Background: Toripalimab (anti–PD-1) in combination with chemotherapy showed significant improvement in progression-free survival (PFS) and overall survival (OS) in the first-line treatment of advanced non–small cell lung cancer (NSCLC) regardless of tumor PD-L1 expression. Whole-exome sequencing (WES) was performed to identify correlative biomarkers for survival. Methods: Patients (465 patients) with treatment-naïve, advanced NSCLC without EGFR/ALK mutations were randomly assigned 2:1 to receive toripalimab 240 mg (309 patients) or placebo (156 patients) in combination with chemotherapy for 4-6 cycles, followed by maintenance of toripalimab or placebo plus standard care until disease progression, intolerable toxicity, or completion of 2 years of treatment. Stratification factors included PD-L1 expression status, histology, and smoking status. The primary endpoint was PFS by investigator per RECIST v1.1. Secondary endpoints included PFS by a blinded independent review committee (BIRC), OS, and safety. Results: At the prespecified final PFS analysis (cutoff date Oct 31, 2021), a significant improvement in PFS as assessed by investigator was observed for the toripalimab arm over the placebo arm: HR, 0.49 (95% CI, 0.39-0.61); two-sided p < .0001; and median PFS 8.4 vs. 5.6 months. The 1-year PFS rates were 36.7% vs. 17.2%. PFS as assessed by BIRC was also significantly longer in the toripalimab arm. The improvements of PFS were observed across key subgroups, including histology and PD-L1 expression. At the interim OS analysis, the toripalimab arm had a significantly longer OS than the placebo arm: HR, 0.69 (95% CI, 0.52-0.92); two-sided p = .0099; median OS not reached vs. 17.1 months. The incidence of grade ≥ 3 adverse events (AEs; 78.6% vs. 82.1%) was similar between the two arms. AEs leading to discontinuation of toripalimab/placebo (14.3% vs. 3.2%) and fatal AEs (5.5% vs. 2.6%) were more frequent in the toripalimab arm. WES results from 394 available patients revealed that patients with high tumor mutational burden (TMB; ≥ 10 mutations per million base pairs) were associated with significantly better PFS in the toripalimab arm over the placebo arm (median PFS 13.1 vs. 5.5 months; interaction p = .026). In addition, patients with mutations in the FAK-PI3K-Akt pathway or IL-7 signaling pathways achieved significantly better PFS and OS from the toripalimab chemotherapy combination (interaction p values ≤ .01). Conclusions: The addition of toripalimab to chemotherapy in patients with advanced NSCLC provided superior PFS and OS when compared to chemotherapy alone with a manageable safety profile. These results support the use of toripalimab with chemotherapy as first-line therapy for patients with advanced NSCLC without EGFR/ALK mutations. Clinical trial information: NCT03856411.