Objective: Tumor microenvironment, especially the host immune system, plays a pivotal role in tumor initiation and progression. Profiling of immune signature within tumor might uncover biomarkers for targeted therapie...Objective: Tumor microenvironment, especially the host immune system, plays a pivotal role in tumor initiation and progression. Profiling of immune signature within tumor might uncover biomarkers for targeted therapies and clinical outcomes. However, systematic analysis of immune-related genes in gastric cancer(GC) has not been reported.Methods: Expressions of a total of 718 immune-related genes were generated in 372 stomach adenocarcinoma(STAD) patients from The Cancer Genome Atlas(TCGA) database using RNA-sequencing data. Integrated bioinformatics analyses were performed to identify prognostic factors as well.Results: Survival analyses revealed 73 genes, which were significantly associated with patient’s overall survival(OS). Taken together with clinicopathological parameters, we established a predictive model, containing 10 immune-related genes, which were NRP1, C6, CXCR4, LBP, PNMA1, TLR5, ITGA6, MICB, PBK and TNFRSF18,with powerful efficiency in distinguishing satisfactory or poor survival of STAD patients. Moreover, the top 3 ranked prognostic genes, NRP1, TGFβ2 and MFGE8, were also significantly associated with patient’s OS by an independent validation achieved from Kaplan-Meier plotter database.Conclusions: We profiled prognostic immune signature and established prognostic predictive model for GC,which could reflect immune disorders within tumor microenvironment, and also may provide novel predictive and therapeutic targets for GC patients in the near future.展开更多
This phase 2/3 trial (NCT04856787) assessed the efficacy and safety of SHR-1701, a bifunctional protein targeting PD-L1 and TGF-β,in combination with BP102 (a bevacizumab biosimilar) and XELOX (capecitabine plus oxal...This phase 2/3 trial (NCT04856787) assessed the efficacy and safety of SHR-1701, a bifunctional protein targeting PD-L1 and TGF-β,in combination with BP102 (a bevacizumab biosimilar) and XELOX (capecitabine plus oxaliplatin) as a first-line treatment forunresectable metastatic colorectal cancer (mCRC). In this phase 2 study, a total of 62 patients with untreated, histologicallyconfirmed colorectal adenocarcinoma and no prior systemic therapy for metastatic disease were enrolled. Patients receivedSHR-1701 (30 mg/kg), bevacizumab (7.5 mg/kg), and oxaliplatin (130 mg/m^(2)) intravenously on day 1, along with oral capecitabine(1 g/m^(2) twice daily) on days 1-14 of 21-day cycles. Up to eight induction cycles were administered, followed by maintenancetherapy for responders or those with stable disease. The primary endpoints were safety and objective response rate (ORR) perRECIST v1.1. The combination achieved an ORR of 59.7% and a disease control rate (DCR) of 83.9%. Median progression-free survival(PFS) was 10.3 months (95% CI: 8.3-13.7), with 6- and 12-month PFS rates of 77.2% and 41.3%, respectively. The estimated12-month overall survival (OS) rate was 67.7%. Grade ≥3 treatment-related adverse events (TRAEs) were reported in 59.7% ofpatients, with anemia and neutropenia (8.1% each) being the most common. Retrospective DNA sequencing revealed that hightumor mutational burden, neo-antigens, and SBS15 enrichment correlated with better responses. Elevated baseline lactatedehydrogenase was linked to shorter PFS. SHR-1701 combined with XELOX and bevacizumab demonstrated a manageable safetyprofile and potent antitumor activity in unresectable mCRC.展开更多
Concurrent inhibition of angiogenesis and immune checkpoints represents a potent therapeutic approach.We conducted a phase 2,multicenter,basket study to assess the efficacy and safety of combination therapy of famitin...Concurrent inhibition of angiogenesis and immune checkpoints represents a potent therapeutic approach.We conducted a phase 2,multicenter,basket study to assess the efficacy and safety of combination therapy of famitinib(anti-angiogenic agent)plus camrelizumab(PD-1 antagonist)in patients with metastatic solid tumors across 11 cohorts(this study was registered at Clinicaltrials.gov[NCT04346381]).This report focuses on the cohort of patients with metastatic or advanced colorectal cancer.Eligible patients,who had previously received R2 lines of systemic treatments for their metastatic disease,were treated with famitinib(20 mg once daily)in combination with camrelizumab(200 mg intravenously every 3 weeks).The primary endpoint was the objective response rate,with secondary endpoints encompassing progressionfree survival,overall survival,duration of response,safety and exploratory biomarkers.A total of 44 patients were enrolled and treated.With a median follow-up time of 9.46 months(range 2.0-22.5 months),objective responses were observed in 6 patients(13.6%;95%confidence interval[CI],5.2%-27.4%),all of whom had rectal cancer.The median duration of response is 6.2 months(95%CI,2.3-10.6 months).Median progression-free survival was 3.3 months(95%CI,2.1-4.1 months),and median overall survival was 10.9 months(95%CI,7.6-15.2 months).Among the 44 patients,29(65.9%)experienced grade 3 or 4 treatment-related adverse events,predominantly hypertension and proteinuria.In conclusion,the combination of famitinib and camrelizumab demonstrates promising antitumor activity with a manageable safety profile in metastatic colorectal cancer patients.Further research is warranted to confirm and extend these findings.展开更多
