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Mismatch Repair–Proficient Recurrent Endometrial Cancer

This is Part 3 of Updates in Gynecologic Oncology, a four-part video roundtable series. Scroll down to watch the other videos from this Roundtable.

Ursula Matulonis, MD; Joyce F. Liu, MD, MPH; and Bobbie J. Rimel, MD, discuss the appropriate management of an older patient with mismatch repair–proficient recurrent endometrioid endometrial cancer, highlighting the importance of histology when determining the best treatment option for patients such as these. They review data from the phase III KEYNOTE-775 study, presented recently at the SGO 2021 Annual Meeting on Women’s Cancer, which evaluated pembrolizumab and lenvatinib in advanced endometrial cancer, and discuss the clinical implications of the findings.


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Transcript

DR. URSULA MATULONIS: Hi there. Welcome back to the ASCO Post Roundtable Series on Updates in Gynecologic Oncology. I'm Dr. Ursula Matulonis, and I am the Chief of Gynecologic Oncology at the Dana-Farber Cancer Institute in Boston. And I'm joined here today by my two wonderful, outstanding, esteemed colleagues, Dr. Joyce Liu and Dr. BJ Rimel. Joyce, would you like to introduce yourself? DR. JOYCE LIU: Yes, I'm Joyce Liu. I'm the Associate Chief in Division of GYN Oncology here at Dana-Farber Cancer Institute in Boston, Massachusetts. DR. BJ RIMEL: Hi. I'm BJ Rimel. I'm a gynecologic oncologist here at Cedars-Sinai Medical Center in Los Angeles, California. I'm also the Associate Director of Clinical Trials in GYN Oncology. DR. MATULONIS: So welcome back, and now we're really, for this case and the next case we're gonna talk about endometrial cancer. The first case is around a patient with mismatched repair proficient recurrent endometrial cancer. And BJ, I wanna start with you and really tell us about how you approach a, sort of deciding treatment options for a patient with, who presents with either stage four disease, or you've given her carboplatin/paclitaxel, and now she recurs with endometrial cancer. So what comes into your decision making around treatment decisions? DR. RIMEL: Sure. So the first thing that I think about is the histology that I'm dealing with. Is this an endometrioid versus a serous histology versus clear cell or MMMT. And then I try to the best of my ability, make sure that we've done mismatch repair, IHC at the bare minimum on all of our patients, regardless of their presenting histology. Then for patients with serous carcinomas, we like to make sure that we've gotten IHC for HER2 testing. And that really sort of opens up the options for patients. Many of our patients that present with advanced or recurrent stage endometrial cancer tend to be older. And so also understanding what their current sort of health status and health comorbidities are is also really important in sort of counseling patients about what they can expect from the treatments that we choose. For patients that have already had a carboplatin and paclitaxel, either less than 6 months prior or even less than 12 months prior, and they have a situation like this case that we've presented here, with large volume disease and they're MMR proficient, my go-to second line regimen currently is pembrolizumab and lenvatinib. DR. MATULONIS: Okay. Great. So let's move to the case. Thank you, and we'll use that as a basis of our discussion. This is a 72-year-old woman who originally is diagnosed with stage IIB high-grade endometrioid endometrial cancer, and she at that point received vaginal brachy testing like Dr. Rimel recommended, MMR proficient. And we do this obviously for Lynch syndrome testing but also now for treatment decisions. She presents 2 years later with pelvic pain and is found to have peritoneal nodules and also some enlarged pelvic lymph nodes, up to 2.5 centimeters. A biopsy of a peritoneal nodule is done, showing recurrent endometrioid endometrial cancer. Consistent with her primary cancer, estrogen receptor–negative. So she undergoes carboplatin paclitaxel for 6 cycles and achieves a partial response. But, unfortunately, a CT scan done four months later shows recurrent cancer with new liver metastases. Joyce, I'm gonna turn to you about treatment decision-making for this particular patient. DR. LIU: Yeah, so this is definitely challenging. This is an older woman. And hopefully quite healthy, but you know as women get older, it is harder to treat with some certain regimens because of the tolerability. She's recurred within 4 months of carboplatin and paclitaxel-based regimen, and so I would agree with BJ that, if medically she's able to tolerate it, my go-to in this situation is pembrolizumab and lenvatinib. So just this month at the SGO 2021 meeting, Vicky Makker presented the final results from the KEYNOTE-775 study which compared pembrolizumab and lenvatinib to two options for standard-of-care therapy, chemotherapy for women with recurrent endometrial cancer. One was Adriamycin (doxorubicin), and the other was paclitaxel, and found that there was both PFS and OS benefit. And so unless I had a contraindication, I would be inclined to offer this woman