Recurrent Endometrial Cancer: Safety of Combination Therapy

Bradley J. Monk, MD, FACS, FACOG: Brian, I want you to weigh in on what I asked Katie. How do you decide in a pretreated patient? The label for pembrolizumab, lenvatinib is you’ve got to have the molecular signature, you have to have had prior systemic therapy, and you can’t be cured with surgery or radiation. Who is it not right for? Or is it basically right for most patients in the second line?

Brian M. Slomovitz, MD: It’s going to be right for most patients in the second line. We always have to talk about the future, until it gets approval in the first line. Because we’re doing the trial, which is accruing nicely. It’s a Merck-sponsored trial that we’re doing. It’s outside of the GOG [Gynecologic Oncology Group] but it’s accruing nicely. It’s looking at pembrolizumab, lenvatinib in the first-line setting.

Bradley J. Monk, MD, FACS, FACOG: Versus chemotherapy, versus carboplatin, paclitaxel.

Brian M. Slomovitz, MD: Versus chemotherapy in the first-line setting. Now remember, the other thing about what you just said is the label for pembrolizumab, lenvatinib as written is for a prior systemic therapy.

Bradley J. Monk, MD, FACS, FACOG: Correct.

Brian M. Slomovitz, MD: They could have gotten 1 dose of cisplatin and 40 mg of…with 1 week of radiotherapy, and they’re indicated to get it. They could have gotten 1 week of Megace and be eligible for pembrolizumab, lenvatinib. It’s a game changer. I know we’re going to talk about the ongoing trials. I think that this one has the potential to have the most impact. Because as I mentioned earlier, it may knock chemotherapy off the pedestal for the first-line treatment of endometrial cancer. It’s exciting.

The toxicities that Dave was talking about, they’re there. In the trenches, we’re learning how to better handle those toxicities. We’re starting at lower doses of the lenvatinib. We’re learning how to deal with some of the diarrhea and hypertension, which happens. It’s an extremely exciting time. Every second you were talking about cervix and ovarian cancer, I’m thinking, let’s get back to endometrial.

Bradley J. Monk, MD, FACS, FACOG: Let’s try not to use the word toxicity, because that word is toxic. These are adverse reactions. All systemic therapies have some adverse reactions associated with them. I just want to review with you, this is a combination. You have the immune-related adverse reactions related to the pembrolizumab, and then those related to lenvatinib. Lenvatinib really is 2-fold. It’s an oral anticancer therapy, so it has some fatigue and some GI [gastrointestinal] disturbances. But it also has the anti-VEGF effect, which includes hypertension, proteinuria, wound healing, and so on. You have to balance the IO [immune-oncology] aspect, the oral aspect, and the anti-VEGF aspect, and we’re good at it.

All of you said you were excited about it. All of you inferred that it’s probably better than chemotherapy. Then you said, Brian, well, we’re comparing it to chemotherapy, in the existing label indication KEYNOTE-775, and comparing it in the front line in LEAP-001. So Dave, 88% of patients have to interrupt or dose reduce their lenvatinib. You start at 20 mg, and you go 20 to 14 to 10 to 8 mg, what’s the right starting dose? Is it 20 mg? Or is it 14 mg?

David M. O’Malley, MD: I don’t start at 20 mg on anybody. But it’s more a practical reason. I start at 18 mg. There’s a package insert, or a tab, of 18 mg. It gives you a 10 mg and two 4 mg. Thus, if you know that 70% are going to be dose reduced, and as you said, almost 90% would have dose interruption, it allows you to get down to 14 mg much easier than waiting for a new script and a new co-pay and all that. I start at 18 mg. If they need dose reduction, they have the 4 mg there. It works perfectly. There are people who are starting at 14 mg. There may be some induction. That’s why I’m a little apprehensive to go all the way down to 14 mg on all my patients, but it’s also very reasonable. I like 18 mg.

Bradley J. Monk, MD, FACS, FACOG: But the study was 20 mg. Where are the data on 18 mg?

David M. O’Malley, MD: There are no data on 18 mg. There are no data on 14 mg….

Bradley J. Monk, MD, FACS, FACOG: There are no data starting at 14 mg, but there are lots of data that if you start at 20 mg you get to 14 mg in the induction effect. I’m not trying to conflict against you, I’m just saying, I try to follow the recipe. Go ahead. Any of the 3 of you, Krish, Brian, or Katie, who want to chime in on this.

Krishnansu S. Tewari, MD: I start at 20 mg, and we’ve had to drop down to 14 mg and down to 10 mg on a few patients. But I’ve got quite a few patients who are tolerating it pretty well. The worst I’ve seen is maybe some grade 1 or 2 hypothyroidism.

Kathleen N. Moore, MD: Yes. I honestly do think there are regional differences in patients. But we have a lot of patients who present late for care and with very advanced disease and a lot of comorbidities. I don’t start at 20 mg and neither do my partners for recurrent disease. They’re so sick, and if they get sick on 20 mg, they’re not going to dose reduce, they’re just going to come off and go to hospice. For us, we start at 14 mg, although you might have just persuaded me, Dave. I like what you just said about starting at 18 mg. Maybe I can start at 14 mg and then escalate up. But I start at 14 mg, and I get 2 months in, and then if they’re doing fine, I escalate them to 18 mg. I’m going to be honest, in our sick population, I can think of 3 patients who were told they needed to go on hospice who are now going to have more time because of this drug.

