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docetaxel plus carboplatin with trastuzumab followed by trastuzumab (n=1075) vs. doxorubicin plus cyclophosphamide followed by docetaxel (n=1073)
randomized controlled trial
docetaxel plus carboplatin with trastuzumab followed by trastuzumab
docetaxel 75mg per square meter plus carboplatin AUC 6mg/mL per minute, every 3 weeks for 6 cycles / trastuzumab: for 1 year beginnig with the first dose of docetaxel, initiailly administered at a dose of 4mg per kg of body weight, followed by 2mg per kg per week during chemotherapy and then 6mg per kg every 3 weeks to complete 1 year of trastuzumab treatment
doxorubicin plus cyclophosphamide followed by docetaxel
doxorubicin: 60mg per square meter every 3 weeks for four cycles / cyclophosphamide: 600mg per square meter every 3 weeks for four cycles / followed by docetaxel: 100 mg per square meter) every 3 weeks for four doses (AC-T)
breast cancer - adjuvant
open label
41 countries
P3 / DFS and OS compared between the 3 study group at 2-sided 5%, a step-down testing procedure has been proposed in order to compare the control arm (AC-T) to each trastuzumab-containing arm (AC-TH and TCH) at a level equal to alpha / 2 to account for multiple testing, if both of these comparisons reach statistical significance, then compare the two trastuzumab-containing arms at level alpha / 3IA: will be conducted after 300 (p=0.0002), 450 (p=0.0030) and 650 (p=0.0111) observed events. Final analysis at 900 (p=0.0461) events.
TCH improve significantly DFS compare to AC-T for women with HER2-positive BC, however results are exploratory for OS.
doxorubicin plus cyclophosphamide followed by docetaxel plus trastuzumab (n=1074) vs. docetaxel plus carboplatin with trastuzumab followed by trastuzumab (n=1075)
randomized controlled trial
doxorubicin plus cyclophosphamide followed by docetaxel plus trastuzumab
trastuzumab: for 1 year beginnig with the first dose of docetaxel, initiailly administered at a dose of 4mg per kg of body weight, followed by 2mg per kg per week during chemotherapy and then 6mg per kg every 3 weeks to complete 1 year of trastuzumab treatment / plus AC-T
docetaxel plus carboplatin with trastuzumab followed by trastuzumab
docetaxel 75mg per square meter plus carboplatin AUC 6mg/mL per minute, every 3 weeks for 6 cycles / trastuzumab: for 1 year beginnig with the first dose of docetaxel, initiailly administered at a dose of 4mg per kg of body weight, followed by 2mg per kg per week during chemotherapy and then 6mg per kg every 3 weeks to complete 1 year of trastuzumab treatment
breast cancer - adjuvant
open label
41 countries
P3 / DFS and OS compared between the 3 study group at 2-sided 5%, a step-down testing procedure has been proposed in order to compare the control arm (AC-T) to each trastuzumab-containing arm (AC-TH and TCH) at a level equal to alpha / 2 to account for multiple testing, if both of these comparisons reach statistical significance, then compare the two trastuzumab-containing arms at level alpha / 3IA: will be conducted after 300 (p=0.0002), 450 (p=0.0030) and 650 (p=0.0111) observed events. Final analysis at 900 (p=0.0461) events.
No significant difference in the rateof disease-free or overall survival was seen between the two trastuzumab-containing regimens, however results were not reported.
doxorubicin plus cyclophosphamide followed by docetaxel plus trastuzumab (n=1074) vs. doxorubicin plus cyclophosphamide followed by docetaxel (n=1073)
randomized controlled trial
doxorubicin plus cyclophosphamide followed by docetaxel plus trastuzumab
trastuzumab: for 1 year beginnig with the first dose of docetaxel, initiailly administered at a dose of 4mg per kg of body weight, followed by 2mg per kg per week during chemotherapy and then 6mg per kg every 3 weeks to complete 1 year of trastuzumab treatment / plus AC-T
doxorubicin plus cyclophosphamide followed by docetaxel
doxorubicin: 60mg per square meter every 3 weeks for four cycles / cyclophosphamide: 600mg per square meter every 3 weeks for four cycles / followed by docetaxel: 100 mg per square meter) every 3 weeks for four doses (AC-T)
breast cancer - adjuvant
open label
41 countries
P3 / DFS and OS compared between the 3 study group at 2-sided 5%, a step-down testing procedure has been proposed in order to compare the control arm (AC-T) to each trastuzumab-containing arm (AC-TH and TCH) at a level equal to alpha/2 to account for multiple testing, if both of these comparisons reach statistical significance, then compare the two trastuzumab-containing arms at level alpha. 3IA: will be conducted after 300 (p=0.0002), 450 (p=0.0030) and 650 (p=0.0111) observed events. Final analysis at 900 (p=0.0461) events.
