Journal Article

Continuous versus intermittent BRAF and MEK inhibition in patients with BRAF-mutated melanoma: a randomized phase 2 trial

Lao, Christopher, Faller, Bryan A., Harker-Murray, Amy, Dreisbach, Luke, Algazi, Alain P., Ribas, Antoni, Mehnert, Janice M., Conry, Robert, Messino, Michael J., Kendra, Kari, Govindarajan, Rangaswamy, Daud, Adil I., Moon, James, Lo, Roger S., Doolittle, Gary C., Moore, Dennis F., Clark, Joseph I., Othus, Megan, Truong, Thach-Giao, Grossmann, Kenneth F.

2020

Overview

Preclinical modeling suggests that intermittent BRAF inhibitor therapy may delay acquired resistance when blocking oncogenic BRAF V600 in melanoma 1 , 2 . We conducted S1320, a randomized, open-label, phase 2 clinical trial (NCT02196181) evaluating whether intermittent dosing of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib improves progression-free survival in patients with metastatic and unresectable BRAF V600 melanoma. Patients were enrolled at 68 academic and community sites nationally. All patients received continuous dabrafenib and trametinib during an 8-week lead-in period, after which patients with non-progressing tumors were randomized to either continuous or intermittent dosing of both drugs on a 3-week-off, 5-week-on schedule. The trial has completed accrual and 206 patients with similar baseline characteristics were randomized 1:1 to the two study arms (105 to continuous dosing, 101 to intermittent dosing). Continuous dosing yielded a statistically significant improvement in post-randomization progression-free survival compared with intermittent dosing (median 9.0 months versus 5.5 months, P  = 0.064, pre-specified two-sided α  = 0.2). Therefore, contrary to the initial hypothesis, intermittent dosing did not improve progression-free survival in patients. There were no differences in the secondary outcomes, including overall survival and the overall incidence of treatment-associated toxicity, between the two groups. The randomized phase 2 trial S1320 comparing different dosing schedules of BRAF/MEK inhibitor combination in BRAF -mutated advanced melanoma shows intermittent therapy does not result in superior progression-free survival in patients.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/67 / 692/308 / 692/699 / Administration, Oral / Adult / Aged / Antineoplastic Combined Chemotherapy Protocols - administration & dosage / Antineoplastic Combined Chemotherapy Protocols - adverse effects / Biomedical and Life Sciences / Biomedicine / Cancer Research / Dosage / Drug Administration Schedule / Drug therapy / Female / Genetic aspects / Health aspects / Humans / Imidazoles - administration & dosage / Imidazoles - adverse effects / Infectious Diseases / Inhibitor drugs / Inhibitors / Letter / Male / MAP Kinase Kinase Kinases - antagonists & inhibitors / MEK inhibitors / Melanoma / Melanoma - drug therapy / Melanoma - genetics / Melanoma - mortality / Melanoma - pathology / Metabolic Diseases / Metastases / Middle Aged / Molecular Medicine / Mutation (Biology) / Mutation, Missense / Neurosciences / Oximes - administration & dosage / Oximes - adverse effects / Patient outcomes / Patients / Protein Kinase Inhibitors - administration & dosage / Protein Kinase Inhibitors - adverse effects / Proto-Oncogene Proteins B-raf - antagonists & inhibitors / Proto-Oncogene Proteins B-raf - genetics / Pyridones - administration & dosage / Pyridones - adverse effects / Pyrimidinones - administration & dosage / Pyrimidinones - adverse effects / Randomization / Schedules / Skin Neoplasms - drug therapy / Skin Neoplasms - genetics / Skin Neoplasms - mortality / Skin Neoplasms - pathology / Statistical analysis / Survival / Survival Analysis / Toxicity / Treatment Outcome / Young Adult