In 2022,gastric cancer(GC)ranked as the fifth most common cancer and the third leading cause of cancer death in China,with 358,672 new cases and 260,372 deaths,accounting for 37.0%and 39.4%of global cases,respectively...In 2022,gastric cancer(GC)ranked as the fifth most common cancer and the third leading cause of cancer death in China,with 358,672 new cases and 260,372 deaths,accounting for 37.0%and 39.4%of global cases,respectively[1].Previous studies have shown that 25.9%and 36.5%of GC patients in China were diagnosed at stages III and IV,respectively,with 5-year overall survival(OS)rates of 33.0%for stage III and 5.5%for stage IV[2,3].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financially supported by the Scientific Research Foundation of Shanxi Province Healthy Commission (No. 2017068)the Doctor Scientific Research Foundation of Shanxi cancer hospital (No. 2017A03)the Natural Science Foundation of Shanxi Province (No. 201801D221259)
文摘Objective: Tumor microenvironment, especially the host immune system, plays a pivotal role in tumor initiation and progression. Profiling of immune signature within tumor might uncover biomarkers for targeted therapies and clinical outcomes. However, systematic analysis of immune-related genes in gastric cancer(GC) has not been reported.Methods: Expressions of a total of 718 immune-related genes were generated in 372 stomach adenocarcinoma(STAD) patients from The Cancer Genome Atlas(TCGA) database using RNA-sequencing data. Integrated bioinformatics analyses were performed to identify prognostic factors as well.Results: Survival analyses revealed 73 genes, which were significantly associated with patient’s overall survival(OS). Taken together with clinicopathological parameters, we established a predictive model, containing 10 immune-related genes, which were NRP1, C6, CXCR4, LBP, PNMA1, TLR5, ITGA6, MICB, PBK and TNFRSF18,with powerful efficiency in distinguishing satisfactory or poor survival of STAD patients. Moreover, the top 3 ranked prognostic genes, NRP1, TGFβ2 and MFGE8, were also significantly associated with patient’s OS by an independent validation achieved from Kaplan-Meier plotter database.Conclusions: We profiled prognostic immune signature and established prognostic predictive model for GC,which could reflect immune disorders within tumor microenvironment, and also may provide novel predictive and therapeutic targets for GC patients in the near future.
基金supported by Jiangsu Hengrui Pharmaceuticals and the following grants:the National Natural Science Foundation of China(NSFC:82321003,82173128,82073377,81930065)the Natural Science Foundation of Guangdong(2021A1515012439)+2 种基金Guangdong Basic and Applied Basic Research Foundation(2024B1515020120)the CAMS Innovation Fund for Medical Sciences(CIFMS:2019-I2M-5-036)Additional funding was provided by the Cancer Innovative Research Program of Sun Yat-sen University Cancer Center(CIRP-SYSUCC-0004).
文摘This phase 2/3 trial (NCT04856787) assessed the efficacy and safety of SHR-1701, a bifunctional protein targeting PD-L1 and TGF-β,in combination with BP102 (a bevacizumab biosimilar) and XELOX (capecitabine plus oxaliplatin) as a first-line treatment forunresectable metastatic colorectal cancer (mCRC). In this phase 2 study, a total of 62 patients with untreated, histologicallyconfirmed colorectal adenocarcinoma and no prior systemic therapy for metastatic disease were enrolled. Patients receivedSHR-1701 (30 mg/kg), bevacizumab (7.5 mg/kg), and oxaliplatin (130 mg/m^(2)) intravenously on day 1, along with oral capecitabine(1 g/m^(2) twice daily) on days 1-14 of 21-day cycles. Up to eight induction cycles were administered, followed by maintenancetherapy for responders or those with stable disease. The primary endpoints were safety and objective response rate (ORR) perRECIST v1.1. The combination achieved an ORR of 59.7% and a disease control rate (DCR) of 83.9%. Median progression-free survival(PFS) was 10.3 months (95% CI: 8.3-13.7), with 6- and 12-month PFS rates of 77.2% and 41.3%, respectively. The estimated12-month overall survival (OS) rate was 67.7%. Grade ≥3 treatment-related adverse events (TRAEs) were reported in 59.7% ofpatients, with anemia and neutropenia (8.1% each) being the most common. Retrospective DNA sequencing revealed that hightumor mutational burden, neo-antigens, and SBS15 enrichment correlated with better responses. Elevated baseline lactatedehydrogenase was linked to shorter PFS. SHR-1701 combined with XELOX and bevacizumab demonstrated a manageable safetyprofile and potent antitumor activity in unresectable mCRC.
