Immunotherapy, New Targeted Approaches Explored in Thyroid Cancer

Gregory Daniels, MD, PhD

As with other solid tumors, researchers are now exploring both BRAF/MEK inhibitor combinations and PD-1 therapy in the field of thyroid cancer for patients who are refractory to radioactive-iodine treatment, according to Gregory Daniels, MD, PhD, who adds that there is an increased emphasis on genetic testing to determine potential driver mutations in these patients.

For example, an ongoing phase II clinical trial is investigating the combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) versus dabrafenib alone in patients with recurrent BRAF-mutated thyroid carcinoma (NCT01723202). This is a next step from other systemic agents, such as sorafenib (Nexavar) and lenvatinib (Lenvima), which are already FDA approved to treat patients with thyroid cancer.

The FDA approved lenvatinib in 2015 as a treatment for patients with progressive, radioactive iodine-refractory differentiated thyroid cancer based on initial progression-free survival results from SELECT, which showed that the drug reduced disease progression and significantly improve overall survival (OS) compared with placebo in patients older than 65 years old.

OncLive: Please provide an overview of your presentation on thyroid cancer.

What have been some recent advancements in the field?

Are there any clinical trials in this space that you are excited about?

In an interview during the 2017 OncLive^® State of the Science Summit^TM on Head and Neck Squamous Cell Carcinoma and Thyroid Cancer, Daniels, a clinical professor in the Department of Medicine at University of California, San Diego, discussed the current treatment landscape of thyroid cancer and the development of immunotherapy for patients with this disease.Daniels: I discussed advanced thyroid cancer, meaning thyroid cancers that have become refractory—usually to radioactive iodine or other conventional therapies, such as surgery. Surgery remains to be the first choice of treatment. However, patients with advanced cancer see their cancer spread to the lungs, bone, or other organs. The main focus of my talk was the current role of medical oncology in the field of thyroid cancers after radioactive-iodine therapy.Like other areas of oncology, thyroid cancer is now getting personalized therapies [targeted to the driver mutations], as well as immunotherapy with checkpoint inhibitors. The 2 FDA-approved medications in thyroid cancer, sorafenib and lenvatinib, are tyrosine kinase inhibitors (TKIs) and target VEGF 1/2/3. That's what is currently happening regarding the genetics for these patients.When looking at a differentiated thyroid cancer—papillary thyroid cancer being the most common—that is refractory to radioactive-iodine therapy and need systemic treatments, the first thing we will do is sequence their somatic mutations in their tumor. That is not whole-genome sequencing, but it is looking at 200 or 300 targets. Thyroid cancer often has the MAP kinase pathway perturbed with a BRAF or RAS mutation in the MAP kinase pathway.

We are attempting to utilize the drugs that we have in other tumor types, such as melanoma, by inhibiting BRAF with either dabrafenib or vemurafenib (Zelboraf). These are not FDA approved in thyroid cancers, but are [being explored] in clinical trials. Dr Manisha Shah at The Ohio State University just completed a study demonstrating that combination therapy with both dabrafenib and trametinib has good activity in thyroid cancers with BRAF mutations.

Another area is the observation that MAP kinase activation appears to be associated with less differentiation in the cancers. There is a hypothesis that we can increase iodine uptake in cancers by inhibiting the MAP kinase pathway.

If drugs such as dabrafenib are approved by the FDA, what impact would they have on the treatment landscape? Would they be better used in combinations?

A study that is ongoing is utilizing a MEK inhibitor compared with placebo in patients who have received radioactive iodine. We are looking to give them another dose, but can we enhance the benefit of radioactive iodine by turning off this MAP kinase pathway? We hope to find the answer in that exciting trial.In my opinion, we should use genetics to discover what is driving the mutation. The next thing that happens with these targeted therapies is resistance. We are beginning to understand these secondary pathways that are coming up. For example, HER3 is activated at MAP kinase resistance when you start turning off BRAF. There are ongoing studies looking at those combinations.

What advice do you have for oncologists who are treating patients with thyroid cancer?

As far as immunotherapy is concerned, we have pembrolizumab (Keytruda), nivolumab (Opdivo), and many other PD-1 inhibitors. These have good activity, but many times they cause stable disease for a period of time. That is also another opportunity for combination therapies that have been successful in melanoma, lung cancer, and other tumor types. That should be coming to thyroid cancer, as well. It is important to start with the genes. A patient with thyroid cancer who is looking at first-line options and is resistant to radioactive-iodine therapy should have a somatic gene panel done to figure out the driver mutation. Even though lenvatinib and sorafenib are first-line agents that are approved in this indication, they do not depend on the gene. However, you will be needing that information if they have toxicities from these agents and need to switch.

What should community oncologists take away from this presentation?

These drugs are not FDA approved in thyroid cancer, but we can use them off-label with sufficient justification. The clinical trials are showing us good activity and a good safety profile. I would advise physicians to go ahead and get sequencing upfront. The treatment paradigm of thyroid cancer continues to move forward. We have gotten out of the realm of cytotoxic chemotherapies that are now giving personalized treatments.

We also now have immunotherapies [in clinical trials]. We need to put more patients with thyroid cancer on clinical trials. I encourage patients and providers to think about that as they are looking at their options. We do have approved agents, but we need to do better and clinical trials are the way to improve.