vemurafenib组合与伊立替康和西妥昔单抗的患者的阶段1B研究BRAF -mutated晚期癌症和转移性结肠直肠癌。
背景： BRAF V600突变，存在于转移性结直肠癌（转移性结直肠癌）的病人（PTS）5-10％，被认为是预后不良的标志，和<10％的BRAF -mutated转移性结直肠癌点西妥昔单抗的结合反应（C）和伊立替康（一）。Vemurafenib（五），口服激酶抑制剂BRAF基因的突变V600亚型，表现出5％的响应率在I期临床试验有BRAF基因 -mutated转移性结直肠癌。在大肠癌细胞系体外实验的结果显示突变的BRAF由vemurafenib是阻断表皮生长因子受体触发的代偿激活。表皮生长因子受体结合vemurafenib导致在临床前模型中的协同细胞毒性的抑制，通过伊立替康进一步增强。组合的点的安全性和有效性的BRAF -mutated晚期恶性肿瘤尚未研究。方法： 在这个3 +3 I期研究分，分难治的BRAF收到升级结合剂vemurafenib的西妥昔单抗与伊立替康在-mutated癌症14天为一周期。通过RECIST 1.1影像学反应进行了评估，每4个周期。不良事件（AE）是由CTCAE 4.0评估。结果： 通过二千零十四分之一，10分都被录取：7剂量水平1（DL）（V-480mg PO BID，C-250毫克/ m2每周和I-180毫克/ m2，每14天）和三个在DL 2（提高到V-PO为720mg BID）。一个剂量限制性毒性，观察到DL1（3级关节痛），并解决了与减少剂量。最常见的不良反应为皮疹，恶心，腹泻等。在DL 1治疗6个评价患者中，5例转移性结直肠癌，1例阑尾腺癌。四转移性结直肠癌5例（80％）获得了部分缓解。为5的mCRC点，中位数最好的反应是减少了44％（范围为0％-70％）为5，5 +，8 +，12 +和14 +个循环的反应时间。阑尾癌PT疾病进展。PK和PD的分析计划。结论： vemurafenib的结合与伊立替康和西妥昔单抗似乎耐受性良好，在点与BRAF -mutated转移性结直肠癌。即使是低剂量的vemurafenib，永久居民则见于4分评价的转移性结直肠癌点在第一队列。附加分继续在vemurafenib的高剂量水平进行注册。一名美国协作组随机的BRAF基因突变的转移性结直肠癌（SWOG1406）这个组合的II期试验计划。临床试验信息：NCT01787500。
Background: BRAF V600 mutations, present in 5-10% of patients (pts) with metastatic colorectal cancer (mCRC), are considered poor prognostic markers, and <10% of BRAF-mutated mCRC pts respond to a combination of cetuximab (C) and irinotecan (I). Vemurafenib (V), an oral kinase inhibitor to the mutated V600 isoform of BRAF, demonstrated a 5% response rate in a phase I trial with BRAF-mutated mCRC. In vitro data in CRC cell lines has shown that blockade of mutated BRAF by vemurafenib triggers compensatory activation of EGFR. Inhibition of EGFR combined with vemurafenib results in synergistic cytotoxicity in preclinical models, further augmented by irinotecan. The safety and efficacy of the combination in pts with BRAF-mutated advanced malignancies have not been studied. Methods: In this 3+3 phase I study, pts with refractory BRAF-mutated cancer received escalating doses of vemurafenib in combination with cetuximab and irinotecan over a 14-day cycle. Radiographic responses were evaluated every 4 cycles by RECIST 1.1. Adverse events (AEs) were assessed by CTCAE 4.0. Results: Through 1/2014, 10 pts have been enrolled: 7 at dose level 1(DL) (V- 480mg PO BID, C-250 mg/m2 weekly and I- 180mg/m2 every 14 days) and three at DL 2 (increased to V-720mg PO BID). One dose-limiting toxicity was observed at DL1 (grade 3 arthralgia) and resolved with dose reduction. The most common AEs were rash, nausea, and diarrhea. Of the 6 evaluable pts treated at DL 1, 5 had mCRC and 1 had appendiceal adenocarcinoma. Four of the 5 mCRC pts (80%) achieved a partial response. For the 5 mCRC pts, median best response was a reduction of -44% (range, 0% to -70%) with duration of responses of 5, 5+, 8+, 12+, and 14+ cycles. The appendiceal carcinoma pt had disease progression. PK and PD analysis is planned. Conclusions: The combination of vemurafenib with irinotecan and cetuximab seems well tolerated in pts with BRAF-mutated mCRC. Even with a low vemurafenib dose, PRs were seen in 4 of 5 evaluable mCRC pts in the first cohort. Additional pts continue to be enrolled at higher dose levels of vemurafenib. A US cooperative group randomized phase II trial of this combination in BRAF-mutated mCRC (SWOG1406) is planned. Clinical trial informatio
http://meetinglibrary.asco.org/content/132589-144
结论： 5例可评价mcrc 4例缩小 中位最好效果缩小44% 并持续 2.5，2.5+ 4+ 6+ 7+ 个月
vemurafenib组合与伊立替康和西妥昔单抗 效果不错.. 并且进一步进行下一期临床试验 http://clinicaltrials.gov/show/NCT01787500
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