PURPOSE: Neratinib is an oral, small-molecule inhibitor that irreversibly binds to pan-HER (ErbB) receptor tyrosine kinases. Studies suggest that dual anti-HER therapies utilized in breast cancer patients are more efficacious than single agents in both the metastatic and neoadjuvant settings. In this phase I study, neratinib was combined with trastuzumab and paclitaxel in metastatic HER2-positive patients. METHODS: Twenty-one patients entered this dose-escalation study to determine the maximum-tolerated dose, safety, and efficacy of neratinib (120 up to 240 mg/day) with trastuzumab (4 mg/kg IV loading dose, then 2 mg/kg IV weekly), and paclitaxel (80 mg/m(2) IV days 1, 8, and 15 of a 28-day cycle) in women with HER2-positive metastatic breast cancer previously treated with anti-HER agent(s) and ataxane. RESULTS: The recommended phase II dose of neratinib with trastuzumab and paclitaxel was 200 mg/day. Common grade 3/4 adverse events were diarrhea (38 %), dehydration (14 %), electrolyte imbalance (19 %), and fatigue (19 %). With mandated primary diarrheal prophylaxis, ≥grade 3 diarrhea was not observed. Objective responses, complete (CR) and partial (PR), occurred in eight patients (38 %), with a clinical benefit of CR + PR+ stable disease (SD) ≥24 weeks in 11 patients (52 %). Median time-to-disease progression was 3.7 months. CONCLUSIONS: Dual anti-HER blockade with neratinib and trastuzumab resulted in significant clinical benefit despite prior exposure to trastuzumab, lapatinib, T-DM1, a taxane, and multiple lines of chemotherapy. In selected populations, inhibiting multiple ErbB-family receptors may be more advantageous than single-agent inhibition. Based on favorable tolerance and efficacy, this three-drug combination will be further assessed in a randomized phase II neoadjuvant trial (NSABP FB-7:NCT01008150).
RCT Entities:
PURPOSE:Neratinib is an oral, small-molecule inhibitor that irreversibly binds to pan-HER (ErbB) receptor tyrosine kinases. Studies suggest that dual anti-HER therapies utilized in breast cancerpatients are more efficacious than single agents in both the metastatic and neoadjuvant settings. In this phase I study, neratinib was combined with trastuzumab and paclitaxel in metastatic HER2-positive patients. METHODS: Twenty-one patients entered this dose-escalation study to determine the maximum-tolerated dose, safety, and efficacy of neratinib (120 up to 240 mg/day) with trastuzumab (4 mg/kg IV loading dose, then 2 mg/kg IV weekly), and paclitaxel (80 mg/m(2) IV days 1, 8, and 15 of a 28-day cycle) in women with HER2-positive metastatic breast cancer previously treated with anti-HER agent(s) and a taxane. RESULTS: The recommended phase II dose of neratinib with trastuzumab and paclitaxel was 200 mg/day. Common grade 3/4 adverse events were diarrhea (38 %), dehydration (14 %), electrolyte imbalance (19 %), and fatigue (19 %). With mandated primary diarrheal prophylaxis, ≥grade 3 diarrhea was not observed. Objective responses, complete (CR) and partial (PR), occurred in eight patients (38 %