Real-World Study Confirms Lenvatinib's Benefit in RAI-Refractory DTC

A US real-world experience showed that the effectiveness of lenvatinib (Lenvima) was consistent across a diverse cohort of patients with radioidine (RAI)-refractory differentiated thyroid cancer (DTC), including in those with BRAF-mutated, wild-type and BRAF untested tumors.

In the study, the effectiveness of lenvatinib was evaluated in a real-world setting. The study involved patients who started treatment with lenvatinib between 2015 and 2020 and experts looked at response rates, progression-free survival and overall survival.

Lenvatinib appeared to be effective regardless of the patient's BRAF mutation status. Overall, this suggests that lenvatinib could be a good first-line treatment option for a wider range of patients with RAI-refractory DTC and shows the role of lenavtinib in the first line for patients with BRAF-mutated disease.

In an interview with Targeted Oncology^TM, Francis P. Worden, MD, professor of medicine at the University of Michigan Rogel Cancer Center, Ann Arbor, Michigan, delved into the rationale behind the study and the implications of this research for patients with RAI-refractory DTC.

Targeted Oncology: Can you discuss the background of this study on lenvatinib for those with RAI-refractory DTC?

This was a real-world experience. As background, we know that the SELECT trial [NCT01321554] showed an improvement in progression-free survival over placebo by about 5 times the difference. Since then, there have not been any other agents that have come forward that have been more effective than lenvatinib. Now is the time for us to start looking at lenvatinib in a real-world setting to see how the drug is being used, are the doses appropriate, are [patients] staying on therapy or when are they coming off therapy? Interestingly enough, we noticed overwhelmingly that in our real-world experience that we published at the end of December last year, that the majority of the [patients], when we surveyed providers from all around the country who treat patients [with thyroid cancer] who were refractory to iodine, the starting dose for the vast majority of [patients] was 24 mg, and that response rates were somewhere around 72%, which was higher than in the SELECT trial. That makes sense because we are not actually controlling for the time to progression or the RECIST criteria that is involved in a clinical study. The majority of [patients] were able to maintain their therapy at 24 mg with some dosage adjustments, and then [patients] came off for progression or for toxicity. This told us that the drug is being used appropriately and [patients] are garnering a response from a treatment when they have RAI-refractory disease.

The big controversy now in thyroid cancers when they become refractory is treatment. We now know from next-generation sequencing assays that we have driver mutations that are mutually exclusive. In papillary thyroid cancers, in particular, we know about 50% to maybe 65% or so of patients who have these cancers have a driver mutation that is BRAF. Others include RET, NTRK, [and] RAS...A patient who has a BRAF mutation is going to have these other mutations. With selpercatinib [Retevmo], treating fusions that are RET fusions that are driving differentiated thyroid cancer, or NTRK with the use of larotrectinib [Vitrakvi] or entrectinib [Rozlytrek], we know that we can get nice responses with those drugs and [adverse] effect profiles that are manageable. Oftentimes, those drugs are used first when we identify those driver mutations. There is in some ways a controversy where folks may identify a BRAF mutation and saying now that we have to darafenib [Tafinlar] and tremetinib [Mekinist] available by an agnostic approval from the FDA for patients who have BRAF V600E-driven tumors that we can use these.

Thyroid cancer of a woman, medically 3D illustration, front view: © Axel Kock - stock.adobe.com

However, a study done out of MD Anderson, a multicenter study, showed that response rates either with darafenib plus trametinib or darafenib by itself are somewhere between 30% and 35% as compared to the 60% or 70% that we see with lenvatinib. So, the question comes up, is it better to use lenvatinib in someone who is BRAF-positive vs automatically going to a MEK inhibitor and a BRAF inhibitor? That was kind of the background to this study.

What did the study look at?

What we did is we looked at our real-world experience. We went ahead and did an analysis retrospectively of the patients who had BRAF V600E mutations, or other BRAF mutations, such as the K601E mutation, and then those who were not available for mutational status, so the mutational status was not identified. What we found is that, overwhelmingly, [patients] did well with these BRAF mutations when treated with lenvatinib. This is important because we believe that we should be considering lenvatinib upfront for patients who have these BRAF mutations. Those [with] BRAF mutations, you can see progression-free survival is around 56 months in survival rates that were not reached. That was also true for the wild-type and those that were essentially not tested. What this is telling us is that, again, based on the data that was published in our real-world experience, patients with BRAF mutations upfront should be treated with lenvatinib over, probably, a BRAF/MEK inhibitor.

