Differentiated Thyroid Cancer - Episode 9
Considerations for how dosing and dose reductions can be used to optimize use of lenvatinib for iodine-refractory DTC.
Lori Wirth, MD: Another thing that we’ve done, Jim, is occasionally we’ve held the lenvatinib and then reduced the dose as well. We started at the full dose initially when you were on lenvatinib, although there were problems on the full dose. That brings us to a discussion about what the right dose is when starting lenvatinib. Bryan, do you want to touch upon the right starting dose? I’d love to hear your thoughts, particularly after the Study 211 data came out.
Bryan McIver, MD: One comment I want to make ahead of time is that it’s very important that we understand the role for clinical trials in our approach to using medications. It used to be said that thyroid cancer would never have any clinical trials performed because there were too few patients and they lived too long. We know now that’s not true. Dr Wirth and her colleagues have really led the way in developing these clinical trials and demonstrating the benefits of these drugs despite their toxic adverse effects and other issues. In my view, the correct dose to start with any drug is the dose that proved itself to be effective in the clinical trial. Even though the SELECT trial did include a whole bunch of patients who had to dose reduce—in fact, I think the majority of patients ended up dose reducing—the starting dose of 24 mg still seems to make sense, and recent data support that we should be starting whenever possible at that full strength, but we should do 2 things. First of all, we should prepare patients ahead of time for the journey they’re about to face. If a patient knows to monitor their blood pressure and has a prescription for the first-line blood pressure medication, and is empowered to start that as soon as that blood pressure goes up, we can sometimes avoid an emergency department visit or a crisis that leads that patient to drop the medications.
It works similarly with diarrhea, similarly with fatigue. The most important preparation we can have for somebody to avoid excessive fatigue is for that individual to be fit and healthy before starting the drug. This concept of preconditioning or preparing the patient to be ready for being on the drug is something that we should pursue aggressively. The healthier my patient is, the better chance they can take that 24 mg of the lenvatinib and tolerate it for a long time. We also have to be clear eyed about it. If somebody’s blood pressure is getting out of control and it’s not responding to the standard treatments, we have to stop the drug. We have to wait until the blood pressure is under control, and then we have to actually do the dose reduction. The starting dose in anything but an exceptional circumstance should be the full 24 mg, and then we should gradually progressively reduce that to the maximum tolerated dose. There are times we have to give brief pauses to handle the adverse effects, a brief holiday to recover—and that’s legitimate and safe to do--but then we go back on the drug at the highest tolerable dose, because that’s what’s going to be most effective for the longest duration.
Lori Wirth, MD: We do have the Study 211 that was done with lenvatinib at 24 mg compared to 18 mg. This was what’s called a noninferiority study, where the goal was to look at the response and adverse effect profile and see if the 18-mg starting dose is as good as starting at the full 24-mg dose. In that regard, the study was negative, which means that the 24-mg starting dose actually had a better overall response rate than starting at a lower dose. That study tells us that if effectiveness of the drug is most important, then in general, we do want to be using the standard 24-mg starting dose.
The other thing that came out from that study that I think was a bit of a surprise, was that in looking at the adverse events that emerge on treatment, the lower 18-mg starting dose group of patients didn’t have fewer treatment-emergent adverse effects overall compared to those patients who started at the 24-mg dose. I think Study 211 was really important in helping give those data so that we didn’t just have to rely on what our thoughts were about what a best starting dose is for patients. Jim, I want to ask you a question, and then I want to ask Gary a question. Jim, you had some difficulty with the highest dose and have experienced dose reductions. Has that been par for the course for you? Has it been difficult for you? Have you worried about the dose, or are you just doing what we tell you?
Jim Lesniak: Oh, I do what you tell me. I’m afraid of you. With the 24-mg dose, with the diarrhea and everything, it felt like I was losing my quality of life. I couldn’t go anywhere. I couldn’t walk. I’d take a short walk and I was heading to the bathroom. It came to a point where I was going to put a TV tray in front of my toilet because whatever was going on, it just was not fun. Then the 18-mg dose was tolerable for a while, but I’ve been on 14 mg now for almost 2 years, and it’s really tolerable and it seems to be at least controlling the disease; nothing is spreading.
Lori Wirth, MD: I think the experience you’re describing is very typical. This is a disease where we have to individualize the therapy for each and every patient. That’s not just the treatment choices that we make in terms of drugs, surgery, and radioactive iodine, but also the dose of drugs like lenvatinib. Some people will tolerate 24 mg for 2 weeks and that’s it. Other people will tolerate it for the duration, and then there’s everything in between. I think our job is to make sure that we have a very patient-focused approach, and we’re not just doing the same thing with everybody who walks through the doors, but treating each patient individually.
Transcript edited for clarity.