Background:The ASTRUM-005 study previously demonstrated a signifi-cant overall survival(OS)benefit with serplulimab(a programmed death1 inhibitor)plus chemotherapy versus chemotherapy alone in previouslyuntreated exte...Background:The ASTRUM-005 study previously demonstrated a signifi-cant overall survival(OS)benefit with serplulimab(a programmed death1 inhibitor)plus chemotherapy versus chemotherapy alone in previouslyuntreated extensive-stage small-cell lung cancer(ES-SCLC).Here,we reportupdated efficacy and safety results after an extended median follow-up of 19.8months,along with the first report on findings from exploratory biomarkeranalyses.Methods:A total of 585 patients were randomized in a 2:1 ratio to receive4.5 mg/kg serplulimab(n=389)or placebo(n=196)intravenously every 3weeks,together with carboplatin and etoposide.The primary endpoint was OS.In addition,genomic profiling was performed to identify mutated genes,and quantitative serum proteome profiling was conducted to identify differ-entially expressed proteins(DEPs)between responders and non-responders ofserplulimab plus chemotherapy.Regression analysis was subsequently used toconstruct a protein signature based on the DEPs.The associations betweenefficacy outcomes(objective response rate[ORR],OS,and progression-free sur-vival[PFS])and gene mutation status or DEP expression were also examinedwith regression analysis.Furthermore,the prognostic value of hematologicalparameters was evaluated.Results:In the intent-to-treat population,the median OS was 15.8 monthsin the serplulimab group versus 11.1 months in the placebo group(haz-ard ratio,0.62;95%confidence interval,0.50-0.76;P<0.001).We identified181 DEPs between responders and non-responders in the serplulimab group,from which a 15-protein signature was constructed.In the serplulimab group,patients with a higher 15-protein signature score were associated with sig-nificantly longer OS and PFS.Also,patients harboring tumor-suppressorretinoblastoma-1(RB1)mutations or mutations in Notch pathway membersshowed improved ORR,OS,or PFS compared with their wild-type counter-parts.Baseline neutrophil-to-lymphocyte ratio(NLR)and lactate dehydrogenase(LDH)level were independent prognosticators of patients with ES-SCLC.Conclusions:First-line serplulimab provided a sustained clinical benefit overplacebo in patients with ES-SCLC.A 15-protein signature and mutations in RB1or Notch pathway genes may serve as predictive biomarkers for benefits fromserplulimab plus chemotherapy,while baseline NLR and LDH were independentprognosticators for ES-SCLC.展开更多
基金Shanghai Henlius Biotech Inc.NationalNatural Science Foundation of China,Grant/Award Number:82473000。
文摘Background:The ASTRUM-005 study previously demonstrated a signifi-cant overall survival(OS)benefit with serplulimab(a programmed death1 inhibitor)plus chemotherapy versus chemotherapy alone in previouslyuntreated extensive-stage small-cell lung cancer(ES-SCLC).Here,we reportupdated efficacy and safety results after an extended median follow-up of 19.8months,along with the first report on findings from exploratory biomarkeranalyses.Methods:A total of 585 patients were randomized in a 2:1 ratio to receive4.5 mg/kg serplulimab(n=389)or placebo(n=196)intravenously every 3weeks,together with carboplatin and etoposide.The primary endpoint was OS.In addition,genomic profiling was performed to identify mutated genes,and quantitative serum proteome profiling was conducted to identify differ-entially expressed proteins(DEPs)between responders and non-responders ofserplulimab plus chemotherapy.Regression analysis was subsequently used toconstruct a protein signature based on the DEPs.The associations betweenefficacy outcomes(objective response rate[ORR],OS,and progression-free sur-vival[PFS])and gene mutation status or DEP expression were also examinedwith regression analysis.Furthermore,the prognostic value of hematologicalparameters was evaluated.Results:In the intent-to-treat population,the median OS was 15.8 monthsin the serplulimab group versus 11.1 months in the placebo group(haz-ard ratio,0.62;95%confidence interval,0.50-0.76;P<0.001).We identified181 DEPs between responders and non-responders in the serplulimab group,from which a 15-protein signature was constructed.In the serplulimab group,patients with a higher 15-protein signature score were associated with sig-nificantly longer OS and PFS.Also,patients harboring tumor-suppressorretinoblastoma-1(RB1)mutations or mutations in Notch pathway membersshowed improved ORR,OS,or PFS compared with their wild-type counter-parts.Baseline neutrophil-to-lymphocyte ratio(NLR)and lactate dehydrogenase(LDH)level were independent prognosticators of patients with ES-SCLC.Conclusions:First-line serplulimab provided a sustained clinical benefit overplacebo in patients with ES-SCLC.A 15-protein signature and mutations in RB1or Notch pathway genes may serve as predictive biomarkers for benefits fromserplulimab plus chemotherapy,while baseline NLR and LDH were independentprognosticators for ES-SCLC.
