things we'll get to in a moment.
Dr. Ying Liu:
Now I'm going to backtrack on what I just said about hormones. This is the patient where I would think about chemotherapy. Right? This is the patient that is progressing and has peritoneal carcinomatosis and liver metastasis. This disease is acting more like high-grade. It's a little bit more aggressive. But I'd also be worried because she's progressing very quickly after my best chemotherapy.
This is the patient where maybe hormonal therapy is less effective. So I'd be thinking either about chemotherapy, different chemotherapy or maybe a targeted clinical trial or even, and I don't know what you guys think, looking for folate receptor alpha or HER2, which I know maybe the rates are going to be a little bit lower and low-grade serous, and I know we have limited data. But this is the patient where I'm looking for all options because it seems to be more aggressive.
Dr. Fernanda Musa:
I agree with you. This particular case is hard because she did progress within six months of her last chemotherapy. So I would be looking more at looking for KRAS and looking to try some of our recent FDA-approved regimens. But just to your point, sometimes these diseases over time start out as low-grade and then transition or are heterogeneous to begin with and the metastatic clones become high-grade. I've seen this in taking people back for secondary debulking and tertiary debulking that my pathology comes back high-grade in the end. So I just wanted to put that out there. But yeah, I would be looking for an opportunity to use one of the newer FDA-approved regimens in this case.
Dr. Oladapo Yeku:
I absolutely agree. I think when we meet patients in the emergency room for symptomatic progression of disease, our minds don't go to hormone therapy in. That setting we're thinking about evolution of the tumor. How can we get this patient feeling better by whatever means we have. So we've all seen recent results of avutometinib and defactinib for patients with KRAS status. And I'm sure we've also seen the data, the more recent data regardless of KRAS status.
But we'll wait on the FDA decision for that and we'll wait on the final manuscript. But for now, we all know about the accelerated approval. How do you guys use this in your practice? I've always been a trametinib person and we'll talk about that later before these results. And now I'm rethinking how should I sequence my therapies. But before I talk about that, Dr. Musa, I'm curious to see how you've incorporated this into your practice.
Dr. Fernanda Musa:
Well, I think that the accelerated approval is specific to KRAS-mutated low-grade serous ovarian cancer, which can be, depending on who you read, somewhere between 30% and 50% of the cases will have some sort of activating mutation. So it's a narrowed population. The data is very compelling, response rates of 44%, progression-free survival of 22 months. So definitely caught my attention. I do think, as you said, trametinib is still relevant in this population. I have not had the opportunity to use the regimen I cannot pronounce, but look forward to it.
Dr. Oladapo Yeku:
Dr. Liu.
Dr. Ying Liu:
Yeah, it's tough. We have experience with both. We had the trial—we had RAMP—open, so I have some experience with avutometinib and defactinib. I'm still working on my pronunciation as well. I agree with Dr. Musa, the FDA approval is currently in the KRAS-mutated population. So that is where I'm sort of discussing both the combination therapy and trametinib. The data we have don't compare them head to head. Right? So we don't know if the combination is better than the single-agent MEK inhibitor. We do know in theory that single-agent MEK inhibitors maybe are more prone to resistance and the combination does target multiple areas in the pathway.
So from a scientific standpoint, there is rationale to think that it would be more effective. From a toxicity standpoint, no, I was very surprised because we know that trametinib can have toxicity specifically with skin toxicities, but the avutometinib and defactinib was actually reasonably well tolerated. The rates of discontinuation were actually higher in the trametinib studies at around 30% compared to the 10% in the combo studies. And I think that's because of the dosing.
The trametinib is dosed continuously, whereas the avutometinib and defactinib are dosed not continuously, and one of them is only twice a week and it's 3 weeks on, 1 week off, which seems to help with the toxicity, but may make it harder for patients to take. So I think we're all still struggling as to how to use these medicines, and as we get more data, I think we'll get a better sense. But there is a lot of interest in the combination therapy. I know a lot of my patients with low-grade serous ovarian cancer are young. They're very active on social media. I know this trial accrued very quickly, had really a big component of patient advocacy, and so a lot of patients are asking and talking about the combination.
