Benmelstobart With or Without Anlotinib After Chemoradiotherapy for Unresectable Non−Small Cell Lung Cancer

Importance: Consolidation immunotherapy improves outcomes after chemoradiotherapy for unresectable stage III non-small cell lung cancer (NSCLC). Disease progression remains common, and more effective consolidation strategies are needed. Objective: To evaluate the efficacy and safety of benmelstobart with or without anlotinib as consolidation therapy after chemoradiotherapy for unresectable stage III NSCLC. Design, Setting, and Participants: This multicenter double-blind phase 3 randomized clinical trial took place at 42 centers in China from 2020 to 2023 among patients with unresectable stage III NSCLC without progression after concurrent or sequential chemoradiotherapy. In stage 1, patients were randomized 1:1:1 to 2 active regimens or placebo; in stage 2, additional patients were randomized 1:1 between the active regimens to power their direct comparison. Data cutoffs were November 30, 2023, for stage 1 and July 8, 2024, for the pooled analysis. Data analysis was performed from January 17 to March 23, 2025. Interventions: Patients were randomized to receive benmelstobart plus anlotinib, benmelstobart plus anlotinib placebo, or their matching placebos. Main Outcomes and Measures: Primary end point was independent review committee (IRC)-assessed progression-free survival (PFS). Results: Of 553 participants (median [IQR] age, 62 [56-67] years; 495 male individuals [89.5%]), 390 were randomized in stage 1 and 163 in stage 2. In stage 1, median PFS was 15.1 months (95% CI, 9.4-21.7) with benmelstobart plus anlotinib, 9.7 months (95% CI, 6.0-34.4) with benmelstobart alone, and 4.2 months (95% CI, 3.2-6.8) with placebo. The hazard ratios (HRs) were 0.49 (95% CI, 0.36-0.66; P < .001) for benmelstobart plus anlotinib vs placebo and 0.53 (95% CI, 0.39-0.72; P < .001) for benmelstobart vs placebo. In the pooled stage 1 and 2 analysis, median PFS was 17.4 (95% CI, 12.5-24.8) months with benmelstobart plus anlotinib and 11.2 (95% CI, 7.0-20.7) months with benmelstobart alone (HR, 0.82; 95% CI, 0.63-1.08; P = .12). Grade 3 to 5 treatment-related adverse events occurred in 48.8%, 29.4%, and 19.7% in the benmelstobart plus anlotinib, benmelstobart alone, and placebo groups, respectively; grade 5 events occurred in 7.2%, 1.4%, and 1.5%, respectively. Conclusions and Relevance: This randomized clinical trial found that benmelstobart with or without anlotinib significantly improved PFS compared with placebo. Adding anlotinib did not significantly improve PFS compared with benmelstobart alone and increased severe and fatal treatment-related adverse events. Trial Registration: ClinicalTrials.gov Identifier: NCT04325763.