Continuous versus intermittent BRAF and MEK inhibition in patients with BRAF mutated melanoma: a randomized phase 2 trial
| Autor: | Gary C. Doolittle, Thach Giao Truong, Bryan A. Faller, James Moon, Robert M. Conry, Janice M. Mehnert, Adil Daud, Amy K. Harker-Murray, Dennis F. Moore, Michael J. Messino, Alain Algazi, Roger S. Lo, Antoni Ribas, Christopher D. Lao, Kenneth F. Grossmann, Joseph I. Clark, Kari Kendra, Rangaswamy Govindarajan, Luke Dreisbach, Megan Othus |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Oncology Male Skin Neoplasms Phases of clinical research Administration Oral Medical and Health Sciences law.invention 0302 clinical medicine Randomized controlled trial law Antineoplastic Combined Chemotherapy Protocols Oximes Melanoma Cancer Trametinib MEK inhibitor Imidazoles General Medicine Middle Aged MAP Kinase Kinase Kinases Treatment Outcome 6.1 Pharmaceuticals 030220 oncology & carcinogenesis Administration Female medicine.drug Oral Adult Proto-Oncogene Proteins B-raf medicine.medical_specialty Pyridones Clinical Trials and Supportive Activities Immunology Mutation Missense Pyrimidinones General Biochemistry Genetics and Molecular Biology Article Drug Administration Schedule 03 medical and health sciences Young Adult Clinical Research Internal medicine medicine Humans Dosing Protein Kinase Inhibitors Aged business.industry Evaluation of treatments and therapeutic interventions Dabrafenib medicine.disease Survival Analysis Clinical trial 030104 developmental biology Mutation Missense business |
| Zdroj: | Nat Med Nature medicine, vol 26, iss 10 |
| Popis: | Preclinical modeling suggests that intermittent BRAF inhibitor therapy may delay acquired resistance when blocking oncogenic BRAFV600 in melanoma1,2. 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 BRAFV600 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. |
| Databáze: | OpenAIRE |
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