Objective:To evaluate the efficacy and safety of QL1206(a denosumab biosimilar to Xgeva■)in breast cancer patients with bone metastasis(BM)through subgroup analysis of a randomized,double-blind phaseⅢtrial(No.NCT045...Objective:To evaluate the efficacy and safety of QL1206(a denosumab biosimilar to Xgeva■)in breast cancer patients with bone metastasis(BM)through subgroup analysis of a randomized,double-blind phaseⅢtrial(No.NCT04550949).Methods:This subgroup analysis included patients with BM from breast cancer enrolled in a phaseⅢtrial.Patients were randomized(1:1)to receive either three cycles of QL1206 or denosumab(120 mg subcutaneously every 4 weeks).Subsequently,they received 10 cycles of QL1206(120 mg)over 40 weeks,followed by a 20-week safety follow-up.The primary endpoint was the percentage changes from baseline to week 13 in urinary Ntelopeptide corrected for creatinine(u NTx/Cr).Results:The breast cancer cohort consisted of 311 patients.Vertebral involvement(66.4%)was the most prevalent BM site at enrollment,while 27.7%of patients presented with≥3 metastatic bone lesions.At week 13,QL1206 demonstrated a median u NTx/Cr reduction of-69.9%(range:-98.1%-568.0%)vs.-74.3%(range:-97.7%-386.3%)for denosumab.The analysis of covariance revealed comparable least-square means for log-transformed changes:-1.416[95%confidence interval(95%CI):-1.736 to-1.096]vs.-1.501(95%CI:-1.824 to-1.178),yielding an between-group difference of 0.085(90%CI:-0.062-0.232;P=0.343).After a 53-week treatment period,83.6%achieved bone density improvement/disease stabilization.Safety profiles were comparable between groups.Conclusions:QL1206 demonstrated similar efficacy and safety to the reference denosumab in patients with BM from breast cancer,supporting QL1206 as a new option for management of BM from breast cancer.展开更多
This phase Ⅲ trial aimed to compare ARX788,a site-specific,construct-homogeneous antibody-drug conjugate,with lapatinib plus capecitabine in patients with human epidermal growth factor receptor 2(HER2)-positive advan...This phase Ⅲ trial aimed to compare ARX788,a site-specific,construct-homogeneous antibody-drug conjugate,with lapatinib plus capecitabine in patients with human epidermal growth factor receptor 2(HER2)-positive advanced breast cancer(ABC)who had progressed on one line of trastuzumab based regimen.Eligible patients were randomized(1:1)to receive ARX788(1.5 mg/kg,IV,Q3W)or lapatinib plus capecitabine(LC:lapatinib 1250 mg QD;capecitabine 1000 mg/m^(2) BID,days 1-14,Q3W)and stratified by prior chemotherapy lines(0-1 versus>1)and visceral metastasis(yes versus no).The primary outcome was progression-free survival(PFS)assessed by a blinded independent central review(BICR).A total of 441 patients were randomly assigned to receive either ARX788(n=221)or LC(n=220).The median PFS was 11.3(95%confidence interval[CI],8.4-13.8)months with ARX788 compared with 8.2(95%CI,6.9-8.7)months with LC,as per BICR(hazard ratio[HR]0.64,p=0.0006).Frequencies of treatment-related adverse events(TRAEs)of any grade were 98.6%and 99.1%for ARX788 and LC,respectively.Grade≥3 TRAEs were 41.4%and 40.0%,respectively,the most common adverse events were blurred vision(12.3%),dry eye(9.1%),keratopathy(5.9%),and interstitial lung disease(ILD,5.9%)with ARX788;hand-foot syndrome(18.1%)and hypokalemia(5.1%)with LC;all the hematological and gastrointestinal events of grade≥3 with ARX788 were less than 3%.Six treatment-related deaths occurred,with three cases possibly related to ILD.ARX788 significantly improved PFS compared with LC in patients with HER2-positive ABC with a distinct toxicity profile,supporting it as a potential treatment option.展开更多
