A medical professional discusses Study 211 data and HRQoL analyses for patients with DTC on lenvatinib.
Marcia S. Brose, MD, PhD: Another important point about lenvatinib [Lenvima] dosing is the concern of side effects, in addition to what age they should be starting lenvatinib. A lot of people have been concerned about starting patients at the starting dose that was shown in the trial to work. Now, in oncology, we usually try to follow as close as possible to the original clinical study that showed efficacy because we can’t expect to get the same result if we don’t give the drug the same way. That said, out of concern for the high blood pressure or people being frail, a lot of the people who were treating these patients felt that they were too nervous to start people at 24 milligrams [mg], so they decided to start them at lower doses, like 10 mg or even 4 mg. And their plan was always to increase the dose up to a higher dose as tolerated. There are 2 things I’ll say about that. We know from data that when people say they’re going to increase the dose, they never get to the same doses as if they were started at the higher dose to begin with. So these people were really getting a subclinical, or at least a sub-studied, dose all the way through as far as treating their cancer. That’s point number 1. The second point is people were making assumptions for how safe they felt the medicine was, if they started at the 24 mg, of course, based on the data. But they’re assuming that if they started at a lesser dose, the patients would do just as well. But they might do it in a way that was either just as safe or would give the patients the same detriment of quality of life. In order to really test this and to remove all the biases of these doctors who are prescribing it, we designed the 211 study. And the 211 study asks 3 important questions. If we randomized patients between 24 mg starting dose, the original FDA [Food and Drug Administration] approved dose, or starting at 18 mg, would they get the same benefit as far as the efficacy? And to do that, we looked at how many people had gotten to a partial response at 6 months. The first question is, is it just as efficacious to treat people with a lesser dose? Because we knew that it was active, but would it be as active as a 24 mg starting dose? The second important question was would it be as safe? We determined safety as the number of people who would have grade 3 toxicity. If more people had a grade 3 toxicity, we could argue that it’s less safe. So we wanted to compare how many people were going to have the toxicity, and would fewer people have grade 3 toxicities at the lower dose? The third question is, putting safety aside, how do the patients feel themselves? In their self-reported questionnaires, would they say that they feel more miserable on a 24 mg starting dose than on an 18 mg starting dose? All 3 of these questions were asked and the first 2 were answered in the study that was published in 2020 for the 211 study. The first 2 answers completely surprised me, not just me, but many of my colleagues also. An answer to the first question, is 18 mg not inferior to 24 mg? The answer was clearly no. Starting people at 18 mg did not achieve the same benefit. In fact, the difference in response rate was 17%. It was a clinically significant difference. By starting people at a lower dose, they clearly weren’t going to get the same benefit as far as how much the patients were going to respond to the therapy. On question number 2, was it just as safe? It turned out that there was no decrease in safety at 24 mg when compared to the 18 mg. There was no statistical significance between those 2 groups. And because of that, I think the first 2 points really do support starting people at the 24 mg a day dose. The third question was, of the patients, how did they feel when they reported it? They had questionnaires that have been well-validated tools, did they say, “I’m much more miserable on 24 [mg] than if I was on 18 [mg]?” It turned out that we totally couldn’t tell the difference. At the end of the day, when you have a doctor, especially as part of a clinical trial, who’s attentive to the side effect profile, adjusts the doses as needed and appropriately, it seemed that there was no difference in experience to the patient, but there was a difference in the efficacy of the doses. Now, taking those 3 points together, we would say that the original 24 mg a day starting dose comes out of this study as clearly being the most appropriate. I will say that there are exceptions to this that I think we have to remember. What this study shows us is in general, most of the patients that we would treat. That means everybody from any age and it also included people with comorbidities. A lot of people say, well, that’s fine for healthy patients, but people with comorbidities would never be on that study. Well, that’s not actually accurate. Many people with comorbidities were in the study because comorbidities were not exclusionary criteria. But what is true is that there are people who had say invasive cancers or cancers that were invading blood vessels that were not included in the study. And I think we do feel that there’s a safety reason to maybe start people at a lower dose of lenvatinib or maybe not start them on lenvatinib at all, but instead start them sorafenib [Nexavar]. For patients who have an invasive disease, I’d say that’s probably the main ones that I worry about. Some people say, well, those are really important patients. I agree. But I still would say that they’re probably only 5% or no more than 10% of the patients that I’m treating.
This transcript has been edited for clarity.
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