Jänne Pasi A, Mann Helen, Ghiorghiu Dana
Lowe Center for Thoracic Oncology and the Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA.
Global Medicines Development, AstraZeneca, Macclesfield, UK.
Clin Lung Cancer. 2016 Mar;17(2):e1-4. doi: 10.1016/j.cllc.2015.12.010. Epub 2015 Dec 30.
Oncogenic KRAS mutations represent the largest genomically defined subset of lung cancer, and are associated with activation of the RAS/RAF/MEK/ERK pathway. There are currently no therapies specifically approved for patients with KRAS-mutant (KRASm) non-small-cell lung cancer (NSCLC), and these patients derive less clinical benefit from chemotherapy than the overall NSCLC population. In a recent phase II study, selumetinib (AZD6244, ARRY-142886), an oral, potent and selective, allosteric MEK1/2 inhibitor with a short half-life, combined with docetaxel, improved clinical outcome as second-line treatment for patients with KRASm NSCLC. This combination will be further evaluated in the phase III SELECT-1 study.
SELECT-1 (NCT01933932) is a randomized, double-blind, placebo-controlled phase III study assessing the efficacy and safety of selumetinib plus docetaxel in patients with KRASm locally advanced or metastatic NSCLC, eligible for second-line treatment. The primary endpoint is progression-free survival (PFS); secondary endpoints include overall survival, objective response rate, duration of response, and safety and tolerability. Approximately 634 patients will be randomized 1:1 to receive selumetinib (75 mg twice daily on a continuous oral administration schedule) in combination with docetaxel (75 mg/m(2), intravenously on day 1 of every 21-day cycle) or placebo in combination with docetaxel (same schedule), until objective disease progression. Patients may continue to receive treatment after objective disease progression if deemed appropriate by the investigator.
If the primary endpoint of PFS is met, selumetinib plus docetaxel would be the first targeted treatment for patients with KRASm advanced NSCLC who are eligible for second-line treatment.
致癌性KRAS突变是肺癌中基因组定义最大的亚组，与RAS/RAF/MEK/ERK通路的激活相关。目前尚无专门批准用于KRAS突变（KRASm）非小细胞肺癌（NSCLC）患者的治疗方法，并且这些患者从化疗中获得的临床益处低于总体NSCLC人群。在最近一项II期研究中，塞鲁替尼（AZD6244，ARRY-142886），一种口服、强效且选择性的变构MEK1/2抑制剂，半衰期短，与多西他赛联合使用，作为KRASm NSCLC患者的二线治疗改善了临床结局。这种联合用药将在III期SELECT-1研究中进一步评估。
SELECT-1（NCT01933932）是一项随机、双盲、安慰剂对照的III期研究，评估塞鲁替尼联合多西他赛用于适合二线治疗的KRASm局部晚期或转移性NSCLC患者的疗效和安全性。主要终点是无进展生存期（PFS）；次要终点包括总生存期、客观缓解率、缓解持续时间以及安全性和耐受性。约634例患者将按1:1随机分组，接受塞鲁替尼（连续口服给药方案，每日两次，每次75 mg）联合多西他赛（75 mg/m²，每21天周期的第1天静脉注射）或安慰剂联合多西他赛（相同给药方案），直至出现客观疾病进展。如果研究者认为合适，患者在出现客观疾病进展后可继续接受治疗。
如果达到PFS这一主要终点，塞鲁替尼联合多西他赛将成为适合二线治疗的KRASm晚期NSCLC患者的首个靶向治疗方案。