The potential benefits of pyrotinib for patients with trastuzumab-insensitive,HER2-positive early-stage breast cancer remain unclear.This prospective,multicentre,response-adapted study evaluated the efficacy and safet...The potential benefits of pyrotinib for patients with trastuzumab-insensitive,HER2-positive early-stage breast cancer remain unclear.This prospective,multicentre,response-adapted study evaluated the efficacy and safety of adding pyrotinib to the neoadjuvant treatment of HER2-positive breast cancer patients with a poor response to initial docetaxel plus carboplatin and trastuzumab(TCbH).Early response was assessed using magnetic resonance imaging(MRI)after two cycles of treatment.Patients showing poor response,as defined by RECIST 1.1,could opt to receive additional pyrotinib or continue standard therapy.The primary endpoint was the total pathological complete response(tpCR;ypT0/isN0)rate.Of the 129 patients enroled,62(48.1%)were identified as MRI-responders(cohort A),26 non-responders continued with four more cycles of TCbH(cohort B),and 41 nonresponders received additional pyrotinib(cohort C).The tpCR rate was 30.6%(95%CI:20.6–43.0%)in cohort A,15.4%(95%CI:6.2–33.5%)in cohort B,and 29.3%(95%CI:17.6–44.5%)in cohort C.Multivariable logistic regression analyses demonstrated comparable odds of achieving tpCR between cohorts A and C(odds ratio=1.04,95%CI:0.40–2.70).No new adverse events were observed with the addition of pyrotinib.Patients with co-mutations of TP53 and PIK3CA exhibited lower rates of early partial response compared to those without or with a single gene mutation(36.0%vs.60.0%,P=0.08).These findings suggest that adding pyrotinib may benefit patients who do not respond to neoadjuvant trastuzumab plus chemotherapy.Further investigation is warranted to identify biomarkers predicting patients’benefit from the addition of pyrotinib.展开更多
Background:Bireociclib(XZP-3287)is a novel selective cyclin-dependent kinase 4 and 6(CDK4/6)inhibitor,with a favorable safety profile demonstrated in preclinical and phase I studies.BRIGHT-1 aimed to further explore t...Background:Bireociclib(XZP-3287)is a novel selective cyclin-dependent kinase 4 and 6(CDK4/6)inhibitor,with a favorable safety profile demonstrated in preclinical and phase I studies.BRIGHT-1 aimed to further explore the efficacy and safety of bireociclib monotherapy in patients with locally advanced,recurrent or metastatic,hormone receptor-positive and human epidermal growth factor receptor 2-negative(HR+/HER2−)breast cancer who had progressed on or after prior chemotherapy and endocrine therapy in advanced settings,without previous exposure to CDK4/6 inhibitors.Methods:In this open-label phase II trial,eligible patients received bireociclib 480 mg twice daily(BID)until disease progression or intolerable toxicities.The primary endpoint was the confirmed objective response rate(ORR)assessed by an independent review committee(IRC).The secondary endpoints included progression-free survival(PFS),investigator-assessed ORR,disease control rate(DCR),clinical benefit rate(CBR),duration of response(DoR),overall survival(OS),safety and the pharmacokinetic properties of bireociclib.Results:A total of 131 patients were enrolled.At data cutoff(July 31,2023),the IRC-assessed ORR was 29.8%(95%confidence interval[CI],22.1%to 38.4%),with a DCR of 73.3%(95%CI,64.8%to 80.6%),CBR of 42.0%(95%CI,33.4%to 50.9%)and a median DoR of 15.2 months(95%CI,9.5 months to not reached).The median PFS was 11.0 months(95%CI,7.3 months to 12.9 months)assessed by the IRC,and the median OS was 29.0 months(95%CI,24.9 months to not reached).The most frequently reported treatment-emergent adverse events(TEAEs)of any grade were diarrhea(93.1%),neutrophil count decreased(87.0%),white blood cell