Hochster H S, Uboha N, Messersmith W, Gold P J, ONeil B H, Cohen D, Denlinger C, Cohen S, Leichman C G, Leichman L, Lenz H-J
Yale Cancer Center, 333 Cedar Street, New Haven, CT, 06520, USA,
Cancer Chemother Pharmacol. 2015 Jan;75(1):17-23. doi: 10.1007/s00280-014-2609-3. Epub 2014 Oct 17.
More than half of colorectal tumors harbor activating mutations in RAS/RAF proteins. Selumetinib (AZD6244, ARRY-142886) is a small molecule kinase inhibitor targeting MEK kinase, downstream of RAS. We examined the efficacy and safety of selumetinib with irinotecan in second-line therapy.
Patients with K-RAS mutated colorectal cancer, progressing on first-line oxaliplatin-based chemotherapy with bevacizumab, were eligible for this multicenter open-label phase I/II trial. In part A, a dose was determined using a standard "3 + 3" design; in part B, efficacy was determined. The primary endpoint was RECIST response rate. Historical data for irinotecan were used as reference. Secondary endpoints included progression-free survival and overall survival.
Thirty-two patients entered the study, and 31 were treated. All had K-RAS exon 2 mutated tumors. In phase I, the recommended oral dose of selumetinib was 75 mg twice per day with intravenous (IV) irinotecan, 180 mg/m² every 2 weeks. Three patients (9.7 %) had partial response . Sixteen patients (51.6 %) had stable disease for ≥4 weeks, including three >1 year. The most common grade 3 adverse events included diarrhea, neutropenia, fatigue, anemia, nausea, and dehydration. The study was terminated before a pre-planned accrual of 45 subjects.
Despite termination before full accrual, the point estimates of RR and median PFS show promising results, suggesting that further investigations of MEK inhibition in the treatment of metastatic colorectal cancer are warranted. Studies combining MEK inhibitors with cytotoxics or other targeted agents may lead to improved clinical activity based on the emerging preclinical data.
超过半数的结直肠肿瘤在RAS/RAF蛋白中存在激活突变。司美替尼（AZD6244，ARRY - 142886）是一种靶向RAS下游MEK激酶的小分子激酶抑制剂。我们研究了司美替尼联合伊立替康用于二线治疗的疗效和安全性。
K - RAS突变的结直肠癌患者，一线接受含奥沙利铂及贝伐单抗的化疗后病情进展，符合本多中心开放标签I/II期试验的条件。A部分采用标准的“3 + 3”设计确定剂量；B部分确定疗效。主要终点为RECIST缓解率。以伊立替康的历史数据作为对照。次要终点包括无进展生存期和总生存期。
32例患者入组研究，31例接受治疗。所有患者肿瘤均为K - RAS外显子2突变。在I期，司美替尼的推荐口服剂量为每日两次，每次75 mg，联合静脉注射（IV）伊立替康，每2周180 mg/m²。3例患者（9.7%）出现部分缓解。16例患者（51.6%）病情稳定≥4周，其中3例超过1年。最常见的3级不良事件包括腹泻、中性粒细胞减少、疲劳、贫血、恶心和脱水。该研究在预先计划的45例受试者入组前终止。
尽管在完全入组前终止，但缓解率（RR）和中位无进展生存期（PFS）的点估计显示出有前景的结果，提示有必要进一步研究MEK抑制在转移性结直肠癌治疗中的作用。基于新出现的临床前数据，将MEK抑制剂与细胞毒性药物或其他靶向药物联合的研究可能会提高临床活性。
