Equivalent efficacy assessment of QL1101 and bevacizumab in nonsquamous non-small cell lung cancer patients:A two-year follow-up data update

Objective: Anti-vascular endothelial growth factor(VEGF) monoclonal antibodies are an effective means of treating non-small cell lung cancer(NSCLC). Here, we aim to update the equivalent efficacy assessment between QL1101 and bevacizumab based on two-year follow-up data.Methods: In total, 535 eligible NSCLC patients were enrolled in this randomized controlled trial. Patients were randomly assigned 1:1 to the QL1101 group and the bevacizumab group. The full end time of this study was defined as 24 months after the last enrolled patient was randomized. The primary endpoint was the objective response rate(ORR);equivalence was confirmed if the two-sided 90% confidence interval(90% CI) of the relative risk was within the range of 0.75-1.33. The secondary endpoints were progression-free survival(PFS) and overall survival(OS).Results: The two-year updated data showed similar ORR(QL1101 vs. bevacizumab: 53.1% vs. 54.3%;relative risk=0.977;90% CI: 0.838-1.144), PFS(235 d vs. 254 d, log-rank P=0.311), and OS(577 d vs. 641 d, log-rank P=0.099) results between the QL1101 group and the bevacizumab group. The mean shrinkage ratio of targeted lesions was also similar between the QL1101 group and the bevacizumab group(22.5% vs. 23.5%). For patients who received QL1101 maintenance therapy, similar results were shown between the QL1101 group(n=157) and the bevacizumab group(n=148)(PFS: 253 d vs. 272 d, log-rank P=0.387;OS: 673 d vs. 790 d, log-rank P=0.101;mean tumor shrinkage rate: 26.6% vs. 27.5%).Conclusions: This study reported that QL1101 had similar efficacy in treating nonsquamous NSCLC in terms of ORR, PFS and OS based on two-year updated data, providing a basis for the clinical application of QL1101.

Essential roles of exosome and circRNA_101093 on ferroptosis desensitization in lung adenocarcinoma

Background:Resistance to ferroptosis,a regulated cell death caused by irondependent excessive accumulation of lipid peroxides,has recently been linked to lung adenocarcinoma(LUAD).Intracellular antioxidant systems are required for protection against ferroptosis.The purpose of the present studywas to investigate whether and how extracellular system desensitizes LUAD cells to ferroptosis.Methods:Established human lung fibroblasts MRC-5,WI38,and human LUAD H1650,PC9,H1975,H358,A549,and H1299 cell lines,tumor and matched normal adjacent tissues of LUAD,and plasma from healthy individuals and LUAD patients were used in this study.Immunohistochemistry and immunoblotting were used to analyze protein expression,and quantitative reverse transcription-PCR was used to analyze mRNA expression.Cell viability,cell death,and the lipid reactive oxygen species generationwere measured to evaluate the responses to ferroptosis.Exosomes were observed using transmission electron microscope.The localization of arachidonic acid(AA)was detected using click chemistry labeling followed by confocal microscopy.Interactions between RNAs and proteins were detected using RNA pull-down,RNA immunoprecipitation and photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation methods.Proteomic analysis was used to investigate RNA-regulated proteins,and metabolomic analysis was performed to analyze metabolites.Cellderived xenograft,patient-derived xenograft,cell-implanted intrapulmonary LUAD mouse models and plasma/tissue specimens from LUAD patients were used to validate the molecular mechanism.Results:Plasma exosome from LUAD patients specifically reduced lipid peroxidation and desensitized LUAD cells to ferroptosis.A potential explanation is that exosomal circRNA_101093(cir93)maintained an elevation in intracellular cir93 in LUAD to modulate AA,a poly-unsaturated fatty acid critical for ferroptosisassociated increased peroxidation in the plasma membrane.Mechanistically,cir93 interacted with and increased fatty acid-binding protein 3(FABP3),which transported AA and facilitated its reaction with taurine.Thus,global AA was reduced,whereas N-arachidonoyl taurine(NAT,the product of AA and taurine)was induced.Notably,the role of NAT in suppressing AA incorporation into the plasma membrane was also revealed.In pre-clinical in vivo models,reducing exosome improved ferroptosis-based treatment.Conclusion:Exosome and cir93 are essential for desensitizing LUAD cells to ferroptosis,and blocking exosome may be helpful for future LUAD treatment.