pembrolizumab and lenvatinib. DR. MATULONIS: Yep. Sounds good. And BJ, I know it, we, there's a lot of discussion at SGO about starting dose of lenvatinib. MD Anderson had a retrospective series about lower dosing for certain patients compared to 20 mgs. Obviously there's been no prospective randomized trials of any dosing besides 20 mgs of lenvatinib, and we know that 30% of patients had to stop lenvatinib because of toxicity. So tell us about how you decide dosing of lenvatinib. DR. RIMEL: So for patients that don't have preexisting hypertension or other significant comorbidities and in my practice who are less than 80 years old, I'm willing to give that 20 mg of lenvatinib a good try. That said, I see dose reductions in my practice probably about 75 to 80% of the time. I expect that I'm gonna have that problem. I follow my patients really closely in the first 6 weeks after starting this regimen because the symptoms of abdominal pain, increased hypertension, especially into the severe, some grade 3 and 4 hypertension can happen pretty quickly. So we often provide them with blood pressure monitoring. And that's kind of, you know, where we start out in our practice. For patients that are older or have preexisting hypertension, I don't start at 20. There's no guidance on this. It's just a personal thing. I generally start at 14. The tablets come in 10 and 4 mg options, so you're really stuck with a couple of different ways to do it. And I like 14. Usually (laughs) because you have 10 mg tablets at home, and you have 4 mg tablets at home. And if you need to make another dose reduction, you don't have to represcribe new tablets. DR. MATULONIS: That makes sense. Joyce, comments about, because I know this is an important decision for patients with mismatch repair proficient recurrent endometrial cancer. And really, it's obviously an active regimen. Dr. Makker showed that very nicely with, as you said, PFS/OS benefit, response rates were higher, duration of response was better than physician's choice chemotherapy, so it's an important regimen. Thoughts about dosing, too? DR. LIU: Yeah, so I agree with BJ. I mean, I think the thing to remember is that we have no prospective data showing that starting at a dose lower than 20 mg is effective. And you know, I think that it's very clear given sort of the 30% discontinuation rate in the KEYNOTE-775 study is that we do need to study sort of the dosing and understand are there patients who really need 20 mg? Are there patients for whom 14 mg is appropriate? Um, you know, what is the right dosing for patients, similar to what we have with niraparib with a weight and platelet-based dosing. You know, that we're not harming people or we're not depriving them of benefit by starting them at lower doses. And at the same time, we're not exposing people to higher risk by starting them at higher doses. But I practice similarly to BJ. If I have somebody who I don't have reasons that I think that they're gonna run into severe or significant lenvatinib-based toxicities, I start the lenvatinib at 20 mg, and I monitor them very carefully with the expectation that a large number of those women will need to dose reduce. But if I have somebody who's fragile or who's older or who has comorbidities that are going to interact with lenvatinib, and as BJ mentioned, the most common of those is hypertension, then I will consider starting at a lower dose. The other thing I was gonna add to what BJ was saying about mitigation strategies is when I start somebody on lenvatinib, I make sure that they have a blood pressure cuff that they know how to use and make sure that they're checking their blood pressure at least once daily and sometimes twice daily. And I actually give them a prescription for an antihypertensive, I have them fill it beforehand, and I have them get Imodium (loperamide) beforehand and have that all at home. DR. MATULONIS: Yep. Yep. The toxicities are obviously not insignificant on this, but obviously a lot of what we do does have significant toxicities. So I think as Joyce alluded to a bit about two-thirds of patients required a dose reduction. So they all started at 20 because they're on the trial, but about two-thirds of those patients required a dose reduction with the most common toxicities being, as you guys talked about, you know, hypertension. Others are fatigue, hypothyroidism, and then diarrhea. And obviously with the combination of lenvatinib and pembrolizumab, diarrhea will be potentially a toxicity of either or both drugs. So BJ, when a patient comes to you and says, you know, I'm really having, you know, significant diarrhea that's just started... How do you figure out how to manage that with regards to both drugs potentially causing that toxicity? DR. RIMEL: That's a really important point. The first go-to for us is also loperamide, so patients should have that at home already. And we try to really help understand the scope of the diarrhea. Is the diarrhea a grade 1, 2, 3? Is it six times a day? Is it 10 times a day? I also ask a lot of questions about the quality of the diarrhea. Is there blood? Is there mucus? Because that tends to look more like a colitis and more like an immunotherapy- or