Dose Reduction in Endometrial Carcinoma Treatment

Krishnansu Tewari, MD: This patient got started on 20 mg of lenvatinib along with pembrolizumab. As you know from the trial, most patients end up getting dose reduced. How do you dose the drug, Brad?

Bradley Monk, MD, FACOG, FACS: I follow the recipe. Just because you reduce the dose, doesn’t mean you started at the wrong dose. Patients get dose reduced on our PARP inhibitors in ovarian cancer, paclitaxel, all this. If the patient is protocol-like—healthy and has good end-organ function—then I’d treat her like the protocol. There are exceptions, and Dave’s going to tell us about what those exceptions are, where patients wouldn’t have been eligible because they’re too fragile. That would be a lower dose. It goes 20, 14, 10, 8 mg. Dave, when do you not use 20 mg as a starting dose?

David O’Malley, MD: It’s exactly what you’re saying with regard to performance status. I have a patient who’s quite frail. We call her an ECOG 2; she’s really a 3. You look at that and the creatinine clearance, which we’ve reduced if we look at the investigator brochure. You start at 10 mL/min, and that’s at 40 mL/min now. I always check to make sure what my calculated creatinine clearance is. I know it’s 10 mL/min, but the creatinine clearance said 40 mL/min. If I have a question in a patient who’s older, I’ll get a 24-hour measured urine. Brad and I go back and forth on this all the time, Krish. I’m pragmatic to a fault. When I have to reduce—and I know that two-thirds of patients are going to need to be reduced, maybe even 80% but probably two-thirds to three-quarters—I start at 18 mL/min. I know it’s not the formula and it’s not the FDA indication, but then they got the 10, the two 4 mL/min. When I have to go down to 14 mL/min, I don’t have to wait for a new script. I don’t have to call anything in. I just go take the 10 mL/min and the 4 mL/min. From that pragmatic standpoint, that’s what we started. It’s not an extra prescription and it allows you to dose reduce without missing a day if that’s appropriate.

Bradley Monk, MD, FACOG, FACS: It’s all about efficiency. In the historical past, they’d have to pay another co-pay, but now there’s a drug replacement program. If the system isn’t very fast, then there can be a big interruption. I want to emphasize that point that you made: 18 mL/min is pretty close to 20 mL/min. But it’s not financial anymore; it’s about the efficiency of your claim.

Krishnansu Tewari, MD: I want to emphasize Brad’s point. If they’re very protocol-like, I encourage starting at 20 mL/min. There’s some thought that the loading dose in the beginning is important, even if you ultimately have to dose reduce.

David O’Malley, MD: A lot of these patients are coming in symptomatic. When we look at the KEYNOTE-775 trial and Vicky Makker, who presented lenvatinib-pembrolizumab vs chemotherapy in patients previously treated in the New England Journal of Medicine, in January 2022, those response rates were doubled in the lenvatinib-pembrolizumab arm, 30 vs 15. You have survival advantage and PFS [progression-free survival] advantage. Even though we had to dose reduce two-thirds to three-quarters of patients, the quality of life was the same. Once you figure out that dosing— it usually takes a couple of months—their tolerance seems to be quite good, particularly when you can get disease reduction and then maintenance.

Bradley Monk, MD, FACOG, FACS: Krish, have you seen a lot of hypertension with the lenvatinib anti-VEGF activity?

Krishnansu Tewari, MD: No, not a lot. I’ve seen a little but mainly fatigue. That’s the biggest issue my patients have.

Bradley Monk, MD, FACOG, FACS: As the audience knows, Krish developed bevacizumab in cervix and ovarian cancer, so you have a lot of experience with bevacizumab and other anti-VEGF therapies. They probably check their blood pressure at home. That’s what we learn together, and you have nursing staff and support, which are key. It’s a team approach, no question.

David O’Malley, MD: The team approach is huge. Even though you don’t see as much as we originally thought about it, I make sure those patients have access to a prescription for antihypertensives. They don’t have to get it, but they have to have access. In addition, what we started instituting with the use of video visits is that APPs [advanced practice providers] have video visits weekly to make sure we’re keeping on top of this. I’d strongly encourage that. Now that we can do weekly video visits, let’s get them on the phone, on the video weekly, and talk about the symptoms they’re having to keep on top of it.

Bradley Monk, MD, FACOG, FACS: In the state of Arizona, it’s the law that they have to reimburse for that, so we’re able to keep our doors open. The other thing we’ve learned is they have to stop the lenvatinib if the blood pressure is too high, so it’s not the medication or the antihypertensive. We tell outpatients to stop if they get somewhere between 160 and 170; 160 begins to make me nervous.

Krishnansu Tewari, MD: Do you sustain that with lenvatinib?

Bradley Monk, MD, FACOG, FACS: Absolutely.

David O’Malley, MD: They’ll go fairly quickly, and then suddenly they’re in trouble. You’re right. With the short half-life, it will get better all the time. But I like them to have that prescription in their hand.

Bradley Monk, MD, FACOG, FACS: That’s a great idea. Brilliant as usual.

Transcript edited for clarity.