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
Background:The combination of anti-PD-1 antibody serplulimab and chemotherapy is considered standard first-line therapy for advanced esophageal squamous cell carcinoma(ESCC),but few later-line treatments are available...Background:The combination of anti-PD-1 antibody serplulimab and chemotherapy is considered standard first-line therapy for advanced esophageal squamous cell carcinoma(ESCC),but few later-line treatments are available.Here we evaluated the therapeutic efficacy of the recombinant,humanized anti-EGFR antibody HLX07 when used alone or together with serplulimab and chemotherapy against advanced ESCC.Methods:This open-label,non-randomized,two-cohort,phase 2 trial involved patients 18-75 years old with histologically or cytologically confirmed locally advanced,unresectable,or metastatic ESCC,and an Eastern Cooperative Oncology Group performance status of 0-1.Patients who had failed first-line immuno-chemotherapy or at least two lines of other systemic therapy received HLX07 monotherapy intravenously at a dose of 1,000 mg once every 2 weeks(Q2W).Patients with no prior systemic therapy received HLX07(1,000 mg,day 1)and serplulimab(200 mg,day 1)intravenously Q2W for up to 2 years,concurrently with cisplatin(50mg/m^(2),day 1)for up to 8 cycles and 5-fluorouracil(1,200mg/m^(2),days 1-2)for up to 12 cycles intravenously Q2W.The primary endpoints were progression-free survival(PFS)and objective response rate(ORR).Results:Overall,50 patients were enrolled.In the HLX07 monotherapy group,ORR was 15.0%(3/20),and the median PFSwas 1.5 months(95% confidence interval[CI],1.3 to 3.7).The median duration of response was not reached,and the rate of patients showing an objective response lasting at least 6monthswas 66.7%(95%CI,5.4 to 94.5).Two(10.0%,2/20)patients experienced grade 3-4 treatmentrelated adverse events(TRAEs),including hypomagnesemia,hypocalcemia,and fatigue.No patient experienced grade 5 TRAEs.In the HLX07 combination group,the ORR was 60.0%(18/30),and the median PFS was 7.8 months(95%CI,3.3 to 9.1).Fourteen(46.7%,14/30)patients experienced grade 3-4 TRAEs,and one(3.3%,1/30)patient died due to serplulimab-related pneumonitis.Conclusions:HLX07 monotherapy and its combination with serplulimab and chemotherapy showed manageable toxicity and promising antitumor activity in patients with recurrent or metastatic ESCC.Randomized controlled trials are warranted to further establish the safety and efficacy of HLX07 against ESCC.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.
文摘Background:The combination of anti-PD-1 antibody serplulimab and chemotherapy is considered standard first-line therapy for advanced esophageal squamous cell carcinoma(ESCC),but few later-line treatments are available.Here we evaluated the therapeutic efficacy of the recombinant,humanized anti-EGFR antibody HLX07 when used alone or together with serplulimab and chemotherapy against advanced ESCC.Methods:This open-label,non-randomized,two-cohort,phase 2 trial involved patients 18-75 years old with histologically or cytologically confirmed locally advanced,unresectable,or metastatic ESCC,and an Eastern Cooperative Oncology Group performance status of 0-1.Patients who had failed first-line immuno-chemotherapy or at least two lines of other systemic therapy received HLX07 monotherapy intravenously at a dose of 1,000 mg once every 2 weeks(Q2W).Patients with no prior systemic therapy received HLX07(1,000 mg,day 1)and serplulimab(200 mg,day 1)intravenously Q2W for up to 2 years,concurrently with cisplatin(50mg/m^(2),day 1)for up to 8 cycles and 5-fluorouracil(1,200mg/m^(2),days 1-2)for up to 12 cycles intravenously Q2W.The primary endpoints were progression-free survival(PFS)and objective response rate(ORR).Results:Overall,50 patients were enrolled.In the HLX07 monotherapy group,ORR was 15.0%(3/20),and the median PFSwas 1.5 months(95% confidence interval[CI],1.3 to 3.7).The median duration of response was not reached,and the rate of patients showing an objective response lasting at least 6monthswas 66.7%(95%CI,5.4 to 94.5).Two(10.0%,2/20)patients experienced grade 3-4 treatmentrelated adverse events(TRAEs),including hypomagnesemia,hypocalcemia,and fatigue.No patient experienced grade 5 TRAEs.In the HLX07 combination group,the ORR was 60.0%(18/30),and the median PFS was 7.8 months(95%CI,3.3 to 9.1).Fourteen(46.7%,14/30)patients experienced grade 3-4 TRAEs,and one(3.3%,1/30)patient died due to serplulimab-related pneumonitis.Conclusions:HLX07 monotherapy and its combination with serplulimab and chemotherapy showed manageable toxicity and promising antitumor activity in patients with recurrent or metastatic ESCC.Randomized controlled trials are warranted to further establish the safety and efficacy of HLX07 against ESCC.
