Drug Targeting BRAF Mutation Elicits Response in One-Third of Metastatic Thyroid Cancer Cases

Lead author Marcia Brose, MD, PhD and Gregory A. Masters, MD, FASCO (American Society Clinical Oncology, ASCO Expert) Comment

The targeted therapy with vemurafenib led to partial responses in at least one-third of patients with metastatic thyroid cancer harboring a BRAF mutation, according to an open-label phase 2 clinical study published online ahead of print in Lancet Oncology.

Vemurafenib joins other multi-targeted kinase inhibitors (MKIs) (sorafenib, lenvatinib) shown to be effective in this patient population; in spite of responses to these drugs, the responses are temporary and additional treatment options are needed. Vemurafenib is indicated for unresectable or metastatic melanoma patients with the BRAFV600E mutation.
Vemurafenib chemical structure”Due to our prior successes in treating these patients with sorafenib and lenvatinib, patients are doing better, but they still ultimately progress, and additional agents with different mechanisms of action are needed,” said lead author Marcia Brose, MD, PhD, Associate Professor of Otorhinolaryngology: Head and Neck Surgery and Medicine, Hematology/Oncology at the University of Pennsylvania, in Philadelphia, in a statement to the press. “Vemurafenib is the first non-VEGFR inhibitor [non-vascular endothelial growth factor receptor] to show activity in this patient population and as such is an important addition to our treatment options for these patients,” said Dr. Brose, who also is Director of the Center for Rare Cancers and Personalized Therapy at Penn’s Abramson Cancer Center.

The findings are based on data from 51 patients from 10 centers worldwide who had progressive, radioactive iodine-refractory papillary thyroid cancer and a BRAFV600Emutation, and were no longer responding to prior therapies. The patients were divided into two cohorts based on whether they had previously received a multi-kinase inhibitor targeting VEGFR (n=26, cohort 1) or had not (n=25, cohort 2).

All patients received vemurafenib 960 mg orally twice daily and were followed for a minimum median duration of 15 months. Treatment response was measured using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

After a 15-month follow-up, 16 patients in each cohort had partial responses, with an overall response rate of 38% and 27% in cohort 1 and cohort 2, respectively. Median progression free survival was 18.2 months and 8.9 months in the respective cohorts.

Adverse Events
Grade 3 or 4 adverse events occurred in 17 patients in cohort 1 (65%) and 17 patients (68%) of cohort 2. The most common adverse events were squamous cell carcinoma of the skin (27% and 20% in cohort 1 and 2, respectively), lymphopenia (8% in each cohort), and increased γ-glutamyltransferase (4% and 12%, respectively).

Two people in cohort 2 died: one from multiorgan failure and one from dyspnoea; none of these deaths were considered treatment-related.

“For this group of patients, who have little to no options, that’s a significant improvement,” Dr. Brose said. “This promising clinical trial is the next step in a series of trials to identify new drugs that are fundamentally shifting the horizon—improving the outcome for patients with advanced differentiated thyroid cancer.”

The study was funded by F. Hoffmann-La Roche.


Gregory A. Masters, MD, FASCO
ASCO Expert, Lung Cancer
Attending Physician, Helen F. Graham Cancer Center
Associate Professor, Thomas Jefferson University Medical School

Vemurafenib appears to be an interesting new option for patients with papillary thyroid cancer that becomes refractory to standard radioactive iodine. This study targeted patients with a BRAF mutation, which is commonly seen in these thyroid cancers. Interestingly, this mutation may be seen more commonly in older patients, which is a group that has been underrepresented in cancer clinical trials.

The fact that this study targets a specific gene mutation allows us to select patients for the most active treatments to maximize the benefit. This improves the value of our treatments.

The efficacy appears similar to other targeted drugs, such as sorafenib or lenvatinib, but this particular agent targets the specific BRAF mutation making it uniquely appropriate for this population. The toxicity seen in the study was acceptable and predictable based on previous trials of this drug in melanoma patients.

Most importantly, this study supports the oncologic concept of targeting molecular changes in cancer cells that make them unique, and using treatments that specifically inhibit a cancer cell’s ability to grow and spread. This offers patients the best chance for individualized treatment and tumor control.

August 16, 2016

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