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. I would like to introduce my two esteemed colleagues joining me today, starting with Dr. Musa.
Dr. Fernanda Musa:
I'm Dr. Fernanda Musa. I'm a gynecologic oncologist at Providence Swedish Cancer Institute in Seattle, Washington.
Dr. Oladapo Yeku:
I would also like to introduce Dr. Liu.
Dr. Ying Liu:
Hi, I am Dr. Ying Liu. I'm a gynecologic medical oncologist at Memorial Sloan Kettering Cancer Center, where I lead our inherited gynecologic cancer program.
Dr. Oladapo Yeku:
Today we'll be discussing the treatment and management of platinum-resistant ovarian cancer with three patient cases. Our second installment will focus on the treatment of HER2-positive platinum-resistant ovarian cancer. So we'll talk about the case of JM, who's a 45-year-old patient with a history of FIGO stage IVA high-grade serous ovarian cancer with a BRCA1 mutation. She received six cycles of adjuvant carboplatin and paclitaxel, and this was followed by 2 years of maintenance olaparib therapy. She developed platinum-sensitive recurrent disease, and at this time she was treated with carboplatin, gemcitabine and bevacizumab and did well for a time, and then developed a second platinum-sensitive recurrence from which she received carboplatin, liposomal doxorubicin and bevacizumab. Now she has developed platinum-resistant progressive disease. She comes with some testing and her archival tissue, which was stained by immunohistochemistry, showed that she had a HER2 expression of 0, she had a folate receptor alpha expression of 10%, and at this time they had checked her mismatch repair protein and this was also intact.
So now we have a patient who has some data available. We know the clinical case. So I'll start with Dr. Liu. Under what circumstances do we obtain fresh biopsies for testing?
Dr. Ying Liu:
Yeah. So in this case, she has a known BRCA1 mutation and has received targeted therapy for that. And her prognosis is very similar to those of other BRCA1 mutation carriers where you have long periods of remission and I think better responses to platinum-based chemotherapy. I think we don't know the overlap necessarily between BRCA1 and two and HRD-positive tumors and HER2 and folate receptor alpha expression. There are some studies that show maybe there's no difference, there's some showing that maybe there's enrichment of higher expression in those with HR proficient tumors. And specifically with HER2, there's been some newer data showing that maybe treatment selects for more resistant clones that are actually more likely to express HER2. So that's a long-winded answer and way to say that for this patient, because it's been a long time since we've had primary tissue, and I really want to give her a chance to have some of these newer antibody drug conjugates, I would probably do my best to get new tissue and retest her.
Dr. Oladapo Yeku:
Dr. Musa, what do you do in your practice?
Dr. Fernanda Musa:
I completely agree in this case. I think for consideration of access, I would retest. HER2 is a very interesting test. Expression has to do with the cold ischemic time. So a fresh biopsy that gets processed immediately is more likely to hit the bar on gastric scoring than, let's say, for instance, a sample from within a uterus or within an ovary that sat for a while prior to being processed in the primary sample. So it's interesting to consider testing. The most recent data I saw a poster at ASCO recently also suggesting that it's overall rare, though, the high expression of HER2 ovarian cancer is very rare with about only 3% of tumors expressing three plus. So I will be guarded in my optimism, but I would try again.
Dr. Oladapo Yeku:
And same here, because I think our goal is to try to make sure a patient is not eligible for any sort of targeted therapy, and this could also include clinical trials. Today we're not really discussing mutations and other things and other orally bioavailable targeted drugs, but typically we cast a wide net. Oftentimes I think, as we all agree, we would convince the patient if it was possible to repeat the biopsy and repeat testing on fresh tissue. Now the question people always ask is, for those of us who might practice at academic centers where we do this routinely, how often have you actually seen a difference when you said, "Oh yes, I'm so glad I retested this because now it's a completely different profile. Now we have something for you." Dr. Musa, you're laughing. What have you found in your experience?
Dr. Fernanda Musa:
No, this study that Dr. Liu quoted, it says that 67% of the time it's a small data set that it goes up. I think anecdotally in my practice, it doesn't go up, but sometimes we do find some next generation sequencing targets, like you said, where we can personalize another trial. Yeah.
Dr. Oladapo Yeku:
What about you, Dr. Liu?
Dr. Fernanda Musa:
In my optimism.
Dr. Oladapo Yeku:
We're all optimistic as oncologists.
Dr. Ying Liu:
We are optimistic oncologists. I feel like I'm always searching for that needle in the haystack and then you remember the ones where it is all of a sudden two plus and you can give therapy or even, like Dr. Yeku said, if it's 1+, they may be eligible for some clinical trials. So I do think it's worth doing just because, like Dr. Musa said, it depends a lot on the biopsy specimen. There's a lot of variation in how people do the staining. I know we use the gastric method, but our pathologists tell me that even from the reader perspective, there's a lot of heterogeneity and interpretation. So you sometimes get the needle in the haystack if you test enough.