decreased(86.3%),vomiting(78.6%),anemia(72.5%),and platelet count decreased(72.5%).The grade≥3 TEAEs occurred in 109(83.2%)patients.The most common grade≥3 TEAEs were neutrophil count decreased(43.5%),white blood cell decreased(32.8%),hypokalemia(20.6%),and diarrhea(19.1%).Conclusions:Bireociclib monotherapy at 480 mg BID exhibited promising and sustained clinical activity,with no unexpected and acceptable toxicity in patients with recurrent or metastatic HR+/HER2−breast cancer who had progressed on or after previous therapy.Trial registration:Clinicaltrials.gov ID,NCT04539496.展开更多
Background:The standard first-line treatment for human epidermal growth factor receptor 2(HER2)-positive recurrent/metastatic breast cancer currently includes pertuzumab plus trastuzumab and docetaxel.This study aimed...Background:The standard first-line treatment for human epidermal growth factor receptor 2(HER2)-positive recurrent/metastatic breast cancer currently includes pertuzumab plus trastuzumab and docetaxel.This study aimed to evaluate the effectiveness of KN026,an anti-HER2 bispecific antibody,plus docetaxel in first-line treatment of HER2-positive recurrent/metastatic breast cancer.Methods:This open-label,single-arm,phase II study enrolled patients with HER2-positive recurrent/metastatic breast cancer in 19 centers across China from December 30,2019 to May 27,2021.Patients were administered KN026(30 mg/kg)plus docetaxel(75 mg/m2)in 21-day cycles.Primary endpoints included the objective response rate(ORR)and duration of response(DOR).In addition,overall survival(OS),progression-free survival(PFS),clinical benefit rate(CBR)and safety profile were examined.Results:A total of 57 patients were included.In the efficacy analysis set of 55 patients,the ORR was 76.4%(95%confidence interval[CI],63.0%-86.8%),and the CBR was 85.5%(95%CI,73.3%-93.5%).The median DOR was not reached(95%CI,20.7 months-not reached).In the safety set of 57 patients,the median PFS was 27.7 months(95%CI,18.0 months-not reached).The median OS was not reached,with OS rates at 12,24 and 30 months of 93.0%,84.1%and 78.5%,respectively.Grade≥3 treatment-emergent adverse events(AEs)were detected in 36(63.2%)patients.No deaths were attributed to KN026 or docetaxel.Conclusion:KN026 plus docetaxel showed promising efficacy and a manageable safety profile in first-line treatment of HER2-positive recurrent/metastatic breast cancer.展开更多
Entinostat plus exemestane in hormone receptor-positive(HR+)advanced breast cancer(ABC)previously showed encouraging outcomes.This multicenter phase 3 trial evaluated the efficacy and safety of entinostat plus exemest...Entinostat plus exemestane in hormone receptor-positive(HR+)advanced breast cancer(ABC)previously showed encouraging outcomes.This multicenter phase 3 trial evaluated the efficacy and safety of entinostat plus exemestane in Chinese patients with HR+ABC that relapsed/progressed after≥1 endocrine therapy.Patients were randomized(2:1)to oral exemestane 25 mg/day plus entinostat(n=235)or placebo(n=119)5 mg/week in 28-day cycles.The primary endpoint was the independent radiographic committee(IRC)-assessed progression-free survival(PFS).The median age was 52(range,28—75)years and 222(62.7%)patients were postmenopausal.CDK4/6 inhibitors and fulvestrant were previously used in 23(6.5%)and 92(26.0%)patients,respectively.The baseline characteristics were comparable between the entinostat and placebo groups.The median PFS was 6.32(95%CI,5.30—9.11)and 3.72(95%CI,1.91—5.49)months in the entinostat and placebo groups(HR,0.76;95%CI,0.58—0.98;P=0.046),respectively.Grade≥3 adverse events(AEs)occurred in 154(65.5%)patients in the entinostat group versus 23(19.3%)in the placebo group,and the most common grade≥3 treatment-related AEs were neutropenia[103(43.8%)],thrombocytopenia[20(8.5%)],and leucopenia[15(6.4%)].Entinostat plus exemestane significantly improved PFS compared with exemestane,with generally manageable toxicities in HR+ABC(ClinicalTrials.gov#NCT03538171).展开更多
