Background:Human epidermal growth factor receptor 2(HER2)overexpression is related to anti-HER2 therapy in many tumors.RC48-antibody-drug conjugate(ADC)has shown promising efficacy in patients with HER2-positive local...Background:Human epidermal growth factor receptor 2(HER2)overexpression is related to anti-HER2 therapy in many tumors.RC48-antibody-drug conjugate(ADC)has shown promising efficacy in patients with HER2-positive locally advanced or metastatic urothelial carcinoma(UC).The characteristic expression and scoring systems of HER2 are nonexistent in UC.We aimed to explore HER2 status and its correlation with the efficacy of HER2-targeting ADC therapy in UC.Methods:A total of 137 and 43 patients were enrolled in cohort 1 and cohort 2,respectively,from March 2009 to December 2018.The patients in cohort 2 were enrolled in a phase II study of RC48-ADC.UC samples were tested for HER2 status using immunohistochemistry(IHC)and/or fluorescence in situ hybridization(FISH).The 2018 ASCO/CAP HER2 scoring system was adopted and modified to score HER2 expression in UC.Results:The HER2-positive(IHC 2+or 3+)rate was 24.1%(33/137).In HER2 IHC 2+or 3+patients,the HER2 gene amplification rate was 31%(13/42).The objective response rates(ORRs)in RC48-ADC-treated patients with IHC 3+,IHC 2+and FISH+,IHC 2+and FISH-were 58.8%,66.7%and 40%,respectively.The ORR showed a trend toward a better benefit for RC48-ADC therapy in patients with HER2 amplification than in those without amplification(61.5%vs.44.8%,P=0.059).The heterogeneity of HER2 expression in the primary tumor was 55.5%(15/27),and the ORR was not significantly different between patients with tumor heterogeneity and homogeneity.Conclusions:IHC testing should be performed to assess the HER2 status before the initiation of HER2-ADC therapy.There was a trend toward a better benefit for patients with HER2 amplification,and tumor heterogeneity did not influence the drug efficacy.展开更多
IBI310 is a recombinant fully human IgG1 antibody against cytotoxic T lymphocyte antigen 4.This study was conducted to evaluate IBI310 monotherapy or combination therapy with sintilimab in the patients with advanced m...IBI310 is a recombinant fully human IgG1 antibody against cytotoxic T lymphocyte antigen 4.This study was conducted to evaluate IBI310 monotherapy or combination therapy with sintilimab in the patients with advanced melanoma or urothelial carcinoma(UC).Patients in phase 1a received IBI310 at 0.3/1/2/3 mg/kg intravenously(IV)every 3 weeks(Q3W)following the accelerated titration and 3+3 escalation design.Patients in phase 1b received IBI310(1/2/3 mg/kg IV,Q3W)plus sintilimab(200 mg IV,Q3W)for four cycles,followed by sintilimab maintenance therapy.The phase 1b expansion of IBI310 plus sintilimab was performed in patients with advanced melanoma or UC.Overall,53 patients were enrolled,including 10 patients with melanoma in phase 1a,34 with melanoma,and 9 with UC in phase 1b.Overall,94.3%of patients(50/53)experienced at least one treatment-related adverse event(TRAE)with most being grade 1–2;26.4%of patients(14/53)experienced grade 3 or higher TRAEs.In phase 1a,the disease control rate(DCR)was 50.0%(95%confidence interval[CI],18.7%–81.3%).In phase 1b,the objective response rate(ORR)and DCR were 17.6%(95%CI,6.8%–34.5%)and 44.1%(95%CI,27.2%–62.1%),respectively,for melanoma,and were 22.2%(95%CI,2.8%–60.0%)and 66.7%(95%CI,29.9%–92.5%),respectively,for UC.IBI310 monotherapy or combination therapy with sintilimab was well tolerated with favorable antitumor activity across patients with advanced melanoma and UC.展开更多