Addition of trastuzumab significantly improve DFS for women with HER2-positive BC, however results are exploratory for OS.
neratinib (n=1420) vs. placebo (n=1420)
randomized controlled trial
neratinib
neratinib: 240mg PO daily for 12 months
placebo
placebo: PO daily for 12 months
breast cancer - adjuvant
double blind
495 centers in Europe, Asia, Australia, New Zealand, and North and South America
P3 / IDFS in ITT population at 2-sided 5%. no IA planned. There were 3 different sponsors during the study, resulting to 3 global amendments with notable changes to study design. Final amendment: IDFS in the ITT population at 2yr.
pertuzumab plus trastuzumab (n=2400) vs. trastuzumab (n=2404)
randomized controlled trial
pertuzumab plus trastuzumab plus chemotherapy
pertuzumab: 840 mg IV as a loading dose, followed by 420 mg IV every 3 weeks / trastuzumab: 8mg per kg of body weight IV as a loading dose, followed by 6 mg per kg IV every 3 weeks / --> both beginning at the first cycle of taxane therapy and continuing for a maximum of 18 cycles within 1 year
placebo plus trastuzumab plus chemotherapy
placebo / trastuzumab: 8mg per kg of body weight IV as a loading dose, followed by 6 mg per kg IV every 3 weeks / --> both beginning at the first cycle of taxane therapy and continuing for a maximum of 18 cycles within 1 year
chemotherapy: Anti-HER2 treatment was given in combination with chemotherapy according to one of the following schedules: 3 or 4 cycles (every 3 weeks) of 5-fluorouracil plus either epirubicin or doxorubicin plus cyclophosphamide, followed by 3 or 4 cycles (every 3 weeks) of docetaxel or 12 weekly cycles of paclitaxel; 4 cycles (every 3 weeks or every 2 weeks) of cyclophosphamide plus either doxorubicin or epirubicin, followed by either 4 cycles (every 3 weeks) of docetaxel or 12 weekly cycles of paclitaxel; or 6 cycles (every 3 weeks) of docetaxel plus carboplatin
breast cancer - adjuvant
Exclusion criteria: Patients with previous invasive breast cancer, nonbreast cancer within 5 years before randomization, any previous chemotherapy or radiotherapy for cancer, any previous anti-HER2 therapy or other previous anticancer biologic therapy or immunotherapy
double blind
549 centers across 43 countries
P3 / controlled at 5% 2-sided, use of a hierarchical testing procedure: if IDFS is significant, following endpoints will be tested in the following order: IDFS including second primary non-breast cancer, DFS, OS. For OS, 3 IA: 1st at IDFS final p<0.00001, 2nd at 4-5 yr after last randomization: p=0.0027, 3rd at 7-8 yr after last randomization p=0.0139, final at 640 OS events (9-10yr) p = 0.0453
IDFS and DFS were significantly higher in the pertuzumab group compare to the placebo group.
trastuzumab plus epirubicin and cyclophosphamide followed by docetaxel (n=309) vs. lapatinib plus epirubicin and cyclophosphamide followed by docetaxel (n=311)
randomized controlled trial
trastuzumab plus epirubicin and cyclophosphamide followed by docetaxel
trastuzumab: IV 6 mg/kg body weight, every 3 weeks (loading dose of 8 mg/kg on day 1 of the first EC cycle) / epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 day 1, every 3 weeks / docetaxel: 100 mg/m2 day 1, every 3 weeks
lapatinib plus epirubicin and cyclophosphamide followed by docetaxel
lapatinib: 1,250 mg per day, starting on day 1 of the first cycle of EC until day 21 of the fourth cycle of docetaxel. Lapatinib was reduced to 1000mg per day to improve tolerability / epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 day 1, every 3 weeks / docetaxel: 100 mg/m2 day 1, every 3 weeks
All patients received four cycles of epidubicin and cyclophosphamide followed by four cycles of docetaxel.
