Department of Gastroenterology, Erasme University Hospital, CP 572/10, route de Lennik 808, 1070, Brussels, Belgium.
Medical Department, Division of Hematology, Oncology and Tumor Immunology, Charity Hospital, Virchow-Klinikum Campus, Augustenburger Platz 1, 13353, Berlin, Germany.
Target Oncol. 2017 Feb;12(1):97-109. doi: 10.1007/s11523-016-0469-y.
Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently inhibits MEK1/2, part of the MAPK signaling pathway. This phase I/II study evaluated the safety and efficacy of refametinib plus gemcitabine in patients with advanced pancreatic cancer.
Phase I comprised dose escalation, followed by phase II expansion. Refametinib and gemcitabine plasma levels were analyzed for pharmacokinetics. KRAS mutational status was determined from circulating tumor DNA.
Ninety patients overall received treatment. The maximum tolerated dose was refametinib 50 mg twice daily plus standard gemcitabine (1000 mg/m weekly). The combination was well tolerated, with no pharmacokinetic interaction. Treatment-emergent toxicities included thrombocytopenia, fatigue, anemia, and edema. The objective response rate was 23% and the disease control rate was 73%. Overall response rate, disease control rate, progression-free survival, and overall survival were higher in patients without detectable KRAS mutations (48% vs. 28%, 81% vs. 69%, 8.8 vs. 5.3 months, and 18.2 vs. 6.6 months, respectively).
Refametinib plus gemcitabine was well tolerated, with a promising objective response rate, and had an acceptable safety profile and no pharmacokinetic interaction. There was a trend towards improved outcomes in patients without detectable KRAS mutations that deserves future investigation.
高达 90%的胰腺癌患者存在 KRAS 突变。Refametinib 能够强力抑制 MEK1/2，即 MAPK 信号通路的一部分。这项 I/II 期研究评估了 refametinib 联合吉西他滨治疗晚期胰腺癌患者的安全性和疗效。
I 期研究包括剂量递增，随后是 II 期扩展。分析了 refametinib 和吉西他滨的药代动力学血浆水平。循环肿瘤 DNA 用于确定 KRAS 突变状态。
共有 90 名患者接受了治疗。最大耐受剂量为 refametinib 50mg 每日两次联合标准吉西他滨（1000mg/m 每周）。该联合方案耐受性良好，无药代动力学相互作用。治疗相关毒性包括血小板减少、疲劳、贫血和水肿。客观缓解率为 23%，疾病控制率为 73%。无检测到 KRAS 突变的患者的总体缓解率、疾病控制率、无进展生存期和总生存期更高（48% vs. 28%、81% vs. 69%、8.8 个月 vs. 5.3 个月和 18.2 个月 vs. 6.6 个月）。
Refametinib 联合吉西他滨耐受性良好，客观缓解率有希望，安全性特征可接受，无药代动力学相互作用。在未检测到 KRAS 突变的患者中，结果有改善的趋势，值得进一步研究。
