Our preclinical work suggests that appropriate angiogenesis inhibition could potentiate PD-1/PD-L1 blockade via alleviating hypoxia, increasing infiltration of CD8+ T cells and reducing recruitment of tumor-associated macrophages. We hereby conducted a clinical trial to evaluate this combination in pretreated patients with advanced NSCLC. The study included phase Ib apatinib dose-escalation and phase II expansion cohorts. Patients received apatinib at doses of 250-500 mg orally once daily, in combination with camrelizumab 200 mg intravenously every 2 weeks. From March, 2017 to October, 2018, 105 chemotherapy-pretreated patients with non-squamous NSCLC were enrolled and received apatinib 250 mg (recommended phase 2 dose) and camrelizumab. Among them, one (1.0%) complete response, 28 (26.7%) partial responses, and 48 (45.7%) stable diseases were observed. In the efficacy-evaluable population (n = 94), objective response rate (ORR) was 30.9% (95% CI, 21.7-41.2). The median progression-free survival was 5.7 months (95% CI, 4.5-8.8) and overall survival was 15.5 months (95% CI, 10.9-24.5). Efficacy of combination therapy was evident across all PD-L1 and tumor mutation burden subgroups, and appeared to be improved in patients with STK11/KEAP1 mutation (mutant vs. wild-type, ORR: 42.9% vs 28.1%; 1-year survival rate: 85.1% vs. 53.1%). No unexpected adverse events were observed. Combined apatinib and camrelizumab showed encouraging antitumor activity and acceptable toxicity in chemotherapy-pretreated patients with advanced non-squamous NSCLC. Patients with STK11/KEAP1 mutation might derive more benefits from this combination. We will validate these results in an ongoing phase III trial (NCT04203485). Copyright ©2020, American Association for Cancer Research.