Department of Pulmonary Diseases and GROW- School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
Clin Cancer Res. 2013 Feb 1;19(3):743-51. doi: 10.1158/1078-0432.CCR-12-1779. Epub 2012 Dec 6.
Sorafenib inhibits the Ras/Raf pathway, which is overactive in cancer patients with a KRAS mutation. We hypothesized that patients with non-small cell lung cancer (NSCLC) with KRAS mutation will benefit from treatment with sorafenib.
In this phase II study, patients with KRAS-mutated, stage IIIb or IV NSCLC that progressed after at least one platinum-containing regimen were treated with sorafenib. Treatment consisted of sorafenib 400 mg twice daily until disease progression or unacceptable toxicity. Pretreatment serum from each patient was obtained to predict outcome using a proteomic assay (VeriStrat). Primary endpoint was disease control rate (DCR) at 6 weeks.
Fifty-nine patients were entered between May 2010 and February 2011. Fifty-seven patients started sorafenib. Mean age was 58.5 (SD = ±8.1) years, 16 male/41 female, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0/1/2 24/30/3. At 6 weeks, 5 partial response, 25 stable disease, and 27 progressive disease were observed; DCR was 52.6%. Median duration of treatment was 9 weeks. The median progression-free survival (PFS) was 2.3 months and median overall survival (OS) was 5.3 months. Patients with a prediction of good prognosis according to VeriStrat serum proteomics assay showed a significantly superior PFS [HR, 1.4; 95% confidence interval (CI), 1.0-1.9] but not OS (HR, 1.3; 95% CI, 0.9-1.7). Sorafenib-related grade III/IV toxicity was reported in 10 patients (17.5%); all but one patient experienced grade III skin toxicity (14.0%) or grade III gastrointestinal toxicity (8.8%).
Treatment with sorafenib has relevant clinical activity in patients with NSCLC harboring KRAS mutations. Further randomized study with this agent is warranted as single-agent or combination therapy.
索拉非尼抑制 Ras/Raf 通路，该通路在具有 KRAS 突变的癌症患者中过度活跃。我们假设具有 KRAS 突变的非小细胞肺癌（NSCLC）患者将从索拉非尼治疗中获益。
在这项 II 期研究中，至少接受过一种含铂方案治疗后进展的 KRAS 突变、IIIb 期或 IV 期 NSCLC 患者接受索拉非尼治疗。治疗包括索拉非尼 400mg，每日两次，直到疾病进展或出现不可接受的毒性。每位患者在治疗前采集血清，使用蛋白质组学检测（VeriStrat）预测疗效。主要终点为 6 周时的疾病控制率（DCR）。
2010 年 5 月至 2011 年 2 月期间，共入组 59 例患者。57 例患者开始服用索拉非尼。患者平均年龄为 58.5（标准差=±8.1）岁，16 例男性/41 例女性，东部肿瘤协作组（ECOG）体能状态（PS）0/1/2 分别为 24/30/3。6 周时，5 例部分缓解，25 例疾病稳定，27 例疾病进展，DCR 为 52.6%。中位治疗持续时间为 9 周。中位无进展生存期（PFS）为 2.3 个月，中位总生存期（OS）为 5.3 个月。根据 VeriStrat 血清蛋白质组学检测预测预后良好的患者 PFS 显著更长[风险比（HR），1.4；95%置信区间（CI），1.0-1.9]，但 OS 无差异（HR，1.3；95%CI，0.9-1.7）。10 例（17.5%）患者报告了与索拉非尼相关的 3/4 级毒性；除 1 例患者外，其余患者均发生了 3 级皮肤毒性（14.0%）或 3 级胃肠道毒性（8.8%）。
索拉非尼在携带 KRAS 突变的 NSCLC 患者中具有显著的临床活性。作为单药或联合治疗，该药物的进一步随机研究是合理的。