Were there any significant differences in outcomes between the patients with the BRAF V600E mutations and those with the K601E mutations?

Essentially, no. But I will have to be honest, because if you look at the Kaplan-Meier curves that are listed on our poster, they pretty much overlap. But you have to be careful, because the numbers are relatively small across the board. There are more of the BRAF V600E mutations as compared with the K601E mutations. Essentially, what our data shows is that across the board those were untested, those who have BRAF V600E and the K601E mutations relatively performed the same.

How did the effectiveness of levatinib in this real-world setting compare with results from other clinical trials?

The issue that arises with RAI-refractory differentiated thyroid cancer is that the recommendation is to obtain next-generation sequencing to look for driver mutations. A lot of [patients with] papillary thyroid cancer express a mutant BRAF V600E. We have targeted therapy for the V600E mutations that was approved by the FDA in an agnostic approval and means that any tumor type that has this kind of mutant driver can be treated with this combination of drugs, so I think there are some who believe that this should be the first treatment of choice.

There was only really 1 public study that looked at this in a prospective manner, and that was from MD Anderson. They compared darafenib and tremetinib to darafenib. There was not really a difference in progression-free survival, but the data shows that when we looked at response rates, they are about half of what we see in SELECT at about 30% or 35% as compared [with] 62%. In our real-world experience, our responses were somewhere around 72%. In our analysis here, we know that patients do well with these mutations when treated with lenvatinib. In essence, we are not robbing them of an opportunity by not providing treatment with directed or targeted therapy upfront. In essence, it probably makes the most sense for us to start with these agents, especially if [patients] have bulky disease or a rapidly growing disease, because you want to gain control of the cancer. Even on the NCCN guidelines, they talk about the use of dabrafenib and trametinib is a second line after an effective therapy has been given such as lenvatinib. So, what this poster is saying is that we are supporting the guidelines in showing in a real-world experience that patients with these mutations do just as well, perhaps better, than starting with a targeted therapy upfront.

What are your key takeaways for other oncologists treating patients with RAI-refractory DTC?

When patients become refractory to iodine, we should obtain next-generation sequencing to look for new treatments. We know they are mutually exclusive. Most papillary thyroid cancers will express a BRAF mutation. There are smaller numbers with RET and NTRK, and those mutations, because we have excellent therapies that target those specifically with excellent responses, long duration of responses, and [adverse] effect profiles that are very manageable, those should be treated with those targets upfront. All other patients, including the BRAF-mutant patients, when the time is ready because of progressive disease, symptomatic disease, lenvatinib should be considered the frontline therapy for these patients. Then, reserving a targeted therapy [like] a MEK inhibitor and BRAF inhibitor as a second-line therapy.

I will say however, the [adverse] effect profiles are different for both of these combinations. So, hypertension, bleeding, and extreme fatigue are issues associated with lenvatinib. The [adverse] effect profiles of darafenib and trametinib have to do with fever and fatigue. Both have their limitations. But for example, if someone has uncontrolled hypertension or other comorbidities, that may warrant not using a multi-targeted [tyrosine kinase inhibitor (TKI)]. It may be more appropriate in those settings to use the targeted therapy upfront. But in general, the message I would like to convey to those treating thyroid cancers is, we should be using lenvatinib as a frontline therapy and reserving targeted therapy for patients who are BRAF V600E-mutated as second-line therapy once the patients have failed upfront therapy with lenvatinib.

How can clinicians better support patients undergoing treatment with them that nib especially in managing these adverse effects and ensuring adherence to therapy?

The majority who are [reading] today have used lenvatinib in some capacity. The drug has been around for a while; it has been used in renal cancers and hepatocellular carcinomas, as well as thyroid cancer. It is important that patients are observed closely. Even prior to starting the therapy, we want to make sure that blood pressures are well controlled. We do know that hypertension exists and is a primary [adverse] effect of these drugs. If a patient's blood pressure is not well controlled, that has to be something that we work either with a hypertension specialist, or a primary care doctor, or within our own clinics to control. We tell patients that blood pressures need to be checked regularly. Oftentimes, cuffs are sent home with these patients, so they have the ability to do that and record their blood pressures.

