Martins on Lenvatinib's Significance in Differentiated Thyroid Cancer

Renato G. Martins, MD

Since lenvatinib (Lenvima) landed in the treatment paradigm as an approved option for patients with differentiated thyroid cancer (DTC), it has had a noticeable effect, explains Renato G. Martins, MD.

Lenvatinib was approved by the FDA as a treatment for patients with progressive, radioactive iodine (RAI)—refractory DTC in February 2015, joining sorafenib (Nexavar), another tyrosine kinase inhibitor, as a first- or second-line treatment option.

The approval was based on findings from the phase III SELECT trial, in which treatment with the multikinase inhibitor reduced the risk of disease progression by 79% (HR, 0.21; 99% CI, 0.14-0.31; P <.0001).

In the SELECT trial, 392 patients with advanced RAI-refractory DTC were randomized in a 2:1 ratio to oral lenvatinib at 24 mg daily in 28-day cycles (n = 262) or placebo (n = 131). Pretreatment with one prior TKI regimen was permitted.

At a median treatment duration of 13.8 months with lenvatinib and 3.9 months with placebo, the median progression-free survival was 18.3 months versus 3.6 months, respectively.

The objective response rate with lenvatinib was 64.8% versus 1.5% with placebo. Four patients in the lenvatinib arm had complete responses versus none in the placebo group, with partial responses in 165 and 2 patients, respectively.

Treatment-related adverse events reported with lenvatinib include hypertension, proteinuria, decreased weight, fatigue, and diarrhea, along with palmar-plantar erythrodysesthesia syndrome.

OncLive: With lenvatinib being on the market for over 1 year, how has the treatment landscape of DTC changed?

In an interview with OncLive, Martins, medical director of Outpatient General Oncology/Hematology at Seattle Cancer Care Alliance, medical director of Thoracic/Head and Neck Oncology, and professor at University of Washington School of Medicine, discusses the impact of lenvatinib in patients with DTC, how and when it should be used in clinical practice, and the future potential for the agent.Martins: The lenvatinib papers show something very important—that there is a lack of cross-resistance between these tyrosine kinase inhibitors for thyroid cancer. In one of the lenvatinib papers, the response rate in patients who had received a prior TKI was actually pretty high.

We now have 2 options that are FDA approved. The number of options for patients who have RAI-refractory disease has expanded quite a bit and, very frequently, these patients have the opportunity to go from one oral TKI to another oral TKI and remain with disease control.

Is lenvatinib being used, more or less, as the standard of care in the first-line setting?

What factors are considered when choosing between sorafenib and lenvatinib as a first-line therapy for patients with DTC?

I would say that lenvatinib is probably the one that has the highest response rates.I think so. I don’t have the data to support that statement, but I would imagine that that is the case.The first question in treating patients with thyroid cancer who are RAI-refractory is, “Do they need therapy, period?” Some patients have a very indolent course of their disease, and they may present with multiple small pulmonary nodules from which they have absolutely no symptoms. We should try to avoid making the treatment into a disease.

There are a number of patients who go years without receiving therapy with very slow-growing tumors. The question is, “When is the appropriate time to pull the trigger in therapy?”

What are some of the side effects with these agents?

What are you seeing done differently in clinical practice? Are patients receiving treatment earlier?

What other work with lenvatinib is ongoing?

I think patients are very attracted to the concept of an oral therapy that is not really conventional chemotherapy, and I can certainly understand that. However, these drugs have side effects. Sometimes, once they start taking them, they realize that its appeal is not as benign as one perhaps would fantasize, despite all of the indications we provide upfront. There’s nothing like having the experience itself.Although they are both tyrosine kinase inhibitors, side effects do differ from drug to drug. Sorafenib may have, in comparison with other drugs, more of the hand-foot syndrome problem, while lenvatinib may have more of the mucositis or gastrointestinal complaints. They need to be proactively managed. Not infrequently we, as the trials with lenvatinib have shown, have to resort to dose reductions.In our practice, we see many more patients with advanced thyroid cancer than we used to. When all we had to offer was conventional chemotherapy, there was a nihilism toward benefits of treatment. Now, because we have so many more options and they’re not conventional chemotherapy, patients are referred to us much more often than they used to be, even at advanced stage.My intuition is that, as far as with the approvals of both sorafenib and lenvatinib, we may go through a period of a “drought” of research with tyrosine kinase inhibitors in this area. Obviously, in solid tumor oncology, there is a lot of interest about immunotherapy. Would that also be an option for this disease? I think time will tell.

What are some of the biggest questions still remaining with lenvatinib?

In lung cancer, which is another disease that I treat, the combination of immunotherapy with TKIs has not that been that exciting.One question that remains is deciding what the ideal starting dose should be. It’s very, very frequent that patients require dose reductions, and I think there is a trial looking at that. That is an important question.

What are the biggest challenges in thyroid cancer to overcome in the next few years?

Traditionally, in oncology, we focus on finding out what the highest tolerated dose we can deliver to someone is. It would be much harder to find out what is the least equally effective drug we can give to somebody because, most of the time, that would be associated with less side effects. But, evidently, designing such research is complicated.There is no question that, despite the reports of driver mutations with anaplastic thyroid cancer, it remains an incredibly hard disease to treat—and, it’s a rare one. In thyroid cancer, that is the biggest challenge.

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