A randomized, open-label, parallel-controlled phase 3 trial of benmelstobart plus chemotherapy and anlotinib for first-line treatment of advanced non-squamous non–small cell lung cancer.

LBA8507 Background: PD-1/PD-L1 inhibitors plus chemotherapy remain standard first-line therapy for EGFR/ALK/ROS1-wild type advanced non-squamous non-small cell lung cancer (nsq-NSCLC). Pre-clinical data suggest angiogenesis inhibitors may potentiate immune checkpoint inhibitors (ICIs). This phase 3 trial evaluated sequential benmelstobart (anti-PD-L1 mAb) plus chemo followed by benmelstobart plus anlotinib versus standard therapy for PFS improvement in this patient population. Methods: TQB2450-III-11 (NCT05346952) is a randomized, open-label, parallel-controlled phase 3 trial. Eligible patients were diagnosed with locally advanced (stage IIIB/C, unfit for surgery or curative-intent chemoradiotherapy) or metastatic nsq-NSCLC. Previous systemic treatment for advanced disease was not allowed. Other key inclusion criteria included ECOG PS of 0-1, aged 18-75 and no EGFR mutations, no ALK or ROS1 rearrangements. Patients were stratified by PD-L1 TPS level (＜1%/1-49%/≥50%) and randomized 1:1 to receive benmelstobart or tislelizumab plus platinum and pemetrexed for 4 cycles, then followed by maintenance with benmelstobart plus anlotinib and pemetrexed or tislelizumab plus pemetrexed until disease progression or unacceptable toxicities. Anlotinib dosing was 10 mg, while benmelstobart or tislelizumab was given at a dose of 1200 mg or 200 mg Q3W. The primary endpoint was PFS by independent review committee according to the RECIST version 1.1. Results: From January 24, 2022 to May 8, 2023, 596 eligible patients were randomized 1:1 to benmelstobart group and tislelizumab group. Baseline characteristics were well balanced between two groups. Median PFS was significantly improved in benmelstobart group (14.42 months, 95% CI, 12.35–NE) versus tislelizumab group (8.34 months, 95% CI, 6.97–12.39), HR 0.67 (95% CI, 0.52–0.86; P = 0.0017). The subgroup analysis showed that PFS benefit favored benmelstobart group in almost all subgroups, particularly in patients with ECOG PS 0 (HR 0.36, 0.20-0.65) and PD-L1 TPS ＜1% (HR 0.61, 0.43-0.86). OS was immature. Safety profiles were similar in two groups. Treatment-emergent adverse events of any grade was 92.28% (benmelstobart group) and 90.94% (tislelizumab group) respectively. ≥Grade 3 treatment-related adverse events was 56.38% (benmelstobart group) and 48.66% (tislelizumab group). Immune-related adverse events was 19.13% (benmelstobart group) and 18.46% (tislelizumab group). Conclusions: Benmelstobart in combination with chemotherapy followed by sequential combination with anlotinib significantly improved PFS compared to tislelizumab in combination with chemotherapy followed by sequential tislelizumab, with a manageable safety profile. It might be a new first-line treatment for nsq-NSCLC. Clinical trial information: NCT05346952 .