Blocking vascular endothelial growth factor (VEGF) pathway can enhance the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC). ACTIVE is the first phase III study conducted in China, evaluating apatinib, a VEGFR2 TKI, plus gefitinib as first-line therapy in EGFR-mutant NSCLC. Treatment-naïve patients with stage IIIB/IV non-squamous NSCLC, an ECOG PS of 0/1 and EGFR ex19del or ex21L858R mutation were randomized 1:1 to receive oral gefitinib (250 mg/day), plus apatinib (500 mg/day; A+G group) or placebo (P+G group). Stratification factors: mutation type, sex and PS. The primary endpoint was PFS by blinded independent radiology review committee (IRRC). Secondary endpoints: investigator-assessed PFS, OS, quality of life (QoL), safety, etc. Next-generation sequencing was used to explore efficacy predictors and acquired resistance. 313 patients were assigned to the A+G (n=157) or P+G group (n=156). Median IRRC-PFS in the A+G group was 13.7 months vs 10.2 months in the P+G group (HR 0.71; P=.0189). Investigator- and IRRC-assessed PFS were similar. OS was immature. The most common treatment-emergent adverse events ≥grade 3 were hypertension (46.5%) and proteinuria (17.8%) in the A+G group and increased ALT (10.4%) and AST (3.2%) in the P+G group. QoL in the two groups had no statistical differences. Post-hoc analysis showed PFS benefits tended to favor the A+G group in patients with TP53 ex8 mutation. Apatinib+gefitinib as first-line therapy demonstrated superior PFS in advanced EGFR-mutant NSCLC vs placebo+gefitinib. Combination therapy brought more adverse events but did not interfere QoL. Copyright © 2021. Published by Elsevier Inc.