Updated findings of the SELECT trial presented at the 2016 American Society of Clinical Oncology (ASCO) meeting showed that patients with progressive radioactive iodine (RAI)-refractory differentiated thyroid cancer treated with Lenvima (lenvatinib) had a significant duration of overall response (DOR).
The new efficacy data show that at cut-off, the median progression-free survival (PFS) was 19.4 months for Lenvima and 3.7 months for placebo.
In the 157 patients who received Lenvima, the median DOR was 30 months. This was similar across subgroups, except in patients with greater disease burden and those with liver metastases.
Earlier findings of the phase 3 trial showed that treatment with the multikinase inhibitor reduced the risk of disease progression by 79 percent. These results led to the FDA approval of Lenvima for this indication in February 2015, creating another option for patients alongside the tyrosine kinase inhibitor Nexavar (sorafenib) for the first- or second-line setting.
Nevertheless, the two therapies have proven to be fairly comparable — and encouraging — in their results.
“Patients really have two options and, because of this, they are probably living longer based on the overall survival data in the 65-and-older group, and they are getting a benefit longer than they ever have before,” says Marcia S. Brose. “The thyroid cancer patients who are getting diagnosed now are doing much better than the patients who are RAI-refractory even 10 years ago. Every option that we develop is basically another plus for patients.”
In an interview with CURE
, Brose, an associate professor of Otorhinolaryngology, Head and Neck Surgery, at the Hospital of the University of Pennsylvania, discusses the updated SELECT findings, how practitioners are treating patients with Lenvima, how its use compares with Nexavar, and the challenges that still exist with both therapies for patients with thyroid cancer.
1. How do you find that practitioners are using Lenvima in comparison with Nexavar?
It is interesting how much both are being used. I find that people are giving the agent that they feel most comfortable with first. There are some people who have a lot of experience with Nexavar and are going ahead and using it as their first-line choice, also because it was FDA approved first. There are other people who like the data on Lenvima and are using that as their first line.
At the end of the day, most patients are getting both. The only difference is, really, which one that practitioners give first. Many of these patients, when they start to fail one therapy, are more than healthy and are able to go on to a second-line agent.
The bottom line for Lenvima—since it has become approved—is that it is being used, probably, for all patients. Everyone is getting both Lenvima and Nexavar.
2. What is the optimal sequencing strategy with Lenvima and Nexavar?
The correct answer for that is that we don’t have an answer, because we don’t have a sequencing study. There were enough differences in the population of the SELECT trial, where the patients were clearly more aggressive. It is impossible to compare the data because it is not apples to apples.
The answer I always give to people is, “It doesn’t matter because everyone is going to get both.” There are reasons why people pick one or the other first—issues that would bias people to choose one over the other is comfort and comorbidity. For instance, Lenvima has a big issue with hypertension, and people with a lot of cardiac problems who are already on three medications are probably not going to get started on that.
For Nexavar, some people may be in manual labor and do a lot of stuff with their hands and feet, and they may choose that they do not want to start with Nexavar. Some patients may need a rapid response, and they may feel that the response with Lenvima might be a little quicker, so they might start with that. At the end of the day, all patients are getting both. We don’t have an answer to optimal sequencing.
The problem is, patients who are getting Nexavar after Lenvima may not do as well because the patients who were on the SELECT study initially were already very aggressive. Therefore, some people anecdotally might say, “I don’t give Nexavar after Lenvima because the patients don’t do well.”
We really have no reliable data, and even our anecdotes aren’t reliable because of the way the trials rolled out. The optimal sequencing remains to be determined.
3. Will a sequencing study be conducted?
I tried, and there is no interest whatsoever by either company to do it. The number of patients you would have to enroll is somewhere between 300 and 700 and, in a rare cancer, that’s just not going to happen.
At the end of the day, both companies know that all patients will get exposed to both drugs. It would be nice to do it, and we might figure out a way to do it some time as a registration study, but right now it is not going to happen. We are not going to have that information anytime soon.
4. What are the treatment challenges with using Lenvima for these patients?
The biggest treatment challenges with Lenvima involve the kidney effects and hypertension. It is very important that doctors giving Lenvima are very aware that hypertension is a problem, and that patients should be rapidly monitored. They should make sure they are reading their blood pressure correctly before they go home, and they should have patients visit at least one week in to make sure that their blood pressure is under control and that they are adequately medicated. That is the most hair-raising of the few treatment challenges with Lenvima.
Weight loss is also a very big one. It is important that we try to recommend that people do muscle-strengthening exercises, because that tends to decrease the amount of weight loss and muscle loss that happens when they’re on the kinase inhibitors. We do that actually with both drugs.
With Nexavar, treatment challenges primarily remain to be the hand-foot skin reaction.
5. What factors do you consider in choosing one therapy versus another in first-line?
It really goes along with the patient. If somebody is very symptomatic and needs to shrink a lesion very quickly, I might choose Lenvima first. If they need more stability, I might take Nexavar first because there are data that Lenvima works well in the second-line setting. We have data that Lenvima works after Nexavar; we just don’t know how that compares to Nexavar after Lenvima.
If patients don’t need a rapid response, I might give them Nexavar first, help them manage the hand-foot skin reaction upfront, and then give them Lenvima in second-line. They are probably just as many patients for whom I would recommend Lenvima first in situations, as I would with Nexavar first. Then, you have to choose it accordingly to the patient in front of you. You have to personalize it based on comorbidities, medical issues, or even desires about what kind of side effects are more manageable for that patient.
6. Updated findings from the SELECT trial were presented at the 2016 ASCO Annual Meeting. Can you provide some insight?
This was a follow-up time point from the SELECT trial. The cut-off PFS was 19.4 months, so it is even a little bit better for Lenvima. In telling us what we often thought throughout is obviously that patients who have a tumor shrinkage of 30 percent or greater often maintain the response for longer; it’s a good prognostic line.
The median DOR to Lenvima was similar among subgroups. It is what I would expect. People with a greater disease burden didn’t last as long but generally patients who had at least a 30 percent response had a very good duration of that response.
One of the other things about the SELECT trial is that it turns out that the overall survival (OS) of patients who were over 65 years was clearly improved. When you start talking about who you’re using it in, that would argue that if you have an OS benefit for the patients over 65, that is important. It was a big finding, because we have never shown an OS benefit in any of these trials, but also because of that data it makes people more willing to use this drug in an over-65 population.
7. Lenvima was also explored in a phase 2 study of patients with differentiated, medullary and anaplastic thyroid cancer. What findings were reported here?
This was a phase 2 Japanese study (NCT01728623
), and it just shows that it looks like there is some activity in anaplastic and medullary thyroid cancer. The PFS was 9.2 months, and that’s pretty good. It is not robust—it’s not as good as in the RAI-refractory group—but it is not bad. In the anaplastic group, the OS is around one year; and the PFS was around 7.4 months. There is a study going on, that will move forward for the anaplastic group.
8. What do these findings suggest about Lenvima going forward?
It is going to play a big role, and there might even be a role in medullary thyroid cancer, but the bottom line is it’s a very active agent. It has a role in thyroid cancer in probably all of the settings. It is interesting to see whether or not there might be other settings it might be involved in, but anaplastic is up right now.