Abstract Background The prognosis for non‐small cell lung cancer (NSCLC) patients treated with standard platinum‐based chemotherapy was suboptimal, with safety concerns. Following encouraging results from a preliminary phase I study, this phase II trial investigated the efficacy and safety of first‐line sintilimab and anlotinib in metastatic NSCLC. Methods In this open‐label, randomized controlled trial (NCT04124731), metastatic NSCLC without epithelial growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or proto‐oncogene tyrosine‐protein kinase ROS (ROS1) mutations, and previous treatments for metastatic disease were enrolled. Participants were randomly assigned in a 1:1 ratio to either sintilimab (200 mg every 3 weeks) plus anlotinib (12 mg D1‐14 every 3 weeks) or a standard platinum‐based chemotherapy regimen. Patients in the chemotherapy group were permitted to switch to sintilimab after disease progression. The primary endpoint was the objective response rate (ORR). Results From November 2019 to March 2023, 99 patients were randomized into the sintilimab plus anlotinib group ( n = 49) and the chemotherapy group ( n = 50). The ORR was significantly higher in the sintilimab plus anlotinib group (44.9%; 95% confidence interval [CI] = 30.7%‐59.8%) compared to the chemotherapy group (18.0%; 95% CI = 8.6%‐31.4%, P = 0.003). Progression‐free survival (PFS) was also notably longer (median: 14.4 vs. 5.6 months; hazard ratio [HR] = 0.39; 95% CI = 0.23‐0.67; P &lt; 0.001). The 24‐month overall survival rate was 58.4% (95% CI = 40.4%‐72.6%) and 43.2% (95% CI = 26.0%‐59.2%), respectively. The rate of grade 3 or higher treatment‐related adverse events was lower in the sintilimab plus anlotinib group (28.0%) than in the chemotherapy group (49.0%), especially for the hematological toxicities. Conclusion First‐line sintilimab plus anlotinib showed improved ORR and PFS, alongside a superior safety profile, compared to the standard platinum‐based chemotherapy for metastatic NSCLC patients.

Efficacy and safety of first‐line sintilimab plus anlotinib versus chemotherapy for metastatic non‐small cell lung cancer: a phase II, open‐label, randomized controlled trial