es-BC - HER2 positive - (neo)adjuvant (NA)
open label
at 126 centres in Germany and one centre in Switzerland
P3 / pCR at 2-sided with alpha at 0.05 in the ITT population
pertuzumab plus trastuzumab (n=129) vs. trastuzumab (n=129)
randomized controlled trial
pertuzumab plus trastuzumab plus an AI (letrozole or anastrozole)
pertuzumab: IV 840 mg and 8 mg/kg loading doses followed by 420 mg / trastuzumab: IV 6 mg/kg maintenance doses / anastrozole: PO 1mg/day or letrozole: PO 2.5mg/day
trastuzumab plus an AI (letrozole or anastrozole)
trastuzumab: IV 6 mg/kg maintenance doses / anastrozole: PO 1mg/day or letrozole: PO 2.5mg/day
investigator could decide to administered chemotherapy: docetaxel and paclitaxel IV
la/mBC - HER2 positive - 1st Line (L1)
open label
80 sites in 8 countries
P2 / PFS at 2-sided at 0.05 / no SAP
pertuzumab plus trastuzumab plus docetaxel (n=-9) vs. trastuzumab plus docetaxel (n=-9)
randomized controlled trial
pertuzumab plus trastuzumab plus docetaxel
pertuzumab: IV 840 mg loading dose,followed by 420 mg every 3 weeks / trastuzumab: IV 8 mg/kgloading dose, then 6 mg/kg every 3 weeks / docetaxel: IV 75 mg/m2 every 3 weeks
placebo plus trastuzumab plus docetaxel
placebo matching pertuzumab / trastuzumab: IV 8 mg/kgloading dose, then 6 mg/kg every 3 weeks / docetaxel: IV 75 mg/m2 every 3 weeks
la/mBC - HER2 positive - 1st Line (L1)
double blind
15 centres in China
P3 / statistical testing is considered exploratory
pertuzumab plus trastuzumab plus docetaxel (n=402) vs. trastuzumab plus docetaxel (n=406)
randomized controlled trial
pertuzumab plus trastuzumab plus docetaxel
pertuzumab: fixed loading dose of 840 mg IV, followed by 420 mg IV every 3 weeks until disease progression / trastuzumab: loading dose of 8 mg/kg of body weight IV, followed by a maintenance dose of 6 mg per kg IV every 3 weeks until disease progression / docetaxel: every 3 weeks at a starting dose of 75 mg per square meter IV (increase possible to100mg if the side-effect profile was acceptable)
placebo plus trastuzumab plus docetaxel
placebo IV / trastuzumab: loading dose of 8 mg/kg of body weight IV, followed by a maintenance dose of 6 mg per kg IV every 3 weeks until disease progression / docetaxel: every 3 weeks at a starting dose of 75 mg per square meter IV (increase possible to100mg if the side-effect profile was acceptable)
la/mBC - HER2 positive - 1st Line (L1)
Exclusion criteria: therapy for metastatic breast cancer, central nervous system metastases.
double blind
204 centers in 25 countries
P3 / The overall type I error rate for the analysis of primary endpoint of PFS, OS and ORR will be controlled at 5% at 2-sided, using the fixed sequence testing procedure, in this order. / 2 IA for OS.
The addition of pertuzumab to trastuzumab and docetaxel increase significantly the PFS and the OS
trastuzumab plus endocrine therapy (n=196) vs. trastuzumab plus chemotherapy (n=196)
randomized controlled trial
trastuzumab plus endocrine therapy
trastuzumab: on day 1 of study treatment as an initial loading dose of 8 mg/kg. Subsequent dosing and scheduling of trastuzumab was 6 mg/kg every 3 weeks / endocrine therapy
trastuzumab plus chemotherapy
trastuzumab: on day 1 of study treatment as an initial loading dose of 8 mg/kg. Subsequent dosing and scheduling of trastuzumab was 6 mg/kg every 3 weeks / chemotherapy
la/mBC - HER2 positive - 1st Line (L1)
open label
in 9 hospitals in China
P3 / nononferiority, PFS at 0.025 and HR <1.35 / All efficacy analysis will be performed based on the ITT population
neratinib plus capecitabine (n=307) vs. lapatinib plus capecitabine (n=314)
randomized controlled trial
neratinib plus capecitabine
neratinib: 240 mg PO once daily continuously in 21-day cycles with no break between cycles / capecitabine: 1,500 mg/m2 PO daily in 2 evenly spaced doses [750 mg/m2 twice a day] on days 1-14 of 21-day cycles ///// Prophylactic antidiarrheal medication was mandated for the duration of cycle 1 in this group
lapatinib plus capecitabine
lapatinib: 1,250 mg PO once daily continuously / capecitabine: 2,000 mg/m2 PO daily in 2 evenly spaced doses [1,000 mg/m2 twice a day] on days 1-14 of 21-day cycles
la/mBC - HER2 positive - 2nd Line (L2)
open-label
203 sites in 28 countries in Europe, North and South America, Asia, and Australia
P3 / Coprimary end points were analyzed using an overall type I error rate of 0.01 for PFS and 0.04 for OS. No interim analysis. (trial was considered positive if either PFS or OS were statistically significant at the split alpha level)
Neratinib plus capecitabine significantly improved PFS but not significantly for OS, compared to lapatinib plus capecitabine.