文摘Objective:To evaluate the efficacy and safety of QL1206(a denosumab biosimilar to Xgeva■)in breast cancer patients with bone metastasis(BM)through subgroup analysis of a randomized,double-blind phaseⅢtrial(No.NCT04550949).Methods:This subgroup analysis included patients with BM from breast cancer enrolled in a phaseⅢtrial.Patients were randomized(1:1)to receive either three cycles of QL1206 or denosumab(120 mg subcutaneously every 4 weeks).Subsequently,they received 10 cycles of QL1206(120 mg)over 40 weeks,followed by a 20-week safety follow-up.The primary endpoint was the percentage changes from baseline to week 13 in urinary Ntelopeptide corrected for creatinine(u NTx/Cr).Results:The breast cancer cohort consisted of 311 patients.Vertebral involvement(66.4%)was the most prevalent BM site at enrollment,while 27.7%of patients presented with≥3 metastatic bone lesions.At week 13,QL1206 demonstrated a median u NTx/Cr reduction of-69.9%(range:-98.1%-568.0%)vs.-74.3%(range:-97.7%-386.3%)for denosumab.The analysis of covariance revealed comparable least-square means for log-transformed changes:-1.416[95%confidence interval(95%CI):-1.736 to-1.096]vs.-1.501(95%CI:-1.824 to-1.178),yielding an between-group difference of 0.085(90%CI:-0.062-0.232;P=0.343).After a 53-week treatment period,83.6%achieved bone density improvement/disease stabilization.Safety profiles were comparable between groups.Conclusions:QL1206 demonstrated similar efficacy and safety to the reference denosumab in patients with BM from breast cancer,supporting QL1206 as a new option for management of BM from breast cancer.
文摘This phase Ⅲ trial aimed to compare ARX788,a site-specific,construct-homogeneous antibody-drug conjugate,with lapatinib plus capecitabine in patients with human epidermal growth factor receptor 2(HER2)-positive advanced breast cancer(ABC)who had progressed on one line of trastuzumab based regimen.Eligible patients were randomized(1:1)to receive ARX788(1.5 mg/kg,IV,Q3W)or lapatinib plus capecitabine(LC:lapatinib 1250 mg QD;capecitabine 1000 mg/m^(2) BID,days 1-14,Q3W)and stratified by prior chemotherapy lines(0-1 versus>1)and visceral metastasis(yes versus no).The primary outcome was progression-free survival(PFS)assessed by a blinded independent central review(BICR).A total of 441 patients were randomly assigned to receive either ARX788(n=221)or LC(n=220).The median PFS was 11.3(95%confidence interval[CI],8.4-13.8)months with ARX788 compared with 8.2(95%CI,6.9-8.7)months with LC,as per BICR(hazard ratio[HR]0.64,p=0.0006).Frequencies of treatment-related adverse events(TRAEs)of any grade were 98.6%and 99.1%for ARX788 and LC,respectively.Grade≥3 TRAEs were 41.4%and 40.0%,respectively,the most common adverse events were blurred vision(12.3%),dry eye(9.1%),keratopathy(5.9%),and interstitial lung disease(ILD,5.9%)with ARX788;hand-foot syndrome(18.1%)and hypokalemia(5.1%)with LC;all the hematological and gastrointestinal events of grade≥3 with ARX788 were less than 3%.Six treatment-related deaths occurred,with three cases possibly related to ILD.ARX788 significantly improved PFS compared with LC in patients with HER2-positive ABC with a distinct toxicity profile,supporting it as a potential treatment option.
基金funded by the Clinical Research Center of Shandong University(Grant No.2020SDUCRCA003)the National Natural Science Foundation of China(Grant Nos.82273701 and 82072914)the Fundamental Research Funds for the Central Universities(Grant No.2022JC009).
