Intermittent Dosing of Dabrafenib and Trametinib in Metastatic BRAFV600E Mutated Papillary Thyroid Cancer: Two Case Reports

Background: A multi-institutional, randomized phase II trial of continuous dosing of dabrafenib with or without trametinib is ongoing in metastatic thyroid cancer. Preclinical evidence and emerging clinical experience in other cancers support evaluating intermittent dosing of these two agents to achieve more durable response, while being better tolerated and more cost effective. Patients: Two consecutive patients with symptomatic, metastatic radioactive iodine-resistant BRAF(V600E) mutated papillary thyroid cancer and poor performance status were treated initially with dabrafenib 150 mg twice daily plus trametinib 2mg once daily, first in continuous daily dosing, then in a five-week-on and three-week-off schedule. Results: Both patients showed rapid clinical improvement upon starting the regimen. They also noted improved tolerance of treatment upon transitioning to the intermittent dosing schedule. They continue to show evidence of antitumor activity 27 and 18 months respectively from the start of treatment and 15 and 13 months respectively from the start of the first break using intermittent dosing. Conclusions: Achieving durable palliation in these consecutive patients supports evaluating the intermittent dosing schedule of dabrafenib and trametinib in BRAF(V600E) mutated papillary thyroid cancer. Results of the ongoing phase 3 trial of continuous daily dosing and a subsequent trial of intermittent dosing, as is being tested in other cancers, will be needed to confirm that an intermittent dosing strategy in thyroid cancer can forestall resistant disease, improve tolerability, and decrease the cost of care.