BRAF/MEK Inhibitor Combination Shows Promise in Anaplastic Thyroid Cancer

Yuliya Mikheeva, MD, PhD

Anaplastic thyroid cancer (ATC) is an aggressive cancer with a poor prognosis with a survival rate of only 3 to 5 months with treatment. There is a need for novel therapies for this patient population, especially those with a BRAF mutation.

The phase 2 ANAPLAST-NEO study (NCT04739566) is testing the efficacy of a dabrafenib (Tafinlar), a BRAF inhibitor, and trametinib (Mekinist), a MEK inhibitor, combination as a neoadjuvant strategy in BRAF-positive ATC. The study has an estimated enrollment of 18 participants and an estimated study completion date of January 2026. The primary end points of the study are overall response rate and the number of R0 resections after 3 months of neoadjuvant combination therapy. Secondary end points include safety, complete response rate, health-related quality of life, progression-free survival, and overall survival. 

During the study, all patients received dabrafenib 150 mg orally twice a day and trametinib 2 mg once a day for 3 months.

Principle study investigator Yuliya Mikheeva, MD, PhD, of Saint-Petersburg State University, discussed the combination of dabrafenib and trametinib for the treatment of anaplastic thyroid cancer in an interview with Targeted Oncology™.

TARGETED ONCOLOGY™: What outcomes have been achieved with standard treatment for anaplastic thyroid cancer? How are outcomes different for patients with BRAF mutations?

MIKHEEVA: Anaplastic thyroid cancer is very an aggressive cancer. Among thyroid carcinomas, it accounts for about 2% of cases. The prognosis of treatment is very poor. We only have about 6 weeks from the diagnosis without treatment. And with multimodal approaches, which includes surgery, radiotherapy and chemotherapy, the survival rate increases by 3 to 5 months. That's why it is very aggressive and with poor prognosis. And the patients who have a BRAF mutation, they have an opportunity to be treated with a new targeted therapy. That's why our anti-BRAF is a good choice for these patients and it can increase their survival.

What is the rationale for the use of a BRAF and MEK inhibitor combination for this patient population?

The idea of this study was born when we met our non-metastatic patient with anaplastic thyroid cancer with BRAF mutation. And, of course, we know about several cases where some patients were treated with anti-BRAF therapy in the neoadjuvant strategy, and we decided to design a trial. The combination of dabrafenib and trametinib in a neoadjuvant strategy of BRAF-positive anaplastic thyroid cancer and we have some good results. Our first patient that we meet 2 years ago, and she's now with a very good quality of life without progression. That's why we decided to try and find more patients with whom we can help with such a trial. Unfortunately, this therapy is not approved in Russia. The FDA approved it for patients with metastatic disease, and it is not approved in Russia for neoadjuvant therapy. That's why the only choice to treat people with such cancer is in our trial.

Can you explain what the design of this study is and what methods you'll be using to conduct the study?

It's a phase 2 single center, open label, single arm, non-randomized study. Our primary end points are objective response rate, and number of zero resections after 3 months of neoadjuvant combination therapy with anti-BRAF and MEK inhibitors. Secondary end points are safety profile, health-related quality of life, progression- free survival, and overall survival. The inclusion criteria is any male or female that are over 18 years or years old, and the good in good performance status. Patients must have histologically confirmed disease BRAF-positive anaplastic thyroid cancer determined by immunohistochemistry of the presence of BRAF with a V600E mutation in tumor tissue, they must have the ability of swallow tablets and capsules or gastrectomy, the absence of metastases in the brain and normal organ and bone marrow function. 

What is the current status of the study? Are you actively recruiting patients? Have patients been dosed?

We are recruiting patients, new patients to our study. It is not very easy, of course, because anaplastic throat cancer is so aggressive and most of our patients have metastatic disease. That why it's hard have patients in an early, locally advanced study. They're a small part of patients and we are recruiting, and we are sure that we can find more because we are very actively trying to find out such patients.

Other than the need to improve survival for these patients, what other challenges are doctors trying to overcome for patients with anaplastic thyroid cancer harboring BRAF mutations?

Unfortunately, anaplastic cancer is not very sensitive to a lot of different therapy strategies and standard chemotherapy has a very low effectiveness. And not all patients have BRAF mutation. Only about 50% to 70% of our patients have BRAF mutations. And, of course, we have not enough time to find different approaches for our patients. When we have a patient with anaplastic thyroid cancer, we do the immunochemistry to find the BRAF mutation. And for one day, about 24 hours, we do the data analysis. And in our clinic, we do everything very quickly. And if a patient has no BRAF mutation and their volume of tumors is very high, we started the standard chemotherapy without targeted therapy because we have such opportunities like another target therapy. That's why if we can't find a BRAF mutation, the prognosis of these patient is very poor.

_REFERENCE:

_{Dabrafenib and trametinib combination as a neoadjuvant strategy in BRAF-positive anaplastic thyroid cancer (ANAPLAST-NEO). ClincialTrials.gov. Accessed September 27, 2021. https://bit.ly/3uiMmvJ.}