Biomarker and Tumor Responses of Oral Cavity Squamous Cell Carcinoma to Trametinib: A Phase II Neoadjuvant Window-of-Opportunity Clinical Trial.
Biomarker and Tumor Responses of Oral Cavity Squamous Cell Carcinoma to Trametinib: A Phase II Neoadjuvant Window-of-Opportunity Clinical Trial.
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DOI：
10.1158/1078-0432.ccr-16-1469
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发表时间：
2017-05-01
期刊：
影响因子：
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通讯作者：
Adkins DR
中科院分区：
文献类型：
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作者：
Uppaluri R;Winkler AE;Lin T;Law JH;Haughey BH;Nussenbaum B;Paniello RC;Rich JT;Diaz JA;Michel LP;Wildes T;Dunn GP;Zolkind P;Kallogjeri D;Piccirillo JF;Dehdashti F;Siegel BA;Chernock RD;Lewis JS Jr;Adkins DR
Ras/MEK/ERK信号通路的激活在口腔鳞状细胞癌（oral cavity squamous cell carcinoma，OCSCC）中很常见。我们进行了一项新辅助（术前）试验，以确定OCSCC对曲美替尼MEK抑制的生物标志物和肿瘤反应。II-IV期OCSCC患者在手术前接受曲美替尼（2 mg/天，至少7天）。在曲美替尼治疗前后采集原发性肿瘤标本，以评价p-ERK 1/2和CD 44的免疫组织化学染色（主要终点）。次要终点包括临床肿瘤测量值和代谢活性（通过F-18氟脱氧葡萄糖正电子发射断层扫描/计算机断层扫描获得的最大标准化摄取值[SUVmax]）以及肿瘤降级的变化。评价了药物相关不良事件（AE）和手术/伤口并发症。在20例入组患者中，17例（85%）完成了研究。3例患者因曲美替尼相关（n=2：恶心、十二指肠穿孔）或不相关（n=1：便秘）AE退出研究。最常见的AE为皮疹（9/20例患者，45%）。17名患者接受了手术。未发生非预期手术/伤口并发症。这些患者中有15例（88%）可获得可评价的曲美替尼治疗前后匹配标本。分别有5例（33%）和2例（13%）患者p-ERK 1/2和CD 44表达降低。在17例可评价患者中的11例（65%）中观察到根据修订的世界卫生组织标准的临床肿瘤缓解（中位数降低46%，范围14 - 74%）。在13例可评价患者中的6例（46%）中观察到部分代谢缓解（SUVmax降低≥25%）（中位降低25%，范围6 - 52%）。9/17例（53%）可评价患者发生临床-病理肿瘤降级。曲美替尼导致Ras/MEK/ERK通路活化以及OCSCC患者的临床和代谢肿瘤应答显著降低。
Ras/MEK/ERK pathway activation is common in oral cavity squamous cell carcinoma (OCSCC). We performed a neoadjuvant (pre-operative) trial to determine biomarker and tumor response of OCSCC to MEK inhibition with trametinib. Patients with Stage II–IV OCSCC received trametinib (2 mg/day, minimum 7 days) prior to surgery. Primary tumor specimens were obtained before and after trametinib to evaluate immunohistochemistry staining for p-ERK1/2 and CD44, the primary endpoint. Secondary endpoints included changes in clinical tumor measurements and metabolic activity (maximum Standardized Uptake Values [SUVmax] by F-18 fluorodeoxyglucose positron emission tomography/computed tomography), and in tumor downstaging. Drug-related adverse events (AEs) and surgical/wound complications were evaluated. Of 20 enrolled patients, 17 (85%) completed the study. Three patients withdrew because of either trametinib-related (n=2:nausea, duodenal perforation) or unrelated (n=1:constipation) AEs. The most common AE was rash (9/20 patients, 45%). Seventeen patients underwent surgery. No unexpected surgical/wound complications occurred. Evaluable matched pre- and post-trametinib specimens were available in 15 (88%) of these patients. Reduction in p-ERK1/2 and CD44 expression occurred in 5 (33%) and 2 (13%) patients, respectively. Clinical tumor response by modified World Health Organization criteria was observed in 11 of 17 (65%) evaluable patients (median 46% decrease, range 14 to 74%). Partial metabolic response (≥25% reduction in SUVmax) was observed in 6 of 13 (46%) evaluable patients (median 25% decrease, range 6 to 52%). Clinical-to-pathologic tumor downstaging occurred in 9 of 17 (53%) evaluable patients. Trametinib resulted in significant reduction in Ras/MEK/ERK pathway activation and in clinical and metabolic tumor responses in OCSCC patients.