Birrer Assesses Tolerability Factors in Use of Lenvatinib/Pembrolizumab for Endometrial Cancer

Michael J. Birrer, MD, PhD

Vice Chancellor, University of Arkansas Medical School

Director, Winthrop P. Rockefeller Cancer Institute

Little Rock, AR

EVENT REGION Great Lakes & Great Plains

PARTICIPANT LIST Bei Liu, MD | Lyle Goldman, MD | Kartik Anand, MD | Sunil Babu, MD | Zhaohui Jin, MD | Vijay Rao, MD

LIU: What do you do about lenvatinib? It’s a heavy dose. Do you always start at 20 mg, or do you start with a lower dose?

BIRRER: The toxicity of this regimen is considerable. You’re talking to one of the few people in the United States who is still a purist; I start at 20 mg, but I rapidly de-escalate if there are problems. Every time I present this, [I hear that] the average starting dose [used by others] is 14 mg. I don’t do that, but that’s just me.

GOLDMAN: I usually start at 18 mg because [lenvatinib] comes in 10-mg and 4-mg [capsules] and it gives me flexibility for dosing without having to write a new prescription and waste medication.

BIRRER: How many [of your] patients end up at 14 mg or lower?

GOLDMAN: I’d say three-quarters of them.

ANAND: I start at a lower dose, 14 mg. And even then, a lot of patients at times need dose reduction.

BIRRER: Do you ever dose escalate?

ANAND: I have not done that.

BABU: I start at the full dose, with the reason being that I [am not always able] to dose escalate. With that being an issue, I start at full dose and then may de-escalate as needed.

DISCUSSION QUESTION

• How are VEGFR inhibitors associated with hypertension, and how should oncologists manage hypertension?

BIRRER: There are 2 mechanisms for hypertension: increased systemic vascular resistance or increased cardiac output or a combination of the two.¹ [Many of] the chemotherapeutic and small-molecule inhibitors that we use trigger both increased cardiac output and increased systemic vascular resistance, including some [agents] you might not remember or even think about. But as medical oncologists, you should know even PARP inhibitors, in particular niraparib [Zejula], have a finite instance of increased hypertension, which is from effects on neuron epinephrine uptake. There are a lot of agents that can cause increased blood pressure. It’s important to remember that, and that’s why they evolved an elaborate algorithm to treat that. One example of it was [published in Cardio- Oncology in 2021].²

When you start initiation of anticancer therapy…you clearly need to follow patients closely. From my experience with lenvatinib and pembrolizumab, lenvatinib is not like bevacizumab [Avastin]. Bevacizumab-[related] hypertension happens, but it takes some time. With lenvatinib, it can occur within 24 hours. It’s very important to make sure your patients recognize that and they’re checking their blood pressure. We usually grade it depending upon a 10–mm Hg difference whether it’s grade 1, 2, or 3. Then you can initiate treatment.

What’s [described in the algorithm] is what I call oncologic common sense, meaning that if you have a patient who has some hypertension and they’re already on either calcium channel blocker or β-blocker, angiotensin-converting enzyme inhibitor, or angiotensin receptor blocker [ARB], [etc], then the common sense is to modify those drugs first to see whether you can get the blood pressure under control, rather than adding something new. If it’s de novo hypertension, then there are some recommended agents you can use [From the Data²]. For my patients whom I put on lenvatinib/pembrolizumab, I give them a prescription, and it’s usually a calcium channel blocker to take with them as they go out the door on the first day. So if they call me or call my nurse the following day and say their blood pressure is up or they’ve got headaches, they can just fill the prescription and start it without necessarily having to come back into the hospital and waste all that time.

CASE UPDATE

Antihypertensive monotherapy was initiated with 160 mg oral valsartan daily. The patient returned to office for blood pressure monitoring every other day of week 1, then twice weekly for 28 days. At 30-day follow-up, she reported resolution of morning headaches. Upon focused physical examination, her blood pressure level was 120/84 mm Hg (hypertensive) vs baseline of 118/76 mm Hg, heart rate was 72 beats per minute and regular, and ECG results showed normal sinus rhythm. The physician’s impression was grade 1 VEGFR inhibitor–associated hypertension, improved from grade 2.

The patient was instructed to continue oral ARB daily, check blood pressure level every 2 weeks, continue lenvatinib 20 mg daily plus pembrolizumab 200 mg every 3 weeks, and monitor for continued response to therapy.

DISCUSSION QUESTION

• Following initial systemic therapy for patients with pMMR disease, which factors most influence your systemic therapy selection?

BIRRER: What are you thinking about when you’re deciding for a patient with pMMR disease whether they use this combination?

JIN: [I think first about] progression-free survival. Also, [I think of] overall survival and the adverse event [AE] profile and tolerance. For this regimen, [I consider] cost, especially for the oral pill for lenvatinib. In some situations, patients need financial assistance.

LIU: I think all the above are coming into play. It depends on the specific situation. Maybe one factor will be more important than the other, such as for patients who have coverage issues for oral medication that will influence your choice of oral vs intravenous medication, but efficacy and safety should come into play.

