Li Bob T, Barnes Tristan A, Chan David L, Naidoo Jarushka, Lee Adrian, Khasraw Mustafa, Marx Gavin M, Kris Mark G, Clarke Stephen J, Drilon Alexander, Rudin Charles M, Pavlakis Nick
Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, and Weill Cornell Medical College, 300 East 66th Street, New York, NY 10065, USA; Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia.
Department of Medical Oncology, Royal North Shore Hospital, St Leonards, NSW 2065, Australia.
Lung Cancer. 2016 Dec;102:21-27. doi: 10.1016/j.lungcan.2016.10.004. Epub 2016 Oct 17.
The role of anti-angiogenic tyrosine kinase inhibitors (AATKI) for patients with non-small-cell lung cancers (NSCLC) is uncertain. We conducted a comprehensive meta-analysis to assess the overall utility of adding AATKI to chemotherapy.
We included 15 randomized controlled trials (RCTs) of AATKI plus chemotherapy versus chemotherapy involving 7997 patients with advanced NSCLC. Meta-analysis was performed to obtain pooled hazard ratios (HR) for OS and PFS, and pooled odds ratios (OR) for objective response rate (ORR) and grade 3 or greater toxicity. Pre-specified subgroup analyses were performed according to line of chemotherapy, chemotherapeutic regimen and histology.
The addition of AATKI to chemotherapy significantly increased progression-free survival (PFS) (HR 0.83, 95% CI 0.79, 0.87; P<0.00001) and ORR [OR 1.63, 95% CI 1.45, 1.84; P<0.00001], but not overall survival (OS) (HR 0.96, 95% CI 0.91, 1.01; P=0.14). OS benefit was seen in the subset of patients with adenocarcinomas (HR 0.86; 95% CI 0.79, 0.95; P=0.002), especially in the second line setting (HR 0.85; 95% CI 0.76, 0.96; P=0.008). However, both grade ≥3 toxicity (HR 2.08, 95% CI 1.59, 2.73; P<0.00001) and treatment-related deaths (OR 2.37, 95% CI 1.58, 3.56; P<0.0001) were significantly higher with the addition of AATKI.
The addition of AATKI to chemotherapy in patients with advanced NSCLC significantly increased PFS and ORR but not OS, and did so at the expense of increased toxicity and treatment-related deaths. Preclinical and translational research in predictive biomarkers are essential for the clinical development of this class of drugs.
抗血管生成酪氨酸激酶抑制剂（AATKI）在非小细胞肺癌（NSCLC）患者中的作用尚不确定。我们进行了一项全面的荟萃分析，以评估在化疗中添加AATKI的总体效用。
我们纳入了15项AATKI联合化疗与单纯化疗对比的随机对照试验（RCT），涉及7997例晚期NSCLC患者。进行荟萃分析以获得总生存期（OS）和无进展生存期（PFS）的合并风险比（HR），以及客观缓解率（ORR）和3级及以上毒性的合并比值比（OR）。根据化疗线数、化疗方案和组织学进行预先设定的亚组分析。
在化疗中添加AATKI可显著提高无进展生存期（PFS）（HR 0.83，95%CI 0.79，0.87；P<0.00001）和客观缓解率（ORR）[OR 1.63，95%CI 1.45，1.84；P<0.00001]，但对总生存期（OS）无显著影响（HR 0.96，95%CI 0.91，1.01；P=0.14）。在腺癌患者亚组中观察到总生存期获益（HR 0.86；95%CI 0.79，0.95；P=0.002），尤其是在二线治疗中（HR 0.85；95%CI 0.76，0.96；P=0.008）。然而，添加AATKI后3级及以上毒性（HR 2.08，95%CI 1.59，2.73；P<0.00001）和治疗相关死亡（OR 2.37，95%CI 1.58，3.56；P<0.0001）均显著增加。
在晚期NSCLC患者的化疗中添加AATKI可显著提高PFS和ORR，但对OS无显著影响，且是以增加毒性和治疗相关死亡为代价的。预测生物标志物的临床前和转化研究对于这类药物的临床开发至关重要。