Neoadjuvant PD-1 inhibitor is promising in cutaneous melanoma but remains unknown in acral melanoma(AM).This phase Ib trial study(Clinicaltrials.gov NCT04197882)assessed the efficacy and safety of the combination of n...Neoadjuvant PD-1 inhibitor is promising in cutaneous melanoma but remains unknown in acral melanoma(AM).This phase Ib trial study(Clinicaltrials.gov NCT04197882)assessed the efficacy and safety of the combination of neoadjuvant oncolytic virus orienX010(ori)and anti-PD-1 toripalimab(tori)for resectable AM.Thirty patients of stage III/IV received neoadjuvant therapy of ori and tori for 12 weeks before surgery,followed by adjuvant treatment with tori for 1 year.Primary endpoints were radiographic and pathological response rates,with secondary endpoints of 1-and 2-year recurrence-free survival(RFS)rates,event-free survival(EFS)rates,and safety.Twenty-seven completed surgery and tori adjuvant treatment and median follow-up was 35.7 months.Radiographic and pathological response rates were 36.7%and 77.8%,with complete response rates of 3.3%and 14.8%,1-and 2-year RFS rates of 85.2%and 81.5%,and 1-and 2-year EFS rates of 83%and 73%,respectively.Adverse events occurred in all patients,mainly grade 1-2.There was no correlation between PET/CT evaluation and pathological response or progression-free survival/overall survival.Patients with pathological response showed tumor beds with high tertiary lymphoid structures(TLSs)and tumor-infiltrating lymphocytes(TILs).Cytokines and chemokines analysis showed the combination therapy significantly increases the secretion of proinflammatory cytokines and chemokines in both responders and non-responders.Therefore,neoadjuvant ori and tori demonstrated promising antitumor activity with high response rates and high 2-year RFS/EFS for AM with acceptable tolerability.展开更多
基金supported by National Key Research and Development Plan(grant number:2022YFC2409902).
文摘Background:Human epidermal growth factor receptor 2(HER2)overexpression is related to anti-HER2 therapy in many tumors.RC48-antibody-drug conjugate(ADC)has shown promising efficacy in patients with HER2-positive locally advanced or metastatic urothelial carcinoma(UC).The characteristic expression and scoring systems of HER2 are nonexistent in UC.We aimed to explore HER2 status and its correlation with the efficacy of HER2-targeting ADC therapy in UC.Methods:A total of 137 and 43 patients were enrolled in cohort 1 and cohort 2,respectively,from March 2009 to December 2018.The patients in cohort 2 were enrolled in a phase II study of RC48-ADC.UC samples were tested for HER2 status using immunohistochemistry(IHC)and/or fluorescence in situ hybridization(FISH).The 2018 ASCO/CAP HER2 scoring system was adopted and modified to score HER2 expression in UC.Results:The HER2-positive(IHC 2+or 3+)rate was 24.1%(33/137).In HER2 IHC 2+or 3+patients,the HER2 gene amplification rate was 31%(13/42).The objective response rates(ORRs)in RC48-ADC-treated patients with IHC 3+,IHC 2+and FISH+,IHC 2+and FISH-were 58.8%,66.7%and 40%,respectively.The ORR showed a trend toward a better benefit for RC48-ADC therapy in patients with HER2 amplification than in those without amplification(61.5%vs.44.8%,P=0.059).The heterogeneity of HER2 expression in the primary tumor was 55.5%(15/27),and the ORR was not significantly different between patients with tumor heterogeneity and homogeneity.Conclusions:IHC testing should be performed to assess the HER2 status before the initiation of HER2-ADC therapy.There was a trend toward a better benefit for patients with HER2 amplification,and tumor heterogeneity did not influence the drug efficacy.
