David M. O’Malley, MD: As I look at the experience of lenvatinib-pembrolizumab, we’ve treated a fair amount of patients. Once we had the indication, patients didn’t have any other option. I’ve used a lot of lenvatinib-pembrolizumab. I have an amazing team in place. I have a full-time nurse and a full-time nurse practitioner on my team, and they are 100% essential. In addition, we have a specialty pharmacist who sits down with the patient when prescribed to give them information and prepare them. I talk to them, the nurse talks to them, the specialty pharmacist talks to them, and then we have weekly video conferences with the patient to manage symptoms.

It is absolutely essential to educate the team about the problems these patients will have so that they get recognized and we don’t turn a small problem into a big 1. My experience is that the data in the clinical trials showing 70% to 80% dose reduction are absolutely accurate. Most patients will require dose reduction. Sometimes, I’m surprised when a patient who I think is going to require dose reduction actually tolerates the medication better than I predicted. What are some of the other things I worry about? You have to make sure you’re keeping an eye on the creatinine clearance. Patients who come in with preexisting renal disease with a creatinine clearance less than 40 mL/min should be dosed with only 10 mg of lenvatinib.

I’ve talked about how I practically manage the dose reduction, which is the 18-mg prescription. Some people have managed it by starting at a lower dose, but that always makes me a little worried. There’s some hint in the data that the loading dose of the higher dose may be helpful. I’m not sure. My concern is starting at a lower dose. If they tolerate it, fine. Then you give them the higher 14 mg, they have a little bit of symptoms, and they want to return to the 10 mg.

These patients are going to have symptoms. We have to continue to get better at managing their control, which every single day my nurse, nurse practitioner, and I are learning. We continue to improve. There are now some really nice guidelines and patient education that shows when these toxicities occur. Most of the dose reductions with lenvatinib are going to be in the first or second cycle. Then the I/O [immuno-oncology] toxicities will be beyond that. Of those, I always worry about the diarrhea. Is it the immune-associated colitis? The diarrhea will occur in the first cycle or maybe the second cycle, so it’s very unlikely to be I/O associated.

Some of the dermatologic conditions are usually able to be managed. I have become very good friends with my multidisciplinary collaborators. Our dermatologists have also instituted a remote consult where we can take a picture and send it to them. I’ve had a lot of run-ins recently with endocrinology. I have a couple of patients on single-agent I/O or the combination who have had significant development of type 1 diabetes. I’ve had a recent run of other complications for which I’ve had to involve rheumatology—some of them on single-agent I/O, some on a combination, but not all of them on lenvatinib-pembrolizumab.

This is across the spectrum of the I/O toxicities. The multidisciplinary approach is very important. It’s very important to educate your nursing team, nurse practitioner, physician extenders, and most important, your patients.

Kathleen Moore, MD: This is the accelerated, now likely confirmed, approval of lenvatinib and pembrolizumab, the already-established approval of pembrolizumab for mismatch repair–deficient patients and the pending approval of dostarlimab. We used to have nothing in this space that helped patients, and now we’re going to have 3 new regimens for patients with recurrent endometrial cancer. You would select it based on biomarker selection. Either mismatch repair deficient can get monotherapy or mismatch repair intact can get the combination. We’ll have to see the data from the phase 3 study, where there were patients with mismatch repair deficiency enrolled on that, and see if we need to use the combination in that patient population or just stick with monotherapy. That’s 1 of the questions I still have about the data. Sometimes the enemy of good is better. If I can do really well with a monotherapy and have less toxicity, should I stick with that or should I go for broke and use both in a mismatch repair–deficient patient? That’s 1 of the clinical questions that remains outstanding.

The phase 3 study won’t answer that because, if you remember, the control arm is chemotherapy, not single-agent immunotherapy. We can get a sense from the efficacy in the mismatch repair–deficient population compared with monotherapy of what we think the add-on is from the lenvatinib and that group. Unquestionably, in a mismatch repair–intact population, the combination is the new standard of care.

While that response rate and durability of response rate importantly are very exciting, this combination is challenging to use because of the toxicity. If you recall, the starting dose of lenvatinib is 20 mg, and if you look at Dr Vicky Makker’s original paper, over 80% of patients required a dose reduction because of mainly—not entirely—lenvatinib-related toxicity. Fatigue and diarrhea were some of the main ones. You can also get some PPE [palmar-plantar erythrodysesthesia] about 8 weeks in from starting lenvatinib or from increasing the dose. So there are some toxicities that are a challenge, especially if you’re starting it in a patient who is already somewhat ill.

Those of us who have been using this for a while have developed our own strategies for how to start it. This is off-label, so I’m just going to say that. The label is 20 mg. There are certainly providers that start at 20 mg and dose reduce in the event of toxicity. I tend to start at 14 or 18 mg. Honestly, I prescribe 18 mg because it comes as 10 mg and two 4s. I start them at 14 mg for the first month or 2 and make sure we’re not going to have hypertension—another big issue, fatigue, or diarrhea. I just see how they’re doing. If they tolerate that very well and it usually works, and they at least have stable disease or some disease reduction, then they have that other 4 mg. And I just add it on, bump them up to 18 mg, and then keep them on that for a while. That’s really where I’ve stayed.

My patient population is potentially a little older and a little more medically frail than other places, but I haven’t really taken anyone up to 20 mg. I’ve definitely seen efficacy. I was a little dubious when I first heard about this. I wasn’t convinced because of the toxicity. But now that I’ve used it and I’ve gotten some familiarity with the drug and comfort with how I’m going to dose escalate it, I’m using it much more frequently. It has worked in patients who are pretty heavily pretreated, and we’ve used things instead of this combination. It has worked. It’s January. I have a patient right now who I did not think was going to make it to Christmas. She not only made it to Christmas but got to drive to Florida and see family, and she’s continuing on with stable disease right now. I’m pretty amazed. We’re 6 months in.

This is a transformative regimen, but it takes education around the adverse effects and an office that understands the patients on this drug and can respond very promptly to a patient call with problems, so that you can adjust, hold, and maintain patients on this very effective therapy for as long as possible. If they come off it or are constantly being held because of uncertainty, it won’t be very effective. Drugs don’t work if you don’t take them. This is 1 that’s fantastic, but it requires quite a bit of intentional education to use. I think we’re all up for that challenge.

Transcript Edited for Clarity