neratinib plus capecitabine (n=51) vs. lapatinib plus capecitabine (n=50)
randomized controlled trial
neratinib plus capecitabine
neratinib: 240 mg PO once daily continuously in 21-day cycles with no break between cycles / capecitabine: 1,500 mg/m2 PO daily in 2 evenly spaced doses [750 mg/m2 twice a day] on days 1-14 of 21-day cycles ///// Prophylactic antidiarrheal medication was mandated for the duration of cycle 1 in this group
lapatinib plus capecitabine
lapatinib: 1,250 mg PO once daily continuously / capecitabine: 2,000 mg/m2 PO daily in 2 evenly spaced doses [1,000 mg/m2 twice a day] on days 1-14 of 21-day cycles
la/mBC - HER2 positive - 2nd Line (L2)
open-label
203 sites in 28 countries in Europe, North and South America, Asia, and Australia
P3 / Coprimary end points were analyzed using an overall type I error rate of 0.01 for PFS and 0.04 for OS. No interim analysis. (trial was considered positive if either PFS or OS were statistically significant at the split alpha level).Descriptive analysis for this study population (patients with brain metastasis)
Descriptive analysis for this population (patients with brain metastasis)
tucatinib plus trastuzumab plus capecitabine (n=198) vs. trastuzumab plus capecitabine (n=93)
randomized controlled trial
tucatinib plus trastuzumab plus capecitabine
tucatinib: 300mg PO twice daily / trastuzumab: 6 mg IV per kg of body weight once every 21 days, with an initial loading dose of 8 mg per kg; subcutaneous administration was allowed / capecitabine: 1000 mg PO per square meter of body-surface area orally twice daily on days 1 to 14 of each 21-day cycle
placebo plus trastuzumab plus capecitabine
placebo: PO twice daily / trastuzumab: 6 mg IV per kg of body weight once every 21 days, with an initial loading dose of 8 mg per kg; subcutaneous administration was allowed / capecitabine: 1000 mg PO per square meter of body-surface area orally twice daily on days 1 to 14 of each 21-day cycle
la/mBC - HER2 positive - 2nd Line (L2)
Excludion criteria: had previously received treatment for metastatic disease with capecitabine or a HER2-targeted tyrosine kinase inhibitor (although patients who had received lapatinib more than 12 months before initiating a trial regimen), patients with leptomeningeal disease
double-blind
155 sites in 15 countries
P2 / To maintain strong control of the family-wise type I error rate at 0.05, the PFS in the ITT population will be tested at 0.05, if it is significant, te alpha will be split between OS (0.02) and the PFS (in patients with brain metastases) (0.03) (If only one of OS and PFS(with brain metastases) is statistical significant, the unused alpha can be passed to the other one following the GSHv procedure.) / 1 IA for PFS (with brain metastases) with alpha at 0.008, and 2 IA for OS (1st IA alpha at 0.007) / (ITT population was not the same for PFS and OS, because authors continued to include patients to increase the power for the analyses)
Adding tucatinib to trastuzumab and capecitabine increase significantly PFS for patients with brain metastases.
tucatinib plus trastuzumab plus capecitabine (n=410) vs. trastuzumab plus capecitabine (n=202)
randomized controlled trial
tucatinib plus trastuzumab plus capecitabine
tucatinib: 300mg PO twice daily / trastuzumab: 6 mg IV per kg of body weight once every 21 days, with an initial loading dose of 8 mg per kg; subcutaneous administration was allowed / capecitabine: 1000 mg PO per square meter of body-surface area orally twice daily on days 1 to 14 of each 21-day cycle
placebo plus trastuzumab plus capecitabine
placebo: PO twice daily / trastuzumab: 6 mg IV per kg of body weight once every 21 days, with an initial loading dose of 8 mg per kg; subcutaneous administration was allowed / capecitabine: 1000 mg PO per square meter of body-surface area orally twice daily on days 1 to 14 of each 21-day cycle
la/mBC - HER2 positive - 2nd Line (L2)
Excludion criteria: had previously received treatment for metastatic disease with capecitabine or a HER2-targeted tyrosine kinase inhibitor (although patients who had received lapatinib more than 12 months before initiating a trial regimen), patients with leptomeningeal disease
double-blind
155 sites in 15 countries
P2 / To maintain strong control of the family-wise type I error rate at 0.05, the PFS in the ITT population will be tested at 0.05, if it is significant, te alpha will be split between OS (0.02) and the PFS (in patients with brain metastases) (0.03) (If only one of OS and PFS(with brain metastases) is statistical significant, the unused alpha can be passed to the other one following the GSHv procedure.) / 1 IA for PFS (with brain metastases) with alpha at 0.008, and 2 IA for OS (1st IA alpha at 0.007) / (ITT population was not the same for PFS and OS, because authors continued to include patients to increase the power for the analyses)
The study met its primary endpoints. Adding tucatinib to trastzumab and capecitabine incrase significantly the PFS and OS.
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