Dr. Oladapo Yeku:
Absolutely. So if I'm hearing this correctly, at least with the current approval status, if we have a patient that's KRAS wild-type, you'll probably lean towards trametinib or something else. And if they're KRAS mutant, then you might lean more towards the combinations. Is that the feeling that or what you would do in today's current approval landscape?
Dr. Fernanda Musa:
I think so, yeah. And Dr. Liu, I'm very curious if you could share some pearls with us about the skin toxicity management. Are you a person that starts clindamycin at the beginning? What is your personal practice here?
Dr. Ying Liu:
I'm very influenced by my colleague, Dr. Rachel Grisham, who's one of the experts in low-grade serious ovarian cancer and helped write a lot of these protocols. So we are very aggressive with the prophylactic antibiotics for the skin toxicities. There is also some GI toxicity and then you have to monitor the liver enzymes. But I do think that the noncontinuous dosing has really helped. And the study is built in quite a bit of time for holding the drug and dose reductions. So there are adjustments that you can make to help with the tolerability.
Dr. Oladapo Yeku:
I've been compiling over the years, the notes from all the patients I sent through dermatology and now I've been able to synthesize all of that in sort of a comprehensive list. And really only when it gets super out of hand, even after a hold, do they go to dermatology. And they end up doing the same thing, but mostly because I've been copying their notes for years. So that's been my approach and it's worked well so far. But I think eventually at some point these patients do get to dermatology, especially for the ones with really severe activity-limiting skin toxicities.
So slightly different question still on low-grade. Now that we've established a role for hormones upfront or hormonal therapy upfront and then targeted therapy, I also noticed that in the community of some of my colleagues there's this pattern of switching hormone therapy, especially for patients with low-grade progression or just with rising CA-125 and no radiographic issues. I just wanted to pull you guys as to, do you guys believe in that, switching hormonal therapy like our breast colleagues do, or do you guys think if you're tolerating it, you use it till progression and then you just go on ahead and do something else? Just curious.
Dr. Ying Liu:
I do a little bit of both. So I do switch through all three AIs. I will use injectables. It often depends on the patient. I have some very young patients with low-grade serous ovarian cancer that's very indolent. So I'm thinking, "What can I do for this young woman over decades to give her good quality of life?" So in these patients, I do have my colleagues do a lot of surgeries.
Because after surgery they're feeling good and then I often will put them back on AI maintenance because that's really easy for them compared to some of the other therapies. I think switching to an injectable hormone affects their quality of life a little bit more. But you can still give injections once a month or every 3 months. I think to be honest, that the MEK inhibitors and the combination therapy to take that for long periods of time and in young women, sometimes it can really affect the quality of life.
So I actually try to delay that as much as I can and someone who has more indolent disease and I try to use surgery and hormonal therapies for as long as I can before jumping to the more intensive therapy. So that's kind of my approach in my younger patients with more indolent disease. In cases like our patient, who in these older patients with more aggressive disease, then I think we have to jump and I am more prone to stopping a hormonal therapy or switching to a different type of therapy if I'm seeing progression or symptoms.
Dr. Fernanda Musa:
I agree with what you've said and I think not all the antihormonals work exactly the same. So I do think there is a benefit to trying across AIs—I don't know if I would change between brands of an AI other than for toxicity. Sometimes that will help with toxicity management, ie, joint pain, you switch to a different AI and it goes away magically sometimes.
But to change across categories from an AI to fulvestrant and other things, I would try that before I went to a MEK inhibitor for sure. I agree. You confine them to that and then it is a situation that they're exposed to that drug for a long period of time with significant more toxicity than you would with an antihormonal.
Dr. Oladapo Yeku:
I agree. I agree. So the key clinical takeaways I think for a low-grade case is that the combination of avutometinib and defactinib is approved for the management of recurrent low-grade serous carcinoma with KRAS mutations. We've discussed that trametinib also has superior activity compared to cytotoxic chemotherapy and hormone therapy for platinum-resistant low-grade carcinoma.
For patients with asymptomatic or low disease burden hormone therapy with such as fulvestrant could be considered. And early involvement of a subspecialist dermatologist is essential in managing skin toxicities, especially for patients in whom this is really, really burdensome and symptomatic. So this brings us to the end of the case. Please see the other segments for further discussion about the latest research in ovarian cancer or visit ascopost.com.
