Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAF(V600E)-Mutant Colorectal Cancer.
Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAF(V600E)-Mutant Colorectal Cancer.
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DOI：
10.1158/2159-8290.cd-17-1226
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发表时间：
2018-04
期刊：
影响因子：
28.2
通讯作者：
Van Cutsem E
中科院分区：
文献类型：
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作者：
Corcoran RB;André T;Atreya CE;Schellens JHM;Yoshino T;Bendell JC;Hollebecque A;McRee AJ;Siena S;Middleton G;Muro K;Gordon MS;Tabernero J;Yaeger R;O'Dwyer PJ;Humblet Y;De Vos F;Jung AS;Brase JC;Jaeger S;Bettinger S;Mookerjee B;Rangwala F;Van Cutsem E
尽管BRAF抑制剂单药治疗brafv600突变型黑色素瘤的有效率为50%，但BRAFV600E型结直肠癌（CRC）的有效率仅为5%。临床前研究表明，BRAFV600E结直肠癌缺乏疗效是由于MAPK信号的适应性反馈再激活，通常由EGFR介导。该临床试验评估了达非尼(D) +帕尼单抗(P)±MEK抑制曲美替尼(T)对142例BRAFV600E CRC患者的BRAF和EGFR抑制作用，以实现更大的MAPK抑制和改善疗效。D+P、D+T+P和T+P的确诊有效率分别为10%、21%和0%。配对治疗前和治疗中活检的药效学分析发现，D+T+P的疗效与MAPK抑制增加相关。序列无细胞DNA分析揭示了KRAS和NRAS突变对疾病进展的反应和出现的其他相关性。因此，靶向BRAFV600E CRC中的自适应反馈通路可以提高疗效，但MAPK再激活仍然是重要的原发性和获得性耐药机制。
Although BRAF inhibitor monotherapy yields response rates >50% in BRAFV600-mutant melanoma, only ~5% with BRAFV600E colorectal cancer (CRC) respond. Preclinical studies suggest that lack of efficacy in BRAFV600E CRC 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 BRAFV600E CRC. Confirmed response rates for D+P, D+T+P, and T+P were 10%, 21%, and 0%, respectively. Pharmacodynamic analysis of paired pre- 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 BRAFV600E CRC can improve efficacy, but MAPK reactivation remains an important primary and acquired resistance mechanism.