I was real worried about the toxicity, and I was not a super believer, but it works. I like 14 mg because I haven’t harmed anybody, and I can escalate them. That’s what we do.

Krishnansu S. Tewari, MD: What about the induction? What about the induction piece?

David M. O’Malley, MD: Well, the induction piece is interesting. Does it help to get that higher level? I’m not sure of the answer to that. I don’t know we’ll ever have the answer to that. But one thing, Katie, that you just said, they’re going to get to this next holiday. There’s an 11% complete response [CR] rate. I have some sustained partial and near complete response using this combination. Are we talking that we may be able to cure recurrent endometrial cancer?

Bradley J. Monk, MD, FACS, FACOG: In the label, 94 patients, 38.3% response rate, 69% of them remained progression free for 6 months. Krish, to your point, your induction, you taught me that this anti-VEGF effect impacts ascites. If I have a recurrent endometrial cancer that for sure is not MSI [microsatellite instability]-high because that doesn’t exist, I want her to get some serious anti-VEGF activity to help her with her symptomatic ascites. It’s individualization, there’s no one-size-fits-all, but that’s an example where I want to get some anti-VEGF effect because what’s hurting her is her cancer. If I don’t get control of that ascites, she’s going to get a malignant bowel obstruction.

Kathleen N. Moore, MD: Yes. I agree.

Bradley J. Monk, MD, FACS, FACOG: Yes.

Kathleen N. Moore, MD: I totally agree with you, Brad. The patient I was just talking about presented with 8-liter paracenteses for 3 consecutive weeks. Then she came to me for a clinical trials consult. She’s dying. Now we’ve got her on study, and we’re at like 2 liters a week now, from 8 to 2 liters. It’s not perfect, she’s not a CR, but she’s walking and functional and eating again. It’s that VEGF, it’s amazing.

Bradley J. Monk, MD, FACS, FACOG: It is. To your point, if she throws up her lenvatinib, you haven’t accomplished anything.

Kathleen N. Moore, MD: Right.

Brian M. Slomovitz, MD: I don’t switch to 18 mg, I keep it at 14 mg. Brad, to your point, we don’t know the activity, come on, we just got over niraparib. We almost lost niraparib because we started at 300 mg and there were too many adverse events. If they’re doing great, have them go up to 18 mg. It works.

Bradley J. Monk, MD, FACS, FACOG: Krish says, what about Doxil, or liposomal doxorubicin? Liposomal doxorubicin, for all intents and purposes is inactive as a single agent in ovarian cancer. With response rates of around 10%, or I don’t know what it is.

Brian M. Slomovitz, MD: In endometrial cancer.

Kathleen N. Moore, MD: Endometrial and ovary. Both.

Bradley J. Monk, MD, FACS, FACOG: Both. I was talking ovarian cancer. But it’s like 0% in endometrial cancer.

Kathleen N. Moore, MD: Yes. Zero in endometrial. Look at the AURELIA trial, it’s 10%, 13% with bevacizumab.

Bradley J. Monk, MD, FACS, FACOG: Right. My passion, though, for dose intensification of pembrolizumab, lenvatinib is because I get 40% response rate for it. I get a durable duration. To Dr Moore’s point though, if it’s intolerable, it’s going to be 0%. You’re all right.

Krishnansu S. Tewari, MD: My patients are not that sick when we put them on the combination. But I’m doing this talk from my St. Joseph Hospital office. I just remembered what my nurse navigator always says, when this combination works, it really works. Disease isn’t gone, I can scan them and it’s still there, but it’s not hurting them, it’s stable. They’re doing great on the combo.

Bradley J. Monk, MD, FACS, FACOG: Any closing comments on the activity and the tolerability of pembrolizumab, lenvatinib in non–MSI-high endometrial cancer?

Kathleen N. Moore, MD: The message needs to get out. This is something that we need to push out. The question about, do you go to chemotherapy first or do you use this? I don’t know. I feel like maybe we need to use this first. It’s probably more active, is my gut feeling. But that’s something we need to sort out and get into the community a lot more, and tailored instructions as to how to manage the toxicity. Although, again, medical oncologists know how to use lenvatinib. They’ve been using it for a long time. They understand the hypertension’s fast, they know how to manage the fatigue, and they know how to manage the diarrhea. And they understand pembrolizumab. They’re probably ahead of us on that. It’s just remembering to use it.

Bradley J. Monk, MD, FACS, FACOG: Dave, you were going to talk about the importance of the multidisciplinary team, go ahead.

David M. O’Malley, MD: Yes, absolutely. I have an amazing nurse practitioner who works with me, and they take these phone calls and they have strict SOPs [standard operating procedures] in place, with regard to hypertension, with regard to diarrhea. If you’re working together, it can really help control these symptoms.

Brian M. Slomovitz, MD: I agree with that completely. Pembrolizumab, lenvatinib doesn’t start when you take the medicines, it starts when you decide to take the medicines. From that point, you’ve got to get the blood pressure under control, to Dave’s point, getting your nurse extenders involved, and preparing for the diarrhea. If you’re prepared, I find that it’s a tolerable regimen, and obviously, we talked about the efficacy.

Transcript Edited for Clarity