Efficacy and safety of induction benmelstobart plus anlotinib and chemotherapy followed by concurrent chemoradiotherapy and benmelstobart consolidation versus concurrent chemoradiotherapy followed by benmelstobart consolidation in patients with unresectable stage III NSCLC: a randomized, controlled, multicenter phase II trial protocol (BEAM-LUNG).

Background: The PACIFIC and GEMSTONE-301 trials established consolidation immunotherapy post-chemoradiotherapy for unresectable stage III NSCLC, but 22-30% of patients fail initial chemoradiotherapy, precluding consolidation. PACIFIC-2 and CheckMate 73L failures highlight the need for better integration. Induction chemoimmunotherapy before radiotherapy may improve downstaging and immune activation. This trial evaluates whether induction benmelstobart (PD-L1 inhibitor) plus anlotinib (TKI) and chemotherapy, followed by concurrent chemoradiotherapy and benmelstobart consolidation, improves progression-free survival over standard concurrent chemoradiotherapy plus consolidation. Methods and analysis: This prospective, randomized, controlled, multicenter phase II trial will enroll 152 patients with histologically or cytologically confirmed unresectable stage III NSCLC (per UICC/AJCC 9th edition), without sensitizing driver mutations, and ECOG performance status 0-1. Randomization is centralized and stratified by PD-L1 tumor proportion score (<1% vs ≥1%), disease stage (IIIA vs IIIB/IIIC), histology, and participating centre. Patients will be randomized 1:1 to either the experimental arm (Arm A): two cycles of induction benmelstobart (1200 mg, day 1, every 3 weeks) plus anlotinib (8 mg, days 1-14) and platinum-based doublet chemotherapy, followed by concurrent chemoradiotherapy (with benmelstobart withheld during radiotherapy) and benmelstobart consolidation for up to one year; or the control arm (Arm B): concurrent chemoradiotherapy followed by benmelstobart consolidation for up to one year. The primary endpoint is progression-free survival (PFS) measured from randomization. Radiotherapy consists of involved-field IMRT/VMAT to a standard prescription of 60 Gy in 30 fractions, or a simultaneous integrated boost delivering 60-66 Gy to the planning gross tumor volume and 54 Gy to the planning target volume in 30 fractions; in the experimental arm, target volumes are based on post-induction residual disease with inclusion of all initially involved nodal stations. Consolidation benmelstobart will continue for up to one year or until disease progression/unacceptable toxicity. The sample size provides 80% power (two-sided α = 0.05) to detect a PFS hazard ratio of 0.55. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT07643350.