Additionally, these are not [patients] that you send a 30-day supply and say we will see you in a month. These are [patients] who should be seen back or in consultation with perhaps an advanced care provider, such as a nurse practitioner or nurse to check in on blood pressure and how the patients are feeling. Essentially, based on data that Marcia Brose, MD, and colleagues published, 24 mg is the starting dose. We know that patients who started 18 vs 24 mg did not have responses, and if they are going to get [adverse] effects, they are when [given doses of] 18 or 24 mg.

We know a large majority of patients on SELECT had dosage reductions or breaks in treatment or even stopped therapy because of [adverse] effects. I always, for the first month anyway, check in on patients weekly to see how they are feeling, to see if they are having issues with blood pressure, bleeding, or other complications, and if things are bad enough, oftentimes, we will say to hold the medication. We let things resolve and then restart the medication, either at the same dose if it is a shorter interval, or perhaps a dosage reduction. It is important that we get that large dose into effect. Once we have a handle on the blood pressure, diarrhea is another issue we have to be aware of and treat aggressively. Once those conditions are well managed and we have more maintenance, then we can stretch out our visits accordingly.

Are there any plans to investigate combination therapies or any other novel treatments?

We have data that are reasonably accepted for publication with immunotherapy and lenvatinib. Interestingly enough, when lenvatinib was combined with pembrolizumab [Keytruda] upfront, we were hoping to see complete responders and we did not appreciate that. Essentially, the progression-free survival is similar to what we saw on SELECT. The addition of immunotherapy to the TKI or lenvatinib upfront did not necessarily provide any additional benefit. Now when [patients] were on lenvatinib in the second cohort and progressed at whatever dose they were on by RECIST criteria within this 12-to-14-month timeframe, we added in pembrolizumab. Some of those patients showed some stability of disease.

Now, one could argue and say this is the long-term effect of lenvatinib, but I know in my clinical practice I have seen [patients] who were progressing and that was the nature of the entry criteria. [Patients] had to be progressing in order to have the addition of pembrolizumab and I have seen some patients who had disease that became stable. So, there is a group of patients that I may consider as an opportunity to continue lenvatinib before cabozantinib [Cabometyx] or a different targeted therapy. There are other agents that are being investigated, but they are kind of in the early phase. So we have to wait for the results to see if there could be any benefit. But in terms of the addition of other drugs to lenvatinib outside of the published study we just talked about, there really is not anything ongoing where we are going to add lenvatinib to see if things improve or not.

What are the implications of this research for the future of thyroid cancer management and treatment?

It is important that we assess patients closely for those who have iodine-refractory disease. We published a study where we followed [patients] who were refractory to iodine and helped to figure out the timing of when the TKI was started. We did not really find that timeframe, but what we did show in that study is that the time to symptomatic progression was about 55.5 months. Half of the [patients] were above the median and half were below. Interestingly, as a follow-up, we did an evaluation of [patients] who were overseas vs [patients] in the US. What is interesting is that as part of that analysis, we found that the non-US patients went on TKI therapy a little bit earlier than those in the US population. When the US patients were started, we can see a leveling off of the progression-free survival curves.

I think what is important about that data is that we follow patients closely. We should consider therapy in some patients earlier than we do. I think patients read about [adverse] effects and the drugs have toxicity profiles. I think there is a hesitancy by providers as well as patients about starting therapy. I think we may be doing a disservice by not starting therapy in some patients early enough. While there is a group that can safely be followed and we showed that in this study, it is important that we are reminded of when to start and explain to patients why we should be starting therapy when we do.

REFERENCE:

Worden FP, Wirth LJ, Reynolds N, et al. Patients with radioiodine-refractory differentiated thyroid cancer (RAI-R DTC) with BRAF V600E and/or K601E mutation status: A real-world view of effectiveness of lenvatinib monotherapy. J Clin Oncol. 2024;42(suppl 16):6098. doi.org:10.1200/JCO.2024.42.16_suppl.6098