基金supported by Jiangsu Hengrui Pharmaceuticals Co.,Ltd.,National Natural Science Foundation of China(82373402,82272775)Shanghai Shen-kang Hospital Development Center(SHDC2022CRT001)+1 种基金Shanghai Rising-Star Program(21QA1401600)the Cancer Center,Zhongshan Hospital(2023XKPT19-RC1).
文摘Concurrent inhibition of angiogenesis and immune checkpoints represents a potent therapeutic approach.We conducted a phase 2,multicenter,basket study to assess the efficacy and safety of combination therapy of famitinib(anti-angiogenic agent)plus camrelizumab(PD-1 antagonist)in patients with metastatic solid tumors across 11 cohorts(this study was registered at Clinicaltrials.gov[NCT04346381]).This report focuses on the cohort of patients with metastatic or advanced colorectal cancer.Eligible patients,who had previously received R2 lines of systemic treatments for their metastatic disease,were treated with famitinib(20 mg once daily)in combination with camrelizumab(200 mg intravenously every 3 weeks).The primary endpoint was the objective response rate,with secondary endpoints encompassing progressionfree survival,overall survival,duration of response,safety and exploratory biomarkers.A total of 44 patients were enrolled and treated.With a median follow-up time of 9.46 months(range 2.0-22.5 months),objective responses were observed in 6 patients(13.6%;95%confidence interval[CI],5.2%-27.4%),all of whom had rectal cancer.The median duration of response is 6.2 months(95%CI,2.3-10.6 months).Median progression-free survival was 3.3 months(95%CI,2.1-4.1 months),and median overall survival was 10.9 months(95%CI,7.6-15.2 months).Among the 44 patients,29(65.9%)experienced grade 3 or 4 treatment-related adverse events,predominantly hypertension and proteinuria.In conclusion,the combination of famitinib and camrelizumab demonstrates promising antitumor activity with a manageable safety profile in metastatic colorectal cancer patients.Further research is warranted to confirm and extend these findings.
基金approved by the Independent Ethics Committee of Chinese PLA General Hospital(C2021-102-01)Changzhi People’s Hospital(LSPJ2022006)+17 种基金Fujian Provincial Cancer Hospital(2022-016-01)Cancer Hospital of Shandong First Medical University(SDZLEC2022-042-01)The First People’s Hospital of Changde City(2022-016-01)Jilin Cancer Hospital(202201-011-01)Linyi People’s Hospital(2022-lunlishencha-10)Liaoning Cancer Hospital and Institute(20220205)Shanxi Province Cancer Hospital(YW2022009)Affiliated Cancer Hospital of Zhengzhou University,Henan Cancer Hospital(L2022-Y010-002)Harbin Medical University Cancer Hospital(2022-91)Anhui Provincial Cancer Hospital,The First Affiliated Hospital of University of Science and Technology of China(2022-lunlishencha-08)The Fourth Hospital of Hebei Medical University(2022044)Binzhou Medical University Hospital(2022-001-01)Central Hospital Affiliated to Shandong Medical University(jizhongxinlunlilinshen2022-011-01)Qingdao Central Hospital,University of Health and Rehabilitation Science([Y]SY202200401)Liaocheng People’s Hospital(2022006)Suining Central Hospital(2022-lunliyijian-sy002-01)Yanan University Xianyang Hospital(YDXYEC-YWPJ-2022-5)conducted in accordance with the Declaration of Helsinki and Good Clinical Practices.Written informed consent was obtained from all patients before enrollment.
文摘In 2022,gastric cancer(GC)ranked as the fifth most common cancer and the third leading cause of cancer death in China,with 358,672 new cases and 260,372 deaths,accounting for 37.0%and 39.4%of global cases,respectively[1].Previous studies have shown that 25.9%and 36.5%of GC patients in China were diagnosed at stages III and IV,respectively,with 5-year overall survival(OS)rates of 33.0%for stage III and 5.5%for stage IV[2,3].
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.
