Evolving Treatment Paradigms in Endometrial Cancer - Episode 7
Experts give insight on their clinical use of pembrolizumab-lenvatinib. They highlight dose adjustments and the importance of the increased knowledge of adverse events.
Bradley Monk, MD, FACOG, FACS: Dave, we’ve been doing this for over a year. You have a lot of experience because we’ve been using it in routine practice following the accelerated approval, which we’ll flip to. Tell us what your experience has been and what this clinical trial tells you. Go ahead.
David O’Malley, MD: We opened the clinical trial to many more institutions than it was in the original phase 2 study. When we look at this, we’re going to have people with limited experience with lenvatinib-pembrolizumab when enrolling the trial. I love you referring to the PARP inhibitor trials. Let’s look at every phase 3 trial. Look at the dose reduction when we started PARP inhibitors. Where was it, mid-60%? Vicky, you just told us about the 67% dose reduction on lenvatinib-pembrolizumab. What’s different? The discontinuation rate was higher at 31%. When you’re looking at duration of response over 9 months, you’re going to have more discontinuations when you start treating people up to a year, so this is important.
This is driving me nuts because I see in the background that Vicky has all her research out there. I’m thinking, “Vicky, how do you make resistant cell lines?” I know many of us have done it. We start at suboptimal doses to kill the most sensitive cells, and we then go up higher to the next site. In the lab, we give suboptimal doses to make the resistant satellites. I heard on an SGO [Society of Gynecologic Oncology] chat that some people are starting as low as 4 mg. We’re getting patients on suboptimal doses, potentially selecting resistant clones. At the very least, Vicky, you’re 100% right. Every trial, 20 mg. Nicoletta, I 100% agree. In my practice, I start at 18 mg strictly for the ability to dose reduce easier, knowing that two-thirds of patients are going to require dose reduction.
Bradley Monk, MD, FACOG, FACS: What’s so hard about dose reducing? What are you talking about?
David O’Malley, MD: The new prescription of 18 mg is one 10-mg tablet and two 4-mg tablets.
Bradley Monk, MD, FACOG, FACS: You push a button. It’s not that tough, so the patient gets it.
David O’Malley, MD: Maybe in your world, Dr Monk. I don’t have the resources of the US Oncology Network. It takes a bit more than that to get a new prescription to send it to the patient.
Bradley Monk, MD, FACOG, FACS: It shouldn’t.
David O’Malley, MD: You’re right.
Bradley Monk, MD, FACOG, FACS: Respectfully, maybe you need to work with your pharmacy. To be fair, if there’s a co-pay associated with it, it’s important that there’s a co-pay for every dose reduction. Many of us, including me, are trying to make sure that doesn’t happen. When we go from 600 mg to 500 mg of rucaparib, it’s important to call it out. There’s a new prescription too, but you don’t start rucaparib ARIEL2 at 500 mg, just to use the analogy. We need to make dose reductions easier. Yes, it is a challenge, so let’s all work on that as a group. Who else has comments? I can see your faces. All of you want to make a comment. Go ahead. If you don’t, I have a whole list of questions.
Domenica Lorusso, MD, PhD: Brad, I have just a short comment. I agree with Vicky and also with Nicoletta Colombo and David: We need to start a learning curve in the management of adverse effects because this drug will be managed by the gynecologic community, which is not used to managing a TKI [tyrosine kinase inhibitor]. In the same trial in 2 or 3 years after real-life experience, we will probably report differently in terms of reduction of discontinuation, but it’s important to follow the patient because the endometrial cancer patients are a fragile population. They have several comorbidities, and they are older. If we had 66% dose reductions and 33% discontinuation in a clinical trial when you have the protocol that supports you and guides you in the management of toxicities, then I’m curious to see what the real-life experiences will be. In this, you have an advantage because you start using this combination in the real-life population. We need to increase our knowledge in the management of adverse effects, and we need to guide our colleagues who do not have the possibility to do the trial and will use the drug in clinical practice.
Bradley Monk, MD, FACOG, FACS: To your point, Vicky, it takes time. In the MSI [microsatellite instability]–high group, do they need both drugs, or is 1 drug enough? That’s everybody’s question.
Vicky Makker, MD: We hope to report on this in the near future.
Bradley Monk, MD, FACOG, FACS: Come on, give us a little appetizer.
Vicky Makker, MD: At the moment, we have accelerated approval for patients who are microsatellite stable, but we’re going to learn a lot more as we report out more data.
Bradley Monk, MD, FACOG, FACS: Thank you. That’s fair. To Ketta’s point, it takes time to learn and report. You know me: I’m impatient, so that’s OK.
David O’Malley, MD: Let’s call it out. As we move on, we’ll talk about it later in this conversation about moving checkpoint inhibitors to the up-front setting, so we really need to know more for those patients who were previously checkpoint inhibitor exposed. That’s the absolute trial that needs to be done, and we need to answer that question.
Bradley Monk, MD, FACOG, FACS: Thanks, Dave. To pivot, if you progress on checkpoint inhibitor, let’s say you’re MSI high and have progressed, do you think you can add lenvatinib and reverse that resistance? Is that what you’re saying?
David O’Malley, MD: That’s the question I have. I admit that I’ve done that off-label a couple of times with some success. I can’t believe I just said that out loud. You’re going to beat me up for that, but I have done that with some success.
Transcript Edited for Clarity