Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain.
Frontier Science Foundation-Hellas & National and Kapodistrian University of Athens, Athens, Greece.
Lancet Respir Med. 2017 May;5(5):435-444. doi: 10.1016/S2213-2600(17)30129-7. Epub 2017 Apr 10.
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.
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.
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.
The BELIEF trial provides further evidence of benefit for the combined use of erlotinib and bevacizumab in patients with NSCLC harbouring activating EGFR mutations.
European Thoracic Oncology Platform, Roche.
酪氨酸激酶抑制剂厄洛替尼可改善表皮生长因子受体（EGFR）突变的晚期非小细胞肺癌（NSCLC）患者的预后。与不存在 T790M 突变相比，治疗初治患者中同时存在 T790M 耐药突变与另一个 EGFR 突变与 EGFR 抑制的无进展生存期缩短有关。为了在临床上检验这一假说，我们开发了一项概念验证研究，该研究在 8 个欧洲国家的 29 个中心进行，根据治疗前 T790M 突变的存在情况，对携带 EGFR 突变的 NSCLC 患者进行厄洛替尼和贝伐珠单抗联合治疗的分层。
BELIEF 是一项国际性、多中心、单臂、2 期试验，在 8 个欧洲国家的 29 个中心进行。入组患者年龄 18 岁或以上，患有经病理证实的 IIIB 期或 IV 期肺腺癌，且存在经确认的、激活的 EGFR 突变（外显子 19 缺失或 L858R 突变）。患者每天口服厄洛替尼 150 mg，每 21 天静脉注射贝伐珠单抗 15 mg/kg，并通过基于肽核酸探针的实时 PCR 对治疗前 T790M 耐药突变进行中心检测。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，并根据入组患者中心确认的治疗前 T790M 突变状态（T790M 阳性或阴性）分为两个平行的亚研究。安全性分析在至少接受一剂试验治疗的所有患者中进行。该试验在 ClinicalTrials.gov 上注册，编号为 NCT01562028。
2012 年 6 月 11 日至 2014 年 10 月 28 日，共纳入 109 例患者进行疗效分析。37 例患者 T790M 突变阳性，72 例患者 T790M 突变阴性。总的中位无进展生存期为 13.2 个月（95%CI 10.3-15.5），12 个月无进展生存率为 55%（95%CI 45-64）。主要终点仅在亚研究 1（T790M 阳性患者）中达到。在 T790M 阳性组中，中位无进展生存期为 16.0 个月（12.7 至无法评估），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）。在纳入安全性分析的 106 例患者中，有 5 例发生 4 级不良事件（1 例急性冠状动脉综合征、1 例胆道感染、1 例其他肿瘤和 2 例结肠穿孔），1 例因脓毒症死亡。
BELIEF 试验为 EGFR 突变的 NSCLC 患者联合使用厄洛替尼和贝伐珠单抗提供了进一步的获益证据。
欧洲胸科肿瘤学平台、罗氏公司。