基金supported by grants from Beijing Health Technologies Promotion Program(BHTPP2022041)Peking University Clinical Scientist Training Program,the Fundamental Research Funds for the Central Universities(BMU2024PYJH010)+2 种基金Beijing Municipal Administration of Hospitals Incubating Program(PX2021046)Science Foundation of Peking University Cancer Hospital(PY202333)Innovent Biologics,Inc.,Suzhou,China.The funder,Innovent Biologics,was involved in the study design,data collection,data analysis,and data interpretation.
文摘IBI310 is a recombinant fully human IgG1 antibody against cytotoxic T lymphocyte antigen 4.This study was conducted to evaluate IBI310 monotherapy or combination therapy with sintilimab in the patients with advanced melanoma or urothelial carcinoma(UC).Patients in phase 1a received IBI310 at 0.3/1/2/3 mg/kg intravenously(IV)every 3 weeks(Q3W)following the accelerated titration and 3+3 escalation design.Patients in phase 1b received IBI310(1/2/3 mg/kg IV,Q3W)plus sintilimab(200 mg IV,Q3W)for four cycles,followed by sintilimab maintenance therapy.The phase 1b expansion of IBI310 plus sintilimab was performed in patients with advanced melanoma or UC.Overall,53 patients were enrolled,including 10 patients with melanoma in phase 1a,34 with melanoma,and 9 with UC in phase 1b.Overall,94.3%of patients(50/53)experienced at least one treatment-related adverse event(TRAE)with most being grade 1–2;26.4%of patients(14/53)experienced grade 3 or higher TRAEs.In phase 1a,the disease control rate(DCR)was 50.0%(95%confidence interval[CI],18.7%–81.3%).In phase 1b,the objective response rate(ORR)and DCR were 17.6%(95%CI,6.8%–34.5%)and 44.1%(95%CI,27.2%–62.1%),respectively,for melanoma,and were 22.2%(95%CI,2.8%–60.0%)and 66.7%(95%CI,29.9%–92.5%),respectively,for UC.IBI310 monotherapy or combination therapy with sintilimab was well tolerated with favorable antitumor activity across patients with advanced melanoma and UC.
基金supported by the National Key Research and Development Program(2023YFC2506404)National Natural Science Foundation of China(82372869,82272676,and 82073011)+1 种基金Beijing Municipal Administration of Hospitals’Ascent Plan(DFL20220901,QML20231107)Beijing Natural Science Foundation(7242021).
文摘Neoadjuvant PD-1 inhibitor is promising in cutaneous melanoma but remains unknown in acral melanoma(AM).This phase Ib trial study(Clinicaltrials.gov NCT04197882)assessed the efficacy and safety of the combination of neoadjuvant oncolytic virus orienX010(ori)and anti-PD-1 toripalimab(tori)for resectable AM.Thirty patients of stage III/IV received neoadjuvant therapy of ori and tori for 12 weeks before surgery,followed by adjuvant treatment with tori for 1 year.Primary endpoints were radiographic and pathological response rates,with secondary endpoints of 1-and 2-year recurrence-free survival(RFS)rates,event-free survival(EFS)rates,and safety.Twenty-seven completed surgery and tori adjuvant treatment and median follow-up was 35.7 months.Radiographic and pathological response rates were 36.7%and 77.8%,with complete response rates of 3.3%and 14.8%,1-and 2-year RFS rates of 85.2%and 81.5%,and 1-and 2-year EFS rates of 83%and 73%,respectively.Adverse events occurred in all patients,mainly grade 1-2.There was no correlation between PET/CT evaluation and pathological response or progression-free survival/overall survival.Patients with pathological response showed tumor beds with high tertiary lymphoid structures(TLSs)and tumor-infiltrating lymphocytes(TILs).Cytokines and chemokines analysis showed the combination therapy significantly increases the secretion of proinflammatory cytokines and chemokines in both responders and non-responders.Therefore,neoadjuvant ori and tori demonstrated promising antitumor activity with high response rates and high 2-year RFS/EFS for AM with acceptable tolerability.
