Efficacy of Osimertinib Plus Bevacizumab vs Osimertinib in Patients With EGFR T790M-Mutated Non-Small Cell Lung Cancer Previously Treated With Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor: West Japan Oncology Group 8715L Phase 2 Randomized Clinical Trial.
Efficacy of Osimertinib Plus Bevacizumab vs Osimertinib in Patients With EGFR T790M-Mutated Non-Small Cell Lung Cancer Previously Treated With Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor: West Japan Oncology Group 8715L Phase 2 Randomized Clinical Trial.
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DOI：
10.1001/jamaoncol.2020.6758
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发表时间：
2021-03-01
期刊：
影响因子：
28.4
通讯作者：
Yamamoto N
中科院分区：
文献类型：
--
作者：
Akamatsu H;Toi Y;Hayashi H;Fujimoto D;Tachihara M;Furuya N;Otani S;Shimizu J;Katakami N;Azuma K;Miura N;Nishino K;Hara S;Teraoka S;Morita S;Nakagawa K;Yamamoto N
这项随机临床试验评估了奥西替尼联合贝伐单抗与奥西替尼单独治疗EGFR t790m突变肺腺癌患者的疗效和安全性。对于携带EGFR T790M突变的晚期非小细胞肺癌（NSCLC）患者，奥西替尼和贝伐单抗能否协同作用并耐受？在这项针对81例EGFR T790M突变NSCLC患者的2期随机临床试验中，与单独使用奥西替尼相比，奥西替尼联合贝伐单抗未能显示出无进展生存期和总生存期的延长，尽管毒性作用是可耐受的。在EGFR T790M突变的NSCLC患者中，奥西替尼加贝伐单抗是可耐受的，但无效，最近的单组研究表明这一点。虽然第一代表皮生长因子受体(EGFR) -酪氨酸激酶抑制剂（TKI）加抗血管生成抑制剂治疗EGFR突变的肺腺癌患者显示出良好的疗效，但最近的单臂研究表明，奥希替尼加抗血管生成抑制剂可能无法协同作用。探讨奥西替尼联合贝伐单抗与奥西替尼单用治疗EGFR T790M突变肺腺癌患者的疗效和安全性。纳入了先前接受EGFR-TKI治疗（第三代TKI除外）并获得EGFR T790M突变的晚期肺腺癌患者。该研究包括6名患者的导入部分和随后的2期部分。在第二阶段，患者按1:1的比例随机分配到奥希替尼加贝伐单抗或奥希替尼单独用药。联合组接受口服奥西替尼（80mg，每天）加静脉注射贝伐单抗（15mg /kg，每3周），直到进展或不可接受的毒性作用。对照组接受奥希替尼单药治疗。主要终点是研究者评估的无进展生存期（PFS）。次要终点包括总有效率、治疗失败时间、总生存期和安全性。从2017年8月到2018年9月，共登记了87名患者（6名在先导部分，81名在2期部分[意向治疗人群]）。在随机分组中，年龄中位数（范围）为68岁（41-82岁）；男性33例（41%）；37人（46%）的东部肿瘤合作组绩效状态为0；21例（26%）有脑转移。虽然奥西替尼联合贝伐单抗的总有效率优于单独使用奥西替尼（68% vs 54%），但奥西替尼联合贝伐单抗的中位PFS并不更长（9.4个月vs 13.5个月；调整后的风险比为1.44；80% CI为1.00 ~ 2.08;P = 0.20）。与奥西替尼组相比，联合治疗组治疗失败的中位时间也更短（8.4个月vs 11.2个月；P = 0.12）。联合组与奥西替尼组的中位总生存期无差异（未达到vs 22.1个月；P = 0.96）。在联合用药组中，常见的3级或以上不良事件是蛋白尿（n = 9; 23%）和高血压（n = 8; 20%）。在这项比较奥西替尼联合贝伐单抗与奥西替尼单独治疗的随机临床试验中，联合治疗组未能显示出EGFR T790M突变的晚期肺腺癌患者PFS的延长。临床试验注册标识符：UMIN000023761
This randomized clinical trial assesses the efficacy and safety of osimertinib plus bevacizumab vs osimertinib alone in patients with EGFR T790M–mutated lung adenocarcinoma. Can osimertinib plus bevacizumab work synergistically and be tolerable in patients with advanced non–small cell lung cancer (NSCLC) that harbors EGFR T790M mutation? In this phase 2 randomized clinical trial of 81 patients with NSCLC with EGFR T790M mutation, osimertinib plus bevacizumab failed to show prolongation of progression-free survival and overall survival compared with osimertinib alone, although toxic effects were tolerable. In patients with NSCLC with EGFR T790M mutation, osimertinib plus bevacizumab was tolerable but not efficacious , which had been suggested by recent single-arm studies. Although treatment with first-generation epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) plus antiangiogenic inhibitor has shown promising efficacies in patients with EGFR-mutated lung adenocarcinoma, recent single-arm studies have suggested that osimertinib plus antiangiogenic inhibitor might not work synergistically. To explore the efficacy and safety of osimertinib plus bevacizumab compared with osimertinib alone in patients with lung adenocarcinoma with EGFR T790M mutation. Patients with advanced lung adenocarcinoma that progressed with prior EGFR-TKI treatment (other than third-generation TKI) and acquired EGFR T790M mutation were enrolled. This study comprises a lead-in part with 6 patients and a subsequent phase 2 part. In phase 2, patients were randomized to osimertinib plus bevacizumab or osimertinib alone in a 1:1 ratio. The combination arm received oral osimertinib (80 mg, every day) plus intravenous bevacizumab (15 mg/kg, every 3 weeks) until progression or unacceptable toxic effects. The control arm received osimertinib monotherapy. The primary end point was progression-free survival (PFS) assessed by investigators. Secondary end points consisted of overall response rate, time to treatment failure, overall survival, and safety. From August 2017 through September 2018, a total of 87 patients were registered (6 in the lead-in part and 81 in the phase 2 part [intention-to-treat population]). Among those randomized, the median (range) age was 68 (41-82) years; 33 (41%) were male; 37 (46%) had an Eastern Cooperative Oncology Group performance status of 0; and 21 (26%) had brain metastasis. Although the overall response rate was better with osimertinib plus bevacizumab than osimertinib alone (68% vs 54%), median PFS was not longer with osimertinib plus bevacizumab (9.4 months vs 13.5 months; adjusted hazard ratio, 1.44; 80% CI, 1.00 to 2.08; P = .20). Median time to treatment failure was also shorter in the combination arm vs the osimertinib arm (8.4 months vs 11.2 months; P = .12). Median overall survival was not different in the combination arm vs osimertinib arm (not reached vs 22.1 months; P = .96). In the combination arm, common adverse events of grade 3 or higher were proteinuria (n = 9; 23%), hypertension (n = 8; 20%). In this randomized clinical trial comparing osimertinib plus bevacizumab vs osimertinib alone, the combination arm failed to show prolongation of PFS in patients with advanced lung adenocarcinoma with EGFR T790M mutation. UMIN Clinical Trials Registry Identifier: UMIN000023761
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