大药编:NEJM重磅: 奥希替尼有望成为下一个EGFR突变进展期非小细胞肺癌的一线靶向药…

目前,非小细胞肺癌中EGFR突变的靶向治疗药物包括吉非替尼、厄洛替尼和奥希替尼(Osimertinib)以及还未在中国上市的耐昔妥珠单抗等等。不久前,著名的《新英格兰医学杂志》在线发表了有关奥希替尼作为EGFR突变进展期非小细胞肺癌一线靶向用药的临床试验(Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer) 。研究结果显示出良好的应用前景。


研究背景奥希替尼是第三代口服、不可逆性EGFR-TKI药物,它可以选择性地抑制EGFR-TKI敏感以及EGFR T790M突变耐药的蛋白。我们在未经治疗的EGFR突变的进展期非小细胞肺癌中,比较了奥希替尼与标准EGFR-TKI的疗效。


BACKGROUND:

Osimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI–sensitizing and EGFR T790M resistance mutations. We compared osimertinib with standard EGFR-TKIs in patients with previously untreated, EGFR mutation–positive advanced non–small-cell lung cancer (NSCLC).


研究方法:在这项3期双盲研究中,我们随机挑选了556名未经治疗的EGFR突变的进展期非小细胞肺癌患者(第19位外显子缺失或L858R突变)。按照1:1将患者分配到奥希替尼治疗组(每日服用80mg)或标准EGFR-TKI治疗组(每日吉非替尼250mg或每日厄洛替尼150mg)。主要研究重点为研究者确定的无进展生存期。


METHODS:

In this double-blind, phase 3 trial, we randomly assigned 556 patients with previously untreated, EGFR mutation–positive (exon 19 deletion or L858R) advanced NSCLC in a 1:1 ratio to receive either osimertinib (at a dose of 80 mg once daily) or a standard EGFR-TKI (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily). The primary end point was investigator-assessed progression-free survival.


研究结果:与标准EGFR-TKI组相比,奥希替尼组具有显著更长的中位无进展生存期(18.9个月vs.10.2个月,HR:0.46,95%CI:0.37-0.57,P<0.001)。两组客观缓解率相似,奥希替尼组为80%,标准EGFR-TKI组76%(优势比1.27,95% CI, 0.85 to 1.90; P=0.24)。中位缓解持续时间奥希替尼组为17.2个月(95% CI, 13.8-22.0),标准EGFR-TKI组为8.5个月(95% CI, 7.3-9.8)。总生存期结果仍未完善。奥希替尼组18个月时的总生存率为83%(95% CI, 78-87),标准EGFR-TKI组为71%(95% CI, 65-76,HR:0.63; 95% CI, 0.45 to 0.88; P=0.007期中分析无显著差异)。奥希替尼组3级及以上不良事件的发生率较标准EGFR-TKI组更低(34% vs. 45%)。


RESULTS:

The median progression-free survival was significantly longer with osimertinib than with standard EGFR-TKIs (18.9 months vs. 10.2 months; hazard ratio for disease progression or death, 0.46; 95% confidence interval [CI], 0.37 to 0.57; P<0.001). The objective response rate was similar in the two groups: 80% with osimertinib and 76% with standard EGFR-TKIs (odds ratio, 1.27; 95% CI, 0.85 to 1.90; P=0.24). The median duration of response was 17.2 months (95% CI, 13.8 to 22.0) with osimertinib versus 8.5 months (95% CI, 7.3 to 9.8) with standard EGFR-TKIs. Data on overall survival were immature at the interim analysis (25% maturity). The survival rate at 18 months was 83% (95% CI, 78 to 87) with osimertinib and 71% (95% CI, 65 to 76) with standard EGFR-TKIs (hazard ratio for death, 0.63; 95% CI, 0.45 to 0.88; P=0.007 [nonsignificant in the interim analysis]). Adverse events of grade 3 or higher were less frequent with osimertinib than with standard EGFR-TKIs (34% vs. 45%).


研究结论:在EGFR突变的进展期非小细胞肺癌一线治疗中,奥希替尼相比与标准EGFR-TKIs展现出更好的疗效,同时具有更低的严重不良事件发生率和相似的安全性。


CONCLUSIONS:

Osimertinib showed efficacy superior to that of standard EGFR-TKIs in the first-line treatment of EGFR mutation–positive advanced NSCLC, with a similar safety profile and lower rates of serious adverse events. 


Reference: Soria JC et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2017 Nov 18.


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