Novel Treatments, Effective Combinations Still Needed in Thyroid Cancer

Keith Bible, MD, PhD

In recent years, significant advancements have been made in the field of thyroid cancer.

In February 2015, the FDA approved lenvatinib (Lenvima) for the treatment of patients with progressive, radioactive iodine (RAI)—refractory differentiated thyroid cancer (DTC) based on the phase III SELECT trial. The study demonstrated that lenvatinib reduced the risk of disease progression by 79% (HR, 0.21; 99% CI, 0.14-0.31; P <.0001).

Lenvatinib was the second multikinase inhibitor approved in the space, following the November 2013 approval of sorafenib (Nexavar) in (RAI)-resistant metastatic DTC, which was based on the DECISION trial. In the phase III study, treatment with sorafenib improved progression-free survival by 41% compared with placebo.

However, despite these achievements, there is still much to accomplish in thyroid cancer, says Keith C. Bible, MD, PhD, a medical oncologist at Mayo Clinic.

“A big problem we have is that, although thyroid cancer has seen the approval of several drugs in the last few years, those drugs do not cure any of our patients. Ultimately, their disease progresses and they need additional salvage treatments,” says Bible. “Even if a drug is the standard of care in first-line, every treatment will only work for a period of time. Therefore, we need a standard of care in second line, and then third line. Lenvatinib is the standard first-line treatment, but for second-line salvage treatment, we don’t have a standard yet.”

OncLive: What novel single agents or combinations are you most excited about in thyroid cancer?

Nevertheless, there are promising agents and combinations on the horizon, says Bible. In an interview with OncLive, he discusses novel treatments he is excited about, the role of lenvatinib, and what the future may hold for thyroid cancer treatment.Bible: In the case of differentiated thyroid cancer, there is much excitement to see if we can do better with radioactive iodine therapy by enhancing its value utilizing the kinase inhibitors that are also being explored independently in thyroid cancers.

It turns out that radioiodine uptake can be enhanced and sometimes revived effectively by utilizing these agents. This may allow us to get additional benefit for our patients from radioactive iodine, before moving on to more chronic use of toxic kinase inhibitors. The advantage of using this combined strategy is that the kinase inhibitors are used for only 1 month or so, which limits the toxicities—both short-term and long-term.

The problem with this approach is that it only works for a fraction of patients, like most of our therapies do. Approximately 20% of patients treated with this approach in the pilot trials seem to get the majority of the benefit. We are hoping to do better, but that is where things stand right now.

There are 2 trials ongoing or soon to be ongoing in this area; one is for advanced disease and one is for earlier disease.

What impact has the approval of lenvatinib had in thyroid cancer?

There are other combination therapies being looked at, as well. The question of escape mechanisms from kinase inhibitors is an issue that worries us greatly. Can we prevent the escape by dual targeting the escaped pathways concomitant with a kinase inhibitor that inhibits the VEGFR pathway? This is another strategy.It is always good to have another agent. The chance of dramatic disease regression was much more modest with sorafenib than in the case of lenvatinib or some of the other kinase inhibitors. For sorafenib, it is around 15% while, for lenvatinib, it is closer to 70%. In patients who have very aggressive disease that is symptomatic, we have a greater chance of making the disease less symptomatic using a more cytoreductive approach, such as lenvatinib, than sorafenib. That is 1 very important goal.

It is a different sort of endpoint. If you already have symptoms and have a delayed time to regression, that is favorable, in terms of survival. However, you don’t get any help with your symptoms that are preexisting. In that case, lenvatinib may do better.

Having an agent approved allows us a greater chance to be able to use that agent with our patients. Off-label use [with a therapy] that has demonstrated efficacy in a phase II trial is getting harder and harder to [do], because of insurance and government financials. The [lenvatinib approval] gives us more opportunities to treat our patients with an agent that not only has a potential for less side effects, but also has the potential to improve the symptoms that patients have.

Where do you see the treatment paradigm going in thyroid cancer in the next 5 years?

Most people who work in this area would consider lenvatinib a first-line choice for patients who truly require systemic therapy where there was not a suitable focal or palliative option.Where it is likely to move is partly driven by the availability of drugs. There is fantastic enthusiasm for immunotherapeutic approaches. The only question is, “Can we apply them wisely in thyroid cancer?”

In squamous cell carcinomas, we know that there is activity with these agents in both lung squamous cell carcinomas and also head and neck squamous cell carcinomas. In thyroid cancer, we really don’t have much of a signal, but the laboratory data would suggest that it is probably for the more aggressive thyroid cancers—such as poorly differentiated and autoplastic. This is one direction where I expect trials will head. Whether they will bear fruit will need to be defined.