Faculty Collaboration Database

Dabrafenib and Trametinib in Patients With Tumors With BRAF^V600E Mutations: Results of the NCI-MATCH Trial Subprotocol H. J Clin Oncol 2020 Nov 20;38(33):3895-3904

Date

08/08/2020

Pubmed ID

32758030

Pubmed Central ID

PMC7676884

DOI

10.1200/JCO.20.00762

Scopus ID

2-s2.0-85093919047 (requires institutional sign-in at Scopus site)   140 Citations

Abstract

PURPOSE: BRAF^V600 mutations are commonly found in melanoma and thyroid cancers and to a lesser degree in other tumor types. Subprotocol H (EAY131-H) of the NCI-MATCH platform trial sought to investigate the selective BRAF inhibitor dabrafenib and the MEK1/2 inhibitor trametinib in patients with solid tumors, lymphomas, or multiple myeloma whose tumors harbored a BRAF^V600 mutation.

PATIENTS AND METHODS: EAY131-H is an open-label, single-arm study. Patients with melanoma, thyroid, or colorectal cancer were excluded; patients with non-small-cell lung cancer were later excluded in an amendment. Patients received dabrafenib 150 mg twice per day and trametinib 2 mg per day continuously until disease progression or intolerable toxicity. The primary end point was centrally assessed objective response rate (ORR); secondary end points included progression-free survival (PFS), 6-month PFS, and overall survival.

RESULTS: Thirty-five patients were enrolled, and 29 were included in the primary efficacy analysis as prespecified in the protocol. Median age was 59 years, and 45% of the patients had received ≥ 3 lines of therapy. The confirmed ORR was 38% (90% CI, 22.9% to 54.9%) with P < .0001 against a null rate of 5%, and PFS was 11.4 months (90% CI, 8.4 to 16.3 months); responses were seen in 7 distinct tumor types. Seven patients had a duration of response of > 12 months, including 4 patients with a duration of response of > 24 months. An additional 8 patients had a PFS > 6 months. The median overall survival was 28.6 months. Reported adverse events were comparable to those noted in previously reported profiles of dabrafenib and trametinib.

CONCLUSION: This study met its primary end point, with an ORR of 38% (P < .0001) in this mixed histology, pretreated cohort. This promising activity warrants additional investigations in BRAF^V600-mutated tumors outside of currently approved indications.

Author List

Salama AKS, Li S, Macrae ER, Park JI, Mitchell EP, Zwiebel JA, Chen HX, Gray RJ, McShane LM, Rubinstein LV, Patton D, Williams PM, Hamilton SR, Armstrong DK, Conley BA, Arteaga CL, Harris LN, O'Dwyer PJ, Chen AP, Flaherty KT

Author

Jong-In Park PhD Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols
Clinical Trials, Phase II as Topic
Female
Humans
Imidazoles
MAP Kinase Kinase 1
MAP Kinase Kinase 2
Male
Middle Aged
Mutation
Neoplasms
Oximes
Proto-Oncogene Proteins B-raf
Pyridones
Pyrimidinones
Young Adult