Dr. Fernanda Musa:
Yes.
Dr. Oladapo Yeku:
Absolutely. And I saw this just one time, and this was in a sarcoma case that had a PI3 kinase mutation. We waited a while, she had multiple therapies, we retested again, it was still the same PI3 kinase, but she went on for a while and then she brought up the case on the third or fourth progression, and at this point we're running out of treatments, can we test it again? And I said, "Well, we've done it twice. There's nothing to see." All the usual caveats. And we tested it and there's an NTRK fusion. So every now and then, again, we all build our practices out of anecdotes, but we know that cancer evolves, there's antigen heterogeneity, it's molecular heterogeneity, and we know the disease changes in response to our treatment. So I think we're not rushing to bankrupt the system, but oftentimes the clinical question does lead to a case where you say a retest might be reasonable in this case, or I already have all the data I need and we're just going to pivot in a different direction.
So in this case, we do decide to retest it, and now the patient's HER2 expression is 2+, our folate receptor is 21%, and for reasons, I think, that's clear for everyone mismatch repairs are always intact. That's one thing that very rarely changes. So now we have a different profile that might guide therapy. So we treat the patient with three cycles of trastuzumab deruxtecan, they have a response. Some of us do our scans at different points in time, but three is a common time. And this response deepens by cycle six, which is a phenomenon we see with a lot of ADCs. But now, way in, 15 cycles, the patient's having a good benefit. They're presumably tolerating therapy well. It's that time of year, maybe it's October, November, and they report a persistent cough. And this cough, we watch it for a little bit, we try guaifenesin or your favorite placebo supportive care, and now they have a little bit of shortness of breath, just the one they mentioned as you're leaving the office after spending an hour in the room.
How would you guys approach this just in terms of your awareness of the toxicities from trastuzumab deruxtecan? Dr. Musa.
Dr. Fernanda Musa:
Well, I take it very seriously. I've had some very traumatic experiences with this drug. This is not your average pneumonitis. I like the mnemonic of the five S's of pneumonitis: screen, scans, suspend treatment, steroids, and synergy—meaning that I'm always watching and doing frequent scans. I suspend treatment immediately on suspicion. At this point where the patient already has shortness of breath, I'd be very nervous and would probably start steroids. And then synergy is for collaboration among the multidisciplinary team, and I would be calling my pulmonologist to try to get her in before the average 3-month wait.
Dr. Oladapo Yeku:
I like mnemonics, especially the ones that have the same letter because then I can't swap them.
Dr. Fernanda Musa:
I know, right?
Dr. Ying Liu:
That's a very good one. Very good. I know this is sort of everyone's worst nightmare, right? She's doing so well on T-DXd, and we see this, right? They have quick responses, they have prolonged responses. I think compared to some of the other antibody drug conjugates, I found T-DXd to be very tolerated, well tolerated. This is sort of the side effect and the AE that I worry about the most, and agree, I do take it very seriously, agree with Dr. Musa, I would stop. It sounds like she has at least grade 2, some kind of interstitial lung disease, could be pneumonitis, could even have progressed to pulmonary fibrosis. And unfortunately I've found that you're really not able to rechallenge these patients. It's really not that safe. I think from the breast cancer literature and from some of the gynecologic studies, we see this in maybe at least 10%, maybe more of cases, and there have been fatalities on studies, so this is one AE I take very seriously, especially when they're developing shortness of breath.
If it's just something on imaging and they're asymptomatic, I will maybe hold the drug. I'll have them see a pulmonologist. I'll monitor very carefully. In that setting, you maybe could think about rechallenging depending on how the imaging evolves and if any symptoms come up. But once they have symptoms, I think you have to stop and probably aren't going to be able to rechallenge.
Dr. Oladapo Yeku:
Both of you bring up a couple of interesting points because I know very early on when ADCs were fairly new, most of our patients are always fatigued and they always have dyspnea and exhaustion, dyspnea at rest, and I left this case intentionally vague because we come into the room with our calibration to each patient's chronicity of symptoms and we gauge it in that sense. An athlete who comes in with shortness of breath, that sounds very serious. With somebody who's always brought that up even on chemo, we may recalibrate, so I left that intentionally vague. But the question of involving a pulmonologist, when do you guys do it?
Because we all work at tertiary centers where you always have a buddy, you can call or get them in clinic right away, but some of our other colleagues who might practice in other settings where the pulmonologist is at a different hospital, a different practice, or maybe they're at least a couple weeks or a couple months away to get an appointment, do you guys do it for grade 2, just for grade 1 or do you just get them admitted if you really think they need to see somebody right away? How do you guys navigate that or advise other colleagues who may not have ready access to a pulmonologist? Dr. Musa.
