Erlotinib and bevacizumab in patients with advanced non-small-cell lung cancer and activating EGFR mutations (BELIEF): an international, multicentre, single-arm, phase 2 trial
Erlotinib and bevacizumab in patients with advanced non-small-cell lung cancer and activating EGFR mutations (BELIEF): an international, multicentre, single-arm, phase 2 trial
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DOI：
10.1016/s2213-2600(17)30129-7
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发表时间：
2017-05-01
影响因子：
76.2
通讯作者：
Stahel, Rolf A.
中科院分区：
文献类型：
--
作者：
Rosell, Rafael;Dafni, Urania;Stahel, Rolf A.
背景 酪氨酸激酶抑制剂厄洛替尼可改善携带表皮生长因子受体 (EGFR) 突变的晚期非小细胞肺癌 (NSCLC) 患者的预后。在初治患者中，T790M 耐药突变与另一种 EGFR 突变共存，与不存在 T790M 突变的患者相比，EGFR 抑制后的无进展生存期较短。为了在临床上检验这一假设，我们开展了一项概念验证研究，其中 EGFR 突变 NSCLC 患者接受厄洛替尼和贝伐单抗联合治疗，并根据治疗前 T790M 突变的存在进行分层。方法 BELIEF 是一项国际、多中心、单组 2 期试验，在 8 个欧洲国家的 29 个中心进行。符合条件的患者年龄为 18 岁或以上，患有未经治疗、经病理学证实的 IIIB 期或 IV 期肺腺癌，并确认有激活的 EGFR 突变（外显子 19 缺失或 L858R 突变）。患者每天接受口服厄洛替尼 150 mg，每 21 天静脉注射贝伐单抗 15 mg/kg，并使用基于肽核酸探针的实时 PCR 集中检测治疗前 T790M 耐药突变。主要终点是无进展生存期。主要疗效分析在意向治疗人群中进行，并根据入组患者集中确认的治疗前 T790M 突变状态（T790M 阳性或阴性）分层为两个平行子研究。安全性分析是在所有接受过至少一剂试验治疗的患者中进行的。该试验已在临床试验中注册。 gov，编号 NCT01562028。调查结果 2012 年 6 月 11 日至 2014 年 10 月 28 日期间，招募了 109 名患者并纳入疗效分析。 T790M突变阳性37例，阴性72例。总体中位无进展生存期为 13.2 个月（95% CI 10.3-15.5），12 个月无进展生存期为 55%（95% CI 45-64）。仅在子研究一（T790M 阳性患者）中达到主要终点。在T790M阳性组中，中位无进展生存期为16.0个月（12.7至不可估计），12个月无进展生存率为68%（50-81），而在T790M阴性组中，中位无进展生存期为10.5个月（9.4-14.2），12个月无进展生存率为48%（36-59）。在安全性分析中纳入的 106 名患者中，5 名患者出现 4 级不良事件（1 名急性冠脉综合征、1 名胆道感染、1 名其他肿瘤和 2 名结肠穿孔），1 名患者因败血症死亡。 解释 BELIEF 试验进一步证明了厄洛替尼和贝伐珠单抗联合使用治疗携带激活 EGFR 突变的 NSCLC 患者的益处。
Background The tyrosine kinase inhibitor erlotinib improves the outcomes of patients with advanced non-small-cell lung carcinoma (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations. The coexistence of the T790M resistance mutation with another EGFR mutation in treatment-naive patients has been associated with a shorter progression-free survival to EGFR inhibition than in the absence of the T790M mutation. To test this hypothesis clinically, we developed a proof-of-concept study, in which patients with EGFR-mutant NSCLC were treated with the combination of erlotinib and bevacizumab, stratified by the presence of the pretreatment T790M mutation.Methods BELIEF was an international, multicentre, single-arm, phase 2 trial done at 29 centres in eight European countries. Eligible patients were aged 18 years or older and had treatment-naive, pathologically confirmed stage IIIB or stage IV lung adenocarcinoma with a confirmed, activating EGFR mutation (exon 19 deletion or L858R mutation). Patients received oral erlotinib 150 mg per day and intravenous bevacizumab 15 mg/kg every 21 days and were tested centrally for the pretreatment T790M resistance mutation with a peptide nucleic acid probe-based real-time PCR. The primary endpoint was progression-free survival. The primary efficacy analysis was done in the intention-to-treat population and was stratified into two parallel substudies according to the centrally confirmed pretreatment T790M mutation status of enrolled patients (T790M positive or negative). The safety analysis was done in all patients that have received at least one dose of trial treatment. This trial was registered with ClinicalTrials. gov, number NCT01562028.Findings Between June 11, 2012, and Oct 28, 2014, 109 patients were enrolled and included in the efficacy analysis. 37 patients were T790M mutation positive and 72 negative. The overall median progression-free survival was 13.2 months (95% CI 10.3-15.5), with a 12 month progression-free survival of 55% (95% CI 45-64). The primary endpoint was met only in substudy one (T790M-positive patients). In the T790M-positive group, median progression-free survival was 16.0 months (12.7 to not estimable), with a 12 month progression-free survival of 68% (50-81), whereas in the T790M-negative group, median progression-free survival was 10.5 months (9.4-14.2), with a 12 month progression-free survival of 48% (36-59). Of 106 patients included in the safety analysis, five had grade 4 adverse events (one acute coronary syndrome, one biliary tract infection, one other neoplasms, and two colonic perforations) and one died due to sepsis.Interpretation The BELIEF trial provides further evidence of benefit for the combined use of erlotinib and bevacizumab in patients with NSCLC harbouring activating EGFR mutations.