Combined BRAF, EGFR, and MEK Inhibition in Patients with &ITBRAF&ITV600E-Mutant Colorectal Cancer

被引：467

作者：

Corcoran, Ryan B. ^{[1
,2
]}

Andre, Thierry ^{[3
,4
]}

Atreya, Chloe E. ^{[5
]}

Schellens, Jan H. M. ^{[6
]}

Yoshino, Takayuki ^{[7
]}

Bendell, Johanna C. ^{[8
]}

Hollebecque, Antoine ^{[9
]}

McRee, Autumn J. ^{[10
]}

Siena, Salvatore ^{[11
,12
]}

Middleton, Gary ^{[13
,14
]}

Muro, Kei ^{[15
]}

Gordon, Michael S. ^{[16
]}

Tabernero, Josep ^{[17
]}

Yaeger, Rona ^{[18
]}

O'Dwyer, Peter J. ^{[19
]}

Humblet, Yves ^{[20
]}

De Vos, Filip ^{[21
]}

Jung, A. Scott ^{[22
]}

Brase, Jan C. ^{[23
]}

Jaeger, Savina ^{[24
]}

Bettinger, Severine ^{[23
]}

Mookerjee, Bijoyesh ^{[25
]}

Rangwala, Fatima ^{[25
]}

Van Cutsem, Eric ^{[26
,27
]}

机构：

[1] Harvard Med Sch, Massachusetts Gen Hosp, Canc Ctr, Boston, MA 02129 USA

[2] Harvard Med Sch, Dept Med, Boston, MA 02129 USA

[3] Hop St Antoine, Paris, France

[4] Sorbonne Univ, Paris, France

[5] Univ Calif San Francisco, San Francisco, CA 94143 USA

[6] Netherlands Canc Inst, Amsterdam, Netherlands

[7] Natl Canc Ctr Hosp East, Chiba, Japan

[8] Sarah Cannon Res Inst Tennessee Oncol, Nashville, TN USA

[9] Inst Gustave Roussy, Villejuif, France

[10] Univ N Carolina, Chapel Hill, NC USA

[11] Univ Milan, Grande Osoped Metropolitano Niguarda, Niguarda Canc Ctr, Milan, Italy

[12] Univ Milan, Dept Oncol & Hematooncoll, Milan, Italy

[13] Univ Birmingham, Birmingham, W Midlands, England

[14] Univ Hosp, Birmingham, W Midlands, England

[15] Aichi Canc Ctr Hosp, Nagoya, Aichi, Japan

[16] Pinnacle Oncol Hematol, Scottsdale, AZ USA

[17] Vall dHebron Univ Hosp, Barcelona, Spain

[18] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA

[19] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA

[20] St Luc Univ Hosp, Brussels, Belgium

[21] Univ Med Ctr Utrecht, Dept Med Oncol, Utrecht, Netherlands

[22] Amgen Inc, Thousand Oaks, CA USA

[23] Novartis Pharma AG, Basel, Switzerland

[24] Novartis Inst Biomed Res, Cambridge, MA USA

[25] Novartis Pharmaceut, E Hanover, NJ USA

[26] Univ Hosp Leuven, Leuven, Belgium

[27] Katholieke Univ Leuven, Leuven, Belgium

来源：

CANCER DISCOVERY | 2018年 / 8卷 / 04期

关键词：

ACQUIRED-RESISTANCE; MICROSATELLITE INSTABILITY; RAF INHIBITORS; TARGETED THERAPY; POOLED ANALYSIS; MAPK PATHWAY; COLON-CANCER; OPEN-LABEL; DABRAFENIB; MUTATIONS;

D O I：

10.1158/2159-8290.CD-17-1226

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Although BRAF inhibitor monotherapy yields response rates > 50% in BRAF(V600)-mutant melanoma, only approximately 5% of patients with BRAF(V600E) colorectal cancer respond. Preclinical studies suggest that the lack of efficacy in BRAF(V600E) colorectal cancer is due to adaptive feedback reactivation of MAPK signaling, often mediated by EGFR. This clinical trial evaluated BRAF and EGFR inhibition with dabrafenib (D) + panitumumab (P) +/- MEK inhibition with trametinib (T) to achieve greater MAPK suppression and improved efficacy in 142 patients with BRAF(V600E) colorectal cancer. Confirmed response rates for D+P, D+T+P, and T+P were 10%, 21%, and 0%, respectively. Pharmacodynamic analysis of paired pretreatment and on-treatment biopsies found that efficacy of D+T+P correlated with increased MAPK suppression. Serial cell-free DNA analysis revealed additional correlates of response and emergence of KRAS and NRAS mutations on disease progression. Thus, targeting adaptive feedback pathways in BRAF(V600E) colorectal cancer can improve efficacy, but MAPK reactivation remains an important primary and acquired resistance mechanism. SIGNIFICANCE: This trial demonstrates that combined BRAF + EGFR +MEK inhibition is tolerable, with promising activity in patients with BRAF(V600E) colorectal cancer. Our findings highlight the MAPK pathway as a critical target in BRAF(V600E) colorectal cancer and the need to optimize strategies inhibiting this pathway to overcome both primary and acquired resistance. (C) 2018 AACR.

引用

页码：428 / 443

页数：16

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