文摘The potential benefits of pyrotinib for patients with trastuzumab-insensitive,HER2-positive early-stage breast cancer remain unclear.This prospective,multicentre,response-adapted study evaluated the efficacy and safety of adding pyrotinib to the neoadjuvant treatment of HER2-positive breast cancer patients with a poor response to initial docetaxel plus carboplatin and trastuzumab(TCbH).Early response was assessed using magnetic resonance imaging(MRI)after two cycles of treatment.Patients showing poor response,as defined by RECIST 1.1,could opt to receive additional pyrotinib or continue standard therapy.The primary endpoint was the total pathological complete response(tpCR;ypT0/isN0)rate.Of the 129 patients enroled,62(48.1%)were identified as MRI-responders(cohort A),26 non-responders continued with four more cycles of TCbH(cohort B),and 41 nonresponders received additional pyrotinib(cohort C).The tpCR rate was 30.6%(95%CI:20.6–43.0%)in cohort A,15.4%(95%CI:6.2–33.5%)in cohort B,and 29.3%(95%CI:17.6–44.5%)in cohort C.Multivariable logistic regression analyses demonstrated comparable odds of achieving tpCR between cohorts A and C(odds ratio=1.04,95%CI:0.40–2.70).No new adverse events were observed with the addition of pyrotinib.Patients with co-mutations of TP53 and PIK3CA exhibited lower rates of early partial response compared to those without or with a single gene mutation(36.0%vs.60.0%,P=0.08).These findings suggest that adding pyrotinib may benefit patients who do not respond to neoadjuvant trastuzumab plus chemotherapy.Further investigation is warranted to identify biomarkers predicting patients’benefit from the addition of pyrotinib.
基金supported by the National Major Scientific and Technological Special Project for“Significant New Drugs Development”(No.2018ZX09711002-011-027)the Chinese Academy of Medical Sciences(CAMS)Inno-vation Fund for Medical Sciences(CIFMS,2021-I2M-1-014 and 2023-12M-2-004).
文摘Background:Bireociclib(XZP-3287)is a novel selective cyclin-dependent kinase 4 and 6(CDK4/6)inhibitor,with a favorable safety profile demonstrated in preclinical and phase I studies.BRIGHT-1 aimed to further explore the efficacy and safety of bireociclib monotherapy in patients with locally advanced,recurrent or metastatic,hormone receptor-positive and human epidermal growth factor receptor 2-negative(HR+/HER2−)breast cancer who had progressed on or after prior chemotherapy and endocrine therapy in advanced settings,without previous exposure to CDK4/6 inhibitors.Methods:In this open-label phase II trial,eligible patients received bireociclib 480 mg twice daily(BID)until disease progression or intolerable toxicities.The primary endpoint was the confirmed objective response rate(ORR)assessed by an independent review committee(IRC).The secondary endpoints included progression-free survival(PFS),investigator-assessed ORR,disease control rate(DCR),clinical benefit rate(CBR),duration of response(DoR),overall survival(OS),safety and the pharmacokinetic properties of bireociclib.Results:A total of 131 patients were enrolled.At data cutoff(July 31,2023),the IRC-assessed ORR was 29.8%(95%confidence interval[CI],22.1%to 38.4%),with a DCR of 73.3%(95%CI,64.8%to 80.6%),CBR of 42.0%(95%CI,33.4%to 50.9%)and a median DoR of 15.2 months(95%CI,9.5 months to not reached).The median PFS was 11.0 months(95%CI,7.3 months to 12.9 months)assessed by the IRC,and the median OS was 29.0 months(95%CI,24.9 months to not reached).The most frequently reported treatment-emergent adverse events(TEAEs)of any grade were diarrhea(93.1%),neutrophil count decreased(87.0%),white blood cell decreased(86.3%),vomiting(78.6%),anemia(72.5%),and platelet count decreased(72.5%).The grade≥3 TEAEs occurred in 109(83.2%)patients.The most common grade≥3 TEAEs were neutrophil count decreased(43.5%),white blood cell decreased(32.8%),hypokalemia(20.6%),and diarrhea(19.1%).Conclusions:Bireociclib monotherapy at 480 mg BID exhibited promising and sustained clinical activity,with no unexpected and acceptable toxicity in patients with recurrent or metastatic HR+/HER2−breast cancer who had progressed on or after previous therapy.Trial registration:Clinicaltrials.gov ID,NCT04539496.