BIRRER: [Concerning] toxicities in findings from the [phase 3] KEYNOTE-775 trial [NCT03517449]…the hypertension, hypothyroidism, and diarrhea are all high with the combination of lenvatinib/pembrolizumab, and you’d expect that.³ I always point out the decreased appetite [in 44.8% of patients] and weight loss [in 34% of patients]. When I was up at the Harvard system, we did the single-agent lenvatinib phase 1/2 [trial], and we went up to very high doses. It was remarkable how much of an appetite suppressant it was. I had a patient with endometrial cancer whom I was treating with single-agent [lenvatinib] who lost almost 30 pounds of her body weight, and she refused to come off the drug because it was controlling her tumor. As soon as you stop it, it all reverses within 2 to 3 months. The other point I would make is to look at neutropenia and anemia; that’s in the chemotherapy arm. Don’t forget that chemotherapy is not without its toxicities.

[Data published in The Oncologist] show you the toxicities we talked about, but when they appear, hypertension is fast [Figure⁴]. Fatigue is fast. Gastrointestinal [toxicity] is a little bit slower. If you’re looking at hypothyroidism, which is a true immunotherapy problem, and weight decrease, which takes time, they all [appear] later.

DISCUSSION QUESTIONS

• What are your thoughts on the KEYNOTE-775 data?
• Have you prescribed pembrolizumab plus lenvatinib in the treatment of endometrial cancer or other malignancies? At what doses do you typically initiate this dual therapy?
• Are you familiar with the dose modifications for this regimen?

BABU: The lenvatinib/immunotherapy combination is showing impressive data. I want to talk about a patient whom I started on lenvatinib/pembrolizumab after chemotherapy. After a year, the disease went into a partial remission then stabilized. But because of the AEs, I pulled lenvatinib; within 3 months, the disease progressed. Then I put her back on it, and again it’s stabilized. Just 3 months ago, she was having a perirectal abscess, so I stopped lenvatinib again, and she was hospitalized with progression. My plan is to put her back in trials and change the regimen. She’s been on the combination for 3 years, but every time I pull lenvatinib, she seems to experience progression. I was planning to change the regimen, but now that we had this discussion, I’m thinking I’ll put her back on lenvatinib and see how it goes.

LIU: Even though patients with MMR-deficient status were included in the trial, I have encountered some insurances that will not pay for lenvatinib. For patients who had deficient MMR status, they mandate you use pembrolizumab as a single agent.

BIRRER: That’s interesting, and I have not heard that before. My guess is they’re adding the 2 drugs together and figuring it’s more expensive for them. There are great data with single-agent pembrolizumab, and for that matter, dostarlimab [Jemperli].

LIU: Initially, I used single-agent pembrolizumab. She stabilized for almost 2 years, and then the disease started progressing. Then I argued with insurance, and they agreed to cover the lenvatinib. I added it to pembrolizumab, and she had another good response, and she’s at 2 years with no detectable disease.

BIRRER: That’s fascinating. As you all know, there’s a recommended dosage. We’ve already talked about how a lot of you start lower. I will emphasize that the average dose that patients received on the randomized phase 3 trial was 14 mg.³

RAO: The dose discontinuation rates in renal cell cancer [RCC] are up to almost 50% or 55%.⁵ What about in findings from this trial?

BIRRER: The dose interruption rate was close to 70%.³ The discontinuation rate was between 30% and 40%. So it’s high; it’s not as high as what you’re quoting from RCC. [It could depend on whether] they are using 20 mg or higher.

RAO: The [RCC] clinical trial was 20 mg.⁵

BIRRER: It’s hard for me to say, but patients with RCC are tough to treat. In thyroid cancer, they use a higher dose [24 mg daily] and they get away with it. But it all depends on the patient population.

REFERENCES:

1. Butel-Simoes LE, Haw TJ, Williams T, et al. Established and emerging cancer therapies and cardiovascular system: focus on hypertension-mechanisms and mitigation. Hypertension. 2024;80(4):685-710. doi:10.1161/HYPERTENSIONAHA.122.17947

2. Mohammed T, Singh M, Tiu JG, Kim AS. Etiology and management of hypertension in patients with cancer. Cardiooncology. 2021;7(1):14. doi:10.1186/s40959-021-00101-2

3. Makker V, Colombo N, Casado Herráez A, et al; Study 309–KEYNOTE-775 Investigators. Lenvatinib plus pembrolizumab for advanced endometrial cancer. N Engl J Med. 2022;386(5):437-448. doi:10.1056/NEJMoa2108330

4. Colombo N, Lorusso D, Monk BJ, et al. Characterization and management of adverse reactions in patients with advanced endometrial cancer receiving lenvatinib plus pembrolizumab. Oncologist. 2024;29(1):25-35. doi:10.1093/oncolo/oyad201

5. Motzer R, Alekseev B, Rha SY, et al; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384(14):1289-1300. doi:10.1056/NEJMoa20357165