This article is more than 5 years old. Information may no longer be current.
Vemurafenib shows antitumor activity in BRAF V600E–positive, iodine-refractory thyroid cancer
The BRAF kinase inhibitor vemurafenib demonstrated antitumor activity in patients with BRAF V600E–positive papillary thyroid cancer that is refractory to radioactive iodine, according to the results of an open-label, multicenter phase 2 trial.
Patients who had never been treated with a multikinase inhibitor appeared more likely to respond, results showed.
Marcia S. Brose
Surgery, thyroid-stimulating hormone therapy and selective radioactive iodine therapy are standard treatments for differentiated thyroid cancer. However, 25% to 50% of patients with locally advanced or metastatic disease become refractory to radioactive iodine.
Multikinase inhibitors sorafenib (Nexavar, Bayer) and lenvatinib (Lenvima, Eisai) have demonstrated clinical activity in this setting and are approved for patients with refractory disease. However, these treatments are not curative, and some patients experience intolerable adverse events.
“Due to our prior success in treating these patients with sorafenib and lenvatinib, patients are doing better, but they still ultimately progress, and we need additional agents with different mechanisms of action,” Marcia S. Brose, MD, PhD, associate professor of otorhinolaryngology: head and neck surgery at Perelman School of Medicine of University of Pennsylvania, said in a press release. “Vemurafenib (Zelboraf, Genentech/Roche) is the first non-VEGFR inhibitor to show activity in this patient population and, as such, is an important addition to our treatment options for these patients.”
Between 37% and 50% of papillary thyroid tumors harbor the BRAF V600E mutation, leading to more aggressive disease and a decreased ability to incorporate radioactive iodine, resulting in treatment failure or recurrent disease.
Vemurafenib — approved for BRAF–positive melanoma — showed benefit for three patients with BRAF V600E–positive papillary thyroid cancer in a phase 1 trial. Based on those data, Brose and colleagues assessed the safety and efficacy of vemurafenib in 51 patients with BRAF V600E–positive, radioactive iodine–refractory papillary thyroid cancer.
Researchers separated patients into two cohorts. Patients in cohort 1 had never received a VEGFR multikinase inhibitor (n = 26; median age, 67 years; 58% men), and patients in cohort 2 had received one (n = 25; median age, 65 years; 52% men).
All patients received 960 mg oral vemurafenib twice daily.
Investigator-assessed best overall response in cohort 1 served as the primary endpoint, and best overall response in cohort 2 served as a secondary endpoint.
Median follow-up was 18.8 months (interquartile range [IQR], 14.2-26) in cohort 1 and 12 months (IQR, 6.7-20.3) in cohort 2.
Ten patients in cohort 1 achieved partial response, equating to a best overall response rate of 38.5% (95% CI, 20.2-59.4). Six patients in cohort 2 achieved partial response for a best overall response rate of 27.3% (95% CI 10.7-50.2).
Seventeen patients in each cohort experienced grade 3 or grade 4 adverse events. The most common adverse events included squamous cell carcinoma of the skin (cohort 1 27%; cohort 2, 20%), lymphopenia (8% in each) and increased gamma-glutamyltransferase (4%; 12%).
Serious adverse events occurred in 62% of patients in cohort 1 and 68% of patients in cohort 2. Two patients from cohort 2 died due to dyspnea and multiorgan failure; however, neither were deemed treatment related.
Researchers acknowledged that these data may be limited due to the absence of data for historical comparison of OS among patients in this setting.
“For this group of patients, who have little to no options, [the results show] a significant improvement,” 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.” – by Nick Andrews
Disclosure: Roche AG funded this research. Brose reports consultant fees, research grants and honoraria from Bayer Healthcare Pharmaceuticals, Eisai, Exelixis, Genentech, Novartis and Onyx Pharmaceuticals. Other researchers report grants and current employment with Roche and Roche/Genentech. Please see the full study for a list of all other researchers' relevant financial disclosures.