文摘Background:The standard first-line treatment for human epidermal growth factor receptor 2(HER2)-positive recurrent/metastatic breast cancer currently includes pertuzumab plus trastuzumab and docetaxel.This study aimed to evaluate the effectiveness of KN026,an anti-HER2 bispecific antibody,plus docetaxel in first-line treatment of HER2-positive recurrent/metastatic breast cancer.Methods:This open-label,single-arm,phase II study enrolled patients with HER2-positive recurrent/metastatic breast cancer in 19 centers across China from December 30,2019 to May 27,2021.Patients were administered KN026(30 mg/kg)plus docetaxel(75 mg/m2)in 21-day cycles.Primary endpoints included the objective response rate(ORR)and duration of response(DOR).In addition,overall survival(OS),progression-free survival(PFS),clinical benefit rate(CBR)and safety profile were examined.Results:A total of 57 patients were included.In the efficacy analysis set of 55 patients,the ORR was 76.4%(95%confidence interval[CI],63.0%-86.8%),and the CBR was 85.5%(95%CI,73.3%-93.5%).The median DOR was not reached(95%CI,20.7 months-not reached).In the safety set of 57 patients,the median PFS was 27.7 months(95%CI,18.0 months-not reached).The median OS was not reached,with OS rates at 12,24 and 30 months of 93.0%,84.1%and 78.5%,respectively.Grade≥3 treatment-emergent adverse events(AEs)were detected in 36(63.2%)patients.No deaths were attributed to KN026 or docetaxel.Conclusion:KN026 plus docetaxel showed promising efficacy and a manageable safety profile in first-line treatment of HER2-positive recurrent/metastatic breast cancer.
基金sponsored by EOC Pharmaceutical CO,and CAMS Innovation Fund for Medical Sciences(CIFMS,2021I2M-1-014,China)Taizhou EOC Pharma Co.,Ltd.for supporting,developing and sponsoring this trial。
文摘Entinostat plus exemestane in hormone receptor-positive(HR+)advanced breast cancer(ABC)previously showed encouraging outcomes.This multicenter phase 3 trial evaluated the efficacy and safety of entinostat plus exemestane in Chinese patients with HR+ABC that relapsed/progressed after≥1 endocrine therapy.Patients were randomized(2:1)to oral exemestane 25 mg/day plus entinostat(n=235)or placebo(n=119)5 mg/week in 28-day cycles.The primary endpoint was the independent radiographic committee(IRC)-assessed progression-free survival(PFS).The median age was 52(range,28—75)years and 222(62.7%)patients were postmenopausal.CDK4/6 inhibitors and fulvestrant were previously used in 23(6.5%)and 92(26.0%)patients,respectively.The baseline characteristics were comparable between the entinostat and placebo groups.The median PFS was 6.32(95%CI,5.30—9.11)and 3.72(95%CI,1.91—5.49)months in the entinostat and placebo groups(HR,0.76;95%CI,0.58—0.98;P=0.046),respectively.Grade≥3 adverse events(AEs)occurred in 154(65.5%)patients in the entinostat group versus 23(19.3%)in the placebo group,and the most common grade≥3 treatment-related AEs were neutropenia[103(43.8%)],thrombocytopenia[20(8.5%)],and leucopenia[15(6.4%)].Entinostat plus exemestane significantly improved PFS compared with exemestane,with generally manageable toxicities in HR+ABC(ClinicalTrials.gov#NCT03538171).