pembrolizumab-related diarrhea, which is a much more serious and urgent thing that needs to be dealt with. Versus the lenvatinib-related diarrhea which doesn't tend to be colitis so much as a more of just a watery persistent diarrhea. Because the lenvatinib is easier to stop, I think that it's easier to hold that medication until the diarrhea reaches grade 1 or less, which is four times a day or less. And then we can restart at a lower dose. Some patients want to be rechallenged. If it's early on and they feel like they've got it under control, they want to be rechallenged at the same dose, especially if they're already at 14 or 10 even. They don't want to go down another (laughs) dose level. So we do try to rechallenge with just better preventive; you know, simple diets, low residual diet, stuff like that. DR. MATULONIS: Yeah. No, that's good. I think the other toxicity that I just have to keep reminding myself about is hypothyroidism, and just remember (laughs) to add that TSH into the patient's labs. Because it happens, it happens frequently, but obviously not particularly high-grade. Joyce, do you check TSHs with every infusion of pembrolizumab, every 3 weeks? And I'm gonna ask you a second question on that... Is, obviously the FDA is also approved a 6-week dosing of pembrolizumab. Have you made the switch to 6 weeks? Or do you just continue to use 3 weeks? DR. LIU: So for lenvatinib and pembrolizumab, I continue to use 3 weeks. Mainly because actually patients have such a difficult time with lenvatinib, it allows me to keep a closer eye on them. DR. MATULONIS: Mm-hmm (affirmative). DR. LIU: And so sort of they have this appointment and they, I mean, sometimes I see them more frequently than every 3 weeks, but I know that I'm seeing them at least every 3 weeks. And so this has been something that patients also feel more comfortable with. And so I've actually stuck with every 3 week dosing for pembrolizumab when I do it together with lenvatinib. In terms of the hypothyroidism, you know, I do check a TSH. I think usually I check it every other cycle, so usually every 6 weeks as opposed to every 3 weeks. TSH is not sort of, you know, the most sensitive marker that it changes sort of, you know, on a day-by-day basis. But I make sure I check it at least once every 6 weeks. DR. MATULONIS: Yeah. Sounds good. Okay before we wrap up this case, I'm gonna ask you both, because I know you both have trials that have either been presented recently or published recently. So BJ, I'm gonna start with you. And GY012 that you presented as a late-breaking abstract at SGO 2021. Can you give us a quick synopsis and next steps of that trial? DR. RIMEL: Sure. So GY012 was a three-arm phase II study looking at cediranib alone, olaparib alone, and the combination of cediranib and olaparib together. We found in our study that the control arm of, or the comparator arm of cediranib performed as expected with a PFS about 3.6 months. And that olaparib did very poorly with a PFS closer to 2.5 months. And that the combination arm gave a PFS of 5.4 months but didn't reach our prespecified end point or prespecified hazard ratio. So our study was negative, but we had some really nice signal in the combination arm with several long-term responders, greater than 18 months of therapy. So we're hoping that our translational endpoints that are still to come will give us some idea of how to predict who those responders will be. That study, GY012, is also a platform trial, and the next four arms have been submitted to our beloved government. And hopefully, we will see a reopening of GY012 in the summer. DR. MATULONIS: Sounds great. Congratulations on great work. I'm remember when you started that a few years ago, and it's great to see it come to fruition. So good job. Great job. DR. RIMEL: Thanks. DR. MATULONIS: Joyce, some parting comments about your, I think, very exciting trial as well... Adavosertib for recurrent serous cancers. DR. LIU: Yeah, so adavosertib is a Wee1 inhibitor, so Wee1 regulates the G2/M checkpoint and also, inhibition of Wee1 can increase replication stress. Uterine serous cancers are cancers that have dysregulation of the cell cycle already intrinsically, and also we think are under high replication stress. And so we conducted this phase II single-arm study of adavosertib, and women with recurrent uterine serous cancer saw a response rate of about 29% with durability of that response about 9 months and medium progression-free survival in the study of just over 6 months with half of the women having clinical benefit, meaning either response or stable disease for at least 6 months. So we're really excited that this could be a new sort of approach for uterine serous cancers. There is a now enrolling international study of adavosertib monotherapy and uterine serous cancers. It's called ADAGIO, and so that's enrolling in the US as well as in sites in Europe. DR. MATULONIS: Great work. Thank you, both. So that brings us to the end of case 3. Please see our other roundtable segments for further discussion about the latest data in gynecologic oncology or check out ascopost.com. Thank you so much.
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