Abstract
Dual BRAF/MEK inhibition achieves responses in 69% of BRAFV600E anaplastic thyroid cancers (ATC).
Major finding: Dual BRAF/MEK inhibition achieves responses in 69% of BRAFV600E anaplastic thyroid cancers (ATC).
Clinical relevance: Dabrafenib plus trametinib is well tolerated and achieves durable responses in BRAFV600E-positive ATC.
Impact: BRAF mutation screening may identify patients with ATC likely to benefit from dabrafenib plus trametinib.
Anaplastic thyroid carcinomas (ATC) are aggressive tumors with limited treatment options. The activating BRAFV600E mutation occurs in 20% to 50% of patients with ATC, suggesting the possibility for targeted BRAF inhibition. In patients with BRAFV600E melanoma or lung cancer, combined inhibition of BRAF (with dabrafenib) and MEK (with trametinib) is more effective than BRAF inhibitor monotherapy, and this combination has antitumor activity in transgenic mouse models of ATC. Based on these findings, Subbiah and colleagues investigated the safety and efficacy of dabrafenib plus trametinib in an open-label phase II trial of 16 patients with BRAFV600E-positive locally advanced or metastatic ATC. The primary endpoint was overall response rate, and secondary endpoints included duration of response, progression-free survival, and overall survival. An overall response was observed in 11 of 16 patients (69%), including 1 complete and 10 partial responses, and an additional 3 patients achieved stable disease. Responses were durable, with 7 of 11 responses ongoing. The median duration of response, progression-free survival, and overall survival were not reached. The estimated 12-month duration of response, progression-free survival, and overall survival were 90%, 79%, and 80%, respectively. Treatment with dabrafenib plus trametinib was well tolerated, and the safety profile was similar to what had been observed in other tumor types. Grade 3 or 4 adverse events occurred in 42% of patients, most commonly anemia (in 13% of patients). Taken together, the results of this phase II study indicate that dabrafenib plus trametinib is well tolerated and has antitumor activity in patients with BRAFV600E ATC, and suggest that patients with ATC should be screened for BRAF mutations.
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