Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
Lancet Oncol. 2011 Aug;12(8):735-42. doi: 10.1016/S1470-2045(11)70184-X. Epub 2011 Jul 23.
Activating mutations in EGFR are important markers of response to tyrosine kinase inhibitor (TKI) therapy in non-small-cell lung cancer (NSCLC). The OPTIMAL study compared efficacy and tolerability of the TKI erlotinib versus standard chemotherapy in the first-line treatment of patients with advanced EGFR mutation-positive NSCLC.
We undertook an open-label, randomised, phase 3 trial at 22 centres in China. Patients older than 18 years with histologically confirmed stage IIIB or IV NSCLC and a confirmed activating mutation of EGFR (exon 19 deletion or exon 21 L858R point mutation) received either oral erlotinib (150 mg/day) until disease progression or unacceptable toxic effects, or up to four cycles of gemcitabine plus carboplatin. Patients were randomly assigned (1:1) with a minimisation procedure and were stratified according to EGFR mutation type, histological subtype (adenocarcinoma vs non-adenocarcinoma), and smoking status. The primary outcome was progression-free survival, analysed in patients with confirmed disease who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov, number NCT00874419, and has completed enrolment; patients are still in follow-up.
83 patients were randomly assigned to receive erlotinib and 82 to receive gemcitabine plus carboplatin; 82 in the erlotinib group and 72 in the chemotherapy group were included in analysis of the primary endpoint. Median progression-free survival was significantly longer in erlotinib-treated patients than in those on chemotherapy (13.1 [95% CI 10.58-16.53] vs 4.6 [4.21-5.42] months; hazard ratio 0.16, 95% CI 0.10-0.26; p<0.0001). Chemotherapy was associated with more grade 3 or 4 toxic effects than was erlotinib (including neutropenia in 30 [42%] of 72 patients and thrombocytopenia in 29 [40%] patients on chemotherapy vs no patients with either event on erlotinib); the most common grade 3 or 4 toxic effects with erlotinib were increased alanine aminotransferase concentrations (three [4%] of 83 patients) and skin rash (two [2%] patients). Chemotherapy was also associated with increased treatment-related serious adverse events (ten [14%] of 72 patients [decreased platelet count, n=8; decreased neutrophil count, n=1; hepatic dysfunction, n=1] vs two [2%] of 83 patients [both hepatic dysfunction]).
Compared with standard chemotherapy, erlotinib conferred a significant progression-free survival benefit in patients with advanced EGFR mutation-positive NSCLC and was associated with more favourable tolerability. These findings suggest that erlotinib is important for first-line treatment of patients with advanced EGFR mutation-positive NSCLC.
F Hoffmann-La Roche Ltd (China); Science and Technology Commission of Shanghai Municipality.
表皮生长因子受体（EGFR）的激活突变是针对非小细胞肺癌（NSCLC）的酪氨酸激酶抑制剂（TKI）治疗反应的重要标志物。OPTIMAL 研究比较了 TKI 厄洛替尼与标准化疗在晚期 EGFR 突变阳性 NSCLC 患者一线治疗中的疗效和耐受性。
我们在中国 22 个中心开展了一项开放标签、随机、3 期试验。入组患者为年龄大于 18 岁的组织学证实为 IIIB 或 IV 期 NSCLC 患者，且有明确的 EGFR 激活突变（exon19 缺失或 exon21 L858R 点突变），接受口服厄洛替尼（150mg/天）治疗，直至疾病进展或出现不可耐受的毒性反应，或最多接受 4 个周期的吉西他滨加卡铂治疗。患者按 1:1 比例采用最小化程序随机分组，并根据 EGFR 突变类型、组织学亚型（腺癌与非腺癌）和吸烟状态进行分层。主要终点为无进展生存期，在接受至少一剂研究治疗的确认疾病患者中进行分析。该试验在 ClinicalTrials.gov 注册，编号为 NCT00874419，已完成入组；患者仍在随访中。
83 例患者随机分配接受厄洛替尼治疗，82 例患者接受吉西他滨加卡铂治疗；厄洛替尼组有 82 例和化疗组有 72 例患者纳入主要终点分析。厄洛替尼组患者的无进展生存期显著长于化疗组（中位 13.1[95%CI 10.58-16.53]个月 vs 4.6[4.21-5.42]个月；风险比 0.16，95%CI 0.10-0.26；p<0.0001）。化疗组发生 3 级或 4 级毒性反应的比例高于厄洛替尼组（包括中性粒细胞减少症 72 例患者中有 30 例[42%]和血小板减少症 29 例[40%] vs 厄洛替尼组无任何患者发生这两种事件；厄洛替尼组最常见的 3 级或 4 级毒性反应为丙氨酸氨基转移酶升高（83 例患者中有 3 例[4%]）和皮疹（83 例患者中有 2 例[2%]）。化疗组还与更多的治疗相关严重不良事件相关（72 例患者中有 10 例[血小板计数下降，n=8；中性粒细胞计数下降，n=1；肝功能异常，n=1] vs 83 例患者中有 2 例[均为肝功能异常]）。
与标准化疗相比，厄洛替尼在晚期 EGFR 突变阳性 NSCLC 患者中提供了显著的无进展生存期获益，且具有更好的耐受性。这些发现表明，厄洛替尼对于晚期 EGFR 突变阳性 NSCLC 患者的一线治疗非常重要。
罗氏研发（中国）有限公司（中国）；上海市科学技术委员会。