Dr. Fernanda Musa:
Yeah, I think this is very hard. I think that we've had these drugs in clinical trials and treated a fair amount of patients and learned, sometimes the hard way, about pneumonitis and how rechallenging sometimes is impossible. I have also seen, in my experience, it resolve with long-term hold and steroids. And I've also seen a lot of times things that looked like pneumonitis that were not pneumonitis, that were progression, that were infectious inflammatory, that were just ground glass opacities that people came in with that were obscured by tumor, and when the tumor started melting away with the therapy, we started seeing it. So it is very challenging. We practice in a geographical area that has a relative shortness of sub-specialists. It's not easy to get a pulmonology consult. It takes sometimes a while to get in. I think in the beginning when we started using these drugs, not all of our pulmonologists even knew that ILD was this prevalent and this dangerous. ICU doctors as well.
So I think it's been a learning of the multidisciplinary team, communication and understanding that there are times that you do need to pick up the phone and ask for a sooner appointment because the index of suspicion is high. But I sent people for my own PFT sometimes and for my own high-definition CTs before they get a chance to see a pulmonologist. But I wouldn't necessarily admit them unless I suspected they were kind of crossing the threshold into the grade 3, personally. I would manage them outpatient with steroids.
Dr. Ying Liu:
I completely agree. I've done a lot more just walking O2 sats in clinic, and then if there's some imaging findings, I'll often send for PFTs or high-resolutoin CT imaging. If they have symptoms, I'm more likely to refer to a pulmonologist, but very low threshold to start the steroids myself. And then a lot of this can be managed as an outpatient. Out in the community, I know it's very hard sometimes to find these specialists, so I think we've all gotten very good at interpreting our own PFTs.
Dr. Oladapo Yeku:
So I just have one more question because we've all seen this. It's a patient in whom is having a great response, like the case we just discussed, who now has a grade one. They just did on your restaging scans, you see these ground glass things and then maybe we hold or maybe we hold and give steroids, we all have slightly different practices, all are okay, and then it goes away for whatever reason. Then the question then comes to say in whom do you rechallenge? Do it for all your grade 1s, some grade 1s, or discuss with the patient? I'm just really curious as to what you guys have done and what you guys have seen in the terms of return of the symptoms. Maybe worse, maybe same. Dr. Liu, we'll start with you.
Dr. Ying Liu:
This is tough. I think if they didn't have symptoms, if it's truly just grade 1, some changes on the imaging that go away, then I think I would discuss restarting. But I would have a frank conversation with the patient. We'd use a lot of shared decision-making and I'd tell them we have to balance the benefit you're getting, and sometimes patients get a lot of benefit. It's really controlling their disease well, very few other side effects and maybe they don't have very many other options that would push me to want to rechallenge. But if I had maybe a better option, I wanted to give her a break from therapies that could worsen or cause pneumonitis, then I may switch. So I think it's a very tough situation. I'm interested to see what Dr. Musa would think.
Dr. Fernanda Musa:
No, I agree with you completely, and I think it's a question of, do you have a better option? Because I have a patient that I did rechallenge provided her scan did completely resolve. And still there's a doubt in my mind whether that was pneumonitis in the first place. I feel better saying that. If I knew I had a confirmed pneumonitis, I would have a hard time rechallenging. However, when there's some doubt and it resolved and there is no better option, you tried another line in the interim, they're just progressing and you know that they respond to that, with shared decision making and a lot of care and maybe a little dose reduction. I have done it before and they responded again. And it's tough because I think sometimes you're in a situation with the patient where that is their only lifeline. And they will push you sometimes into these waters that are uncomfortable. But I just want to stress, there is significant risk and the progression is quick and it's not reversible.
That area of the lung where gas exchange happens, it's extremely delicate. Once fibrosis sets in, the only solution is transplant. So I just want to make sure that people understand that this is a potentially fatal. But yes, I do listen to the patients and we kind of arrive at something that we are both confident and happy with.
Dr. Oladapo Yeku:
I agree. And that's very similar with my practice. I've done it both ways where you start the drug, it comes back, or you start the drug, it doesn't come back, and I think it's just that extra vigilance and shared decision making.
So I think our key clinical takeaways are that at least under a certain context, repeat biopsy and repeat genetic testing may be considered in our patients with platinum-resistant ovarian cancer. For patients with platinum-resistant ovarian cancer and HER2 positivity of 2+ or 3+, and this is with or without FISH amplification for the 2+ plus patients, trastuzumab deruxtecan should be considered as part of their therapeutic considerations. And patients and physicians should be very vigilant for signs and symptoms suggestive of pneumonitis. Again, because of the fatal cases that we've all experienced personally, and evaluation and treatment should be prompt. It should be a low threshold to involve pulmonologists to assist with diagnosis and management.
And one other toxicity that we didn't spend a lot of time on is cardiac toxicity, and we all get echocardiograms as part of management anyway. And in this same regard, a low threshold for cardiology colleague involvement in reviewing these discussing options and discussing mitigation strategies if needed. 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.
