[ESMO2016]MEK抑制剂无效，KRAS突变仍是NSCLC的治疗壁垒

写在前面：对于KRAS突变来说，始终是NSCLC的一个瓶颈部分，以下部分是ESMO2016的一些信息进展，摘要原文和翻译内容。

信息来源：http://news.medlive.cn/cancer/info-progress/show-119863_53.html

2016 ESMO大会上，靶向治疗KRAS突变型非小细胞肺癌（NSCLC）的Ⅲ期临床试验SELECT-1报告失败，MEK抑制剂selumetinib联合多西他赛未能增加患者的无进展生存期和总生存期。

主要研究者，美国丹娜法伯癌症研究所的Pasi J?nne教授说：“KRAS突变型肺癌在驱动基因亚型中所占的比重最大，但至今无有效的靶向治疗。”

selumetinib是一种口服、强效、选择性MEK抑制剂，理论上可通过调控Ras-Raf-MEK-ERK通路中关键蛋白激酶MEK水平来抑制KARS突变型肿瘤的生长。在之前的Ⅱ期临床研究中，与多西他赛单药相比，selumetinib联合多西他赛使KRAS突变型NSCLC患者的无进展生存（PFS）和客观缓解率（ORR）得到明显提升。
随后进行的随机、双盲、Ⅲ期临床试验SELECT-1共纳入510例KRAS突变NSCLC患者，随机进入口服selumetinib（75mg/BID）+多西他赛（75mg/m2）治疗或安慰剂+多西他赛治疗。

遗憾的是，数据截止时，selumetinib+多西他赛组和多西他赛单药组的中位PFS（3.9 vs 2.8个月, p=0.44）没有显著差别，中位OS（8.7 vs 7.9个月, p=0.64）也无明显差别。与多西他赛单药组相比，selumetinib联合治疗组的客观缓解率有更高的趋势（20.1% vs 13.7%，p=0.051）。

Selumetinib联合多西他赛治疗组的严重不良事件发生率较多西他赛单药组更高（49% vs 32%），前者的不良事件住院率也高于后者（46% vs 30%）。

J?nne教授说：“Ⅲ期试验结果表明，就改善PFS或OS而言，selumetinib联合多西他赛治疗并不能使KRAS突变型晚期肺癌患者获益。因此，无需进一步发展这种治疗方式了，但对于这种突变亚型的患者，发展其他新的治疗方法是一项迫切的需求，仍然还有机会。”

美国梅奥诊所的Alex Adjei博士评价这个研究说：“应该祝贺J?nne博士及其同事实施了一项设计巧妙的驱动基因临床治疗试验。然而，这种联合用药的所依赖的临床前理论较为薄弱，特别还是在KRAS突变型NSCLC中。Selumetinib和其他MEK抑制剂在KRAS突变型NSCLC细胞系中的有效性就不高，但临床前的数据显示在多瘤种中（包括NSCLC），MEK抑制剂联合多西他赛可有细胞毒协同作用，而这种作用独立于KRAS状态。”

Adjei博士总结道：“另一种MEK抑制剂trametinib联合多西他赛的Ⅱ期随机临床试验显示， KRAS突变型和野生型NSCLC患者之间并未出现疗效差异。另外，该Ⅱ期试验样本量小，这样的Ⅱ期研究当然造成Ⅲ期试验为阴性结果。”

Abstract：LBA47
Title：Selumetinib in combination with docetaxel as second-line treatment for patients with KRAS-mutant advanced NSCLC: Results from the phase III SELECT-1 trial

Background: KRAS-mutant (KRASm) NSCLC is the largest molecular genomic NSCLC subset. Selumetinib (SEL; AZD6244, ARRY-142886) is an oral, potent and selective MEK1/2 inhibitor with a short half-life. In a Phase II KRASm advanced NSCLC trial (n=87), 2L SEL + docetaxel (DOC) significantly improved PFS (median 5.3 vs 2.1 mo) and ORR (37 vs 0%), and numerically improved OS (median 9.4 vs 5.2 mo; primary endpoint) compared with DOC. SELECT-1 (NCT01933932), a Phase III, double-blind, randomised trial aimed to confirm the clinical benefit of SEL + DOC for pts with locally advanced or metastatic KRASm NSCLC.

Methods: Enrolment completed in January 2016 with 3323 pts screened at 202 sites in 25 countries. 510 pts with a centrally confirmed KRAS mutation (cobas? KRAS Mutation Test, Roche Molecular Systems) were randomised 1:1 to SEL 75 mg BID, PO + DOC 75 mg/m2 IV on day 1 of every 21-day cycle (n=254), or placebo (PBO) + DOC (n=256); pts also received prophylactic G-CSF. Primary objective was PFS by investigator assessment (RECIST 1.1). Secondary objectives included OS, ORR (RECIST 1.1) and safety and tolerability. The trial was powered to characterise differences in both PFS and OS.

Results: At data cut-off, 447 pts (88%) had progressed; 346 pts (68%) had died. Median PFS was 3.9 mo with SEL + DOC and 2.8 mo with PBO + DOC; HR for PFS was 0.93 (95% CI 0.77, 1.12; 2-sided p=0.44). Median OS was 8.7 mo with SEL + DOC and 7.9 mo with PBO + DOC (HR 1.05, 95% CI: 0.85, 1.30; 2-sided p=0.64). ORR was 20.1% with SEL + DOC and 13.7% with PBO + DOC (odds ratio: 1.61; 95% CI: 1.00, 2.62; 2-sided p=0.051). AEs (all causality) were reported by 99% and 95% pts in the SEL + DOC and PBO + DOC groups, respectively; ≥G3 AEs were more frequent in the SEL + DOC group (67 vs 45% pts). SAEs (49 vs 32%) and AEs leading to hospitalisation (46 vs 30%) were also more frequent in the SEL + DOC group than the PBO + DOC group. Mean (SD) actual dose intensity relative to intended dose intensity of DOC over 6 cycles was similar between groups: 86.7% (15.90) with SEL+DOC and 90.3% (15.01) with PBO + DOC.

Conclusions: SELECT-1 was the first prospective Phase III trial in KRASm NSCLC. SEL + DOC did not significantly improve PFS, OS or ORR vs PBO + DOC. The safety profile was consistent with historical data.