The addition of anti-angiogenic tyrosine kinase inhibitors to chemotherapy for patients with advanced non-small-cell lung cancers: A meta-analysis of randomized trials

- Meta-analysis involving 7997 patients with non-small cell lung cancers.
- No survival benefit adding antiangiogenic tyrosine kinase inhibitor to chemotherapy.
- Modest survival benefit seen in patients with lung adenocarcinomas.
- Significantly increased toxicity and treatment-related deaths.
- Predictive biomarkers needed for the development of this class of drugs.

ObjectivesThe 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.Materials and MethodsWe 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.ResultsThe 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.ConclusionThe 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.