Advancing the Treatment of Thyroid Cancer With Targeted Therapies

Winston Tan, MD

Winston Tan, MD

Surgery and radioactive iodine (RAI) are the primary treatments for patients with thyroid cancer; however, other therapies have shown efficacy signals in this patient population. Lenvatinib (Lenvima), a multikinase inhibitor, for example, has significantly improved overall survival (OS) in patients with locally recurrent or metastatic, progressive, RAI-refractory differentiated thyroid cancer (RR-DTC).

In the phase III SELECT trial (NCT01321554), which completed in March 2019, older patients who were treated with lenvatinib had a better OS rate than those treated with placebo (HR, 0.53; 95% CI, 0.31-0.91;P= .020). Patients who received placebo Lenvatinib also improved progression-free survival (PFS) by 17 months compared with placebo. The median PFS was 20.2 months versus 3.2 months, respectively. Among the younger patients who were given lenvatinib, the overall response rate was significantly higher than with placebo (72% vs 55%). 

Compared with placebo, lenvatinib was also more tolerable for younger patients in the study, with fewer grade 3 or higher treatment-related adverse events observed. Older patients did experience more high-grade toxicity; however, the investigators suggested that lenvatinib can still be used in patients of all ages with RR-DTC.¹Efficacy has also been seen with another tyrosine kinase inhibitor, sorafenib (Nexavar), in advanced thyroid cancer, said Winston Tan, MD.  

Additionally, oncologists have found thatBRAFandRETare good molecular targets for treating patients with thyroid cancer. Looking forward, the targets will likely be used in combination with other drugs. Tan stated, “mutations are important for the future treatment and diagnostic options of patients with thyroid cancer.”

In an interview withTargeted Oncology, Tan, consultant, Division of Hematology/Oncology, Department of Internal Medicine, and associate professor of medicine, Mayo Clinic, discussed advances in thyroid cancer that may be competitors to the current standard of care. He also shared ongoing challenges that he has experienced in treating patients with thyroid cancer.

TARGETED ONCOLOGY: What is the current standard of care for patients with thyroid cancer?

Tan: The primary treatment of patients with thyroid cancer would be surgery. First, I want to mention that there are a lot of thyroid nodules that are diagnosed each year. The majority of them are benign nodules and it is important to do diagnostic biopsies to determine whether it's benign or malignant. The second step is, if it's benign and it's localized, the treatment would be a thyroidectomy, and for those with locally advanced disease, you would give RAI in addition to surgery.

As an oncologist, I would see those patients if they become refractory to RAI treatment and the standard of care would be tyrosine kinase inhibitors for follicular or well-differentiated metastatic thyroid cancer, and also for medullary thyroid cancer.

TARGETED ONCOLOGY: What advances have you seen in the space? Is there any research you can highlight?

Tan: Primarily, we did use chemotherapy as a treatment for [patients with] thyroid cancer; however, the PFS for those patients was very short. Now with drugs such as lenvatinib or sorafenib, we are able to prolong PFS by at least a year for lenvatinib. In one study it was 18 months compared with 3 months with placebo. And with sorafenib, it is at least 6 months. I think that's very important for us to know that we have 2 FDA-approved drugs for well-differentiated thyroid cancer. For medullary, we have another 2 that can delay the progression of disease.

In addition to that, we have to highlight the significant progress in molecular markers. In anaplastic thyroid cancer with aBRAFmutation, those patients will now benefit from anti-BRAF treatment and MEK treatment in the form of trametinib (Mekinist) and dabrafenib (Tafinlar) as a treatment for anaplastic thyroid cancer with aBRAFmutation. In the past, we did not have an FDA-approved drug and those patients were treated in clinical trials.

I also want to highlight thatRETmutation has been found in a subset of thyroid cancer and there are exciting trials that are being done today to evaluate those patients withRETmutations and thyroid cancer.

TARGETED ONCOLOGY: What emerging studies and treatment options do you find interesting for thyroid cancer?

Tan: As earlier mentioned, looking atRETmutations and treating them with oral agents that are minimally toxic. Hopefully, when the trials are done, we will have one or 2 drugs for patients withRETmutations in thyroid cancer.

TARGETED ONCOLOGY: Has genomic testing become more important for patients with thyroid cancer due to the emergence of more FDA-approved targeted therapy approaches, such as the BRAF/MEK combination for patients withBRAF-mutated anaplastic thyroid cancer? Are there other targets of interest in thyroid cancer?

Tan: There are a lot of different targets, but we don't have combinations yet. BRAF is one of the targets that we have drugs to treat.RETmutation is the other one that I think is emerging at this time. We have to remember that there is what we call an agnostic drug of PD-1 and PD-L1 inhibitors that we can also use if the patients have MSI-high or microsatellite deficient tumors. [Nivolumab (Opdivo) and pembrolizumab (Keytruda) are such drugs]. Mutations are important for the future treatment and diagnostic options of patients with thyroid cancer.

TARGETED ONCOLOGY: What are the biggest challenges that need to be overcome in the thyroid cancer space?

Tan: The biggest change is the appropriate diagnosis and particularly differentiating follicular benign tumors from follicular cancer. The other is getting patients to recognize that these diseases need to be diagnosed and appropriately treated with a team approach. Patients see an oncologist, a thyroid surgeon, a radiologist, in 3 different places. I think today, the treatment approach for thyroid cancer should be in one place and it should be a team approach. That is the greatest challenge that we need to be aware of.

TARGETED ONCOLOGY:What advice would you give a community oncologist treating a patient with thyroid cancer today?

Tan: Oncologists should refer to centers of excellence who have a team approach to the treatment of patients with thyroid cancer.

Reference:

Brose MS, Worden FP, Newbold KL, et al. Effect of Age on the Efficacy and Safety of Lenvatinib in Radioiodine-Refractory Differentiated Thyroid Cancer in the Phase III SELECT Trial.J Clin Oncol.2017;35(23):2692-2699. doi: 10.1200/JCO.2016.71.6472.