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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
la/mBC - HER2 positive - 2nd Line (L2)
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.
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)
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.
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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