Hanna Nasser H, Kaiser Rolf, Sullivan Richard N, Aren Osvaldo Rudy, Ahn Myung-Ju, Tiangco Beatrice, Voccia Isabelle, Pawel Joachim von, Kovcin Vladimir, Agulnik Jason, Gaschler-Markefski Birgit, Barrueco José, Sikken Patricia, Schloss Charles, Kim Joo-Hang
Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indiana University, Indianapolis, IN, USA.
Boehringer Ingelheim Pharmaceuticals GmbH & Co. KG, Biberach, Germany; Institute of Clinical Pharmacology, Georg-August-University Göttingen, Germany.
Lung Cancer. 2016 Dec;102:65-73. doi: 10.1016/j.lungcan.2016.10.011. Epub 2016 Oct 27.
LUME-Lung 2 investigated the efficacy/safety of nintedanib plus pemetrexed in patients with pretreated non-squamous non-small cell lung cancer (NSCLC).
Patients with stage IIIB/IV or recurrent non-squamous NSCLC who had received one prior chemotherapy regimen were randomized (1:1 stratified by histology [adenocarcinoma/non-adenocarcinoma], prior bevacizumab, Eastern Cooperative Oncology Group performance status and presence of brain metastases) to receive intravenous pemetrexed 500mg/m on Day 1 plus nintedanib 200mg orally twice daily or matching placebo on Days 2-21, every 3 weeks until progression/unacceptable toxicity. Progression-free survival (PFS) by independent central review was the primary endpoint. Overall survival (OS) was the key secondary endpoint.
Based on the pre-planned futility analysis of investigator-assessed PFS, conducted by an independent data monitoring committee, recruitment was halted on 18 June 2011 after 713 (n=353 nintedanib/pemetrexed; n=360 placebo/pemetrexed)/1300 planned patients had enrolled. There were no safety concerns. Subsequent analysis demonstrated a significant improvement in PFS favoring nintedanib/pemetrexed over placebo/pemetrexed (median 4.4 months vs 3.6 months; hazard ratio [HR]=0.83, 95% confidence interval [CI] 0.70-0.99, p=0.0435). There was no significant difference in OS (median 12.0 months vs 12.7 months; HR=1.01, 95% CI 0.85-1.21, p=0.8940) after 514 deaths. Nintedanib/pemetrexed resulted in a higher incidence of grade ≥3 elevated alanine aminotransferase (23.3% vs 7.3%), elevated aspartate aminotransferase (12.1% vs 1.7%) and diarrhea (3.5% vs 1.1%) compared with placebo/pemetrexed, but no difference in hypertension, bleeding or thrombosis.
Although recruitment stopped prematurely, combining nintedanib with pemetrexed significantly prolonged PFS in patients with advanced non-squamous NSCLC after first-line chemotherapy, with a manageable safety profile.
LUME-Lung 2研究了尼达尼布联合培美曲塞在经治的非鳞状非小细胞肺癌（NSCLC）患者中的疗效/安全性。
既往接受过一种化疗方案的ⅢB/Ⅳ期或复发性非鳞状NSCLC患者被随机分组（按组织学类型[腺癌/非腺癌]、既往贝伐单抗使用情况、东部肿瘤协作组体能状态和脑转移情况进行1:1分层），在第1天接受静脉注射培美曲塞500mg/m²，联合尼达尼布200mg口服，每日两次，或在第2 - 21天接受匹配的安慰剂，每3周重复一次，直至疾病进展或出现不可接受的毒性。由独立中央审查评估的无进展生存期（PFS）是主要终点。总生存期（OS）是关键次要终点。
基于独立数据监测委员会对研究者评估的PFS进行的预先计划的无效性分析，在计划入组的1300例患者中有713例（尼达尼布/培美曲塞组n = 353例；安慰剂/培美曲塞组n = 360例）入组后，于2011年6月18日停止招募。无安全性问题。后续分析显示，与安慰剂/培美曲塞相比，尼达尼布/培美曲塞组的PFS有显著改善（中位值4.4个月对3.6个月；风险比[HR]=0.83，95%置信区间[CI] 0.70 - 0.99，p = 0.0435）。在514例死亡病例后，OS无显著差异（中位值12.0个月对12.7个月；HR = 1.01，95% CI 0.85 - 1.21，p = 0.8940）。与安慰剂/培美曲塞相比，尼达尼布/培美曲塞组≥3级丙氨酸氨基转移酶升高（23.3%对7.3%）、天冬氨酸氨基转移酶升高（12.1%对1.7%）和腹泻（3.5%对1.1%）的发生率更高，但在高血压、出血或血栓形成方面无差异。
尽管招募提前停止，但尼达尼布与培美曲塞联合使用显著延长了一线化疗后晚期非鳞状NSCLC患者的PFS，且安全性可控。
