Keith T. Flaherty
基思·弗拉赫蒂
MD
Director, Termeer Center for Targeted Therapy; Director, Cancer Clinical Discovery; Professor of Medicine, Harvard Medical School靶向治疗中心主任，哈佛医学院医学教授
👥Biography 个人简介
Keith T. Flaherty, MD is Director of the Termeer Center for Targeted Therapy at Massachusetts General Hospital and a Professor of Medicine at Harvard Medical School, widely recognized as the architect of BRAF-targeted therapy in melanoma. He led the pivotal BRIM-3 phase III trial of vemurafenib (the first selective BRAF inhibitor) that demonstrated a 63% response rate and significant overall survival benefit in BRAF V600E-mutant metastatic melanoma, establishing targeted therapy as a cornerstone of treatment and earning FDA approval in 2011. He subsequently led the coBRIM and coBRIM extension trials evaluating vemurafenib combined with cobimetinib (MEK inhibitor), further improving outcomes by delaying resistance. As principal investigator of the landmark NCI-MATCH (Molecular Analysis for Therapy Choice) trial, Dr. Flaherty has been instrumental in advancing the national precision oncology infrastructure that matches patients to targeted agents based on tumor molecular alterations across cancer types.
🧪Research Fields 研究领域
🎓Key Contributions 主要贡献
BRIM-3: Vemurafenib as First BRAF Inhibitor for Melanoma
Led the BRIM-3 phase III randomized trial demonstrating that vemurafenib produced a 48% reduction in risk of death versus dacarbazine in BRAF V600E-mutant metastatic melanoma, achieving FDA approval in 2011 and fundamentally transforming the therapeutic landscape for the roughly 50% of melanoma patients harboring BRAF V600E mutations.
BRAF + MEK Combination Therapy Development
Directed clinical development of combined BRAF and MEK inhibition (vemurafenib + cobimetinib; coBRIM trial), demonstrating improved progression-free and overall survival compared with vemurafenib alone and reduced paradoxical MAPK activation-driven toxicities, establishing combination targeted therapy as the standard approach.
NCI-MATCH Precision Oncology Platform
Serves as study chair of the NCI-MATCH (Molecular Analysis for Therapy Choice) trial—the nation's largest precision oncology basket study—enrolling thousands of patients with refractory solid tumors for molecular profiling and assignment to 30+ targeted treatment arms, generating critical evidence for biomarker-drug pairings across tumor types.
Mechanisms of BRAF Inhibitor Resistance and Adaptive Responses
Elucidated early adaptive resistance mechanisms to BRAF inhibition including MAPK reactivation via BRAF amplification, splice variant emergence, NRAS mutations, and MEK1/2 mutations, providing the mechanistic rationale for combination BRAF/MEK blockade to delay acquired resistance.
Representative Works 代表性著作
Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation
New England Journal of Medicine (2011)
BRIM-3 phase III trial demonstrating significantly improved overall and progression-free survival with vemurafenib versus dacarbazine in BRAF V600E-mutant metastatic melanoma, establishing the first targeted therapy for this disease.
Cobimetinib Combined with Vemurafenib in Advanced BRAF V600-Mutant Melanoma (coBRIM)
New England Journal of Medicine (2014)
Phase III coBRIM trial showing that adding cobimetinib to vemurafenib significantly improved median PFS from 6.2 to 9.9 months and improved OS in BRAF-mutant melanoma.
Inhibition of Mutated, Activated BRAF in Metastatic Melanoma
New England Journal of Medicine (2010)
Landmark phase I BRIM-1 trial of vemurafenib establishing proof-of-concept for BRAF V600E inhibition with an 81% rate of tumor regression in BRAF-mutant melanoma.
Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma
Cancer Cell (2016)
Identified tumor mutational burden, neoantigen load, and IFN-γ gene expression signatures as predictors of response to pembrolizumab in metastatic melanoma, informing biomarker strategies for immunotherapy.
🏆Awards & Recognition 奖项与荣誉
📄Data Sources 数据来源
Last updated: 2026-04-06 | All information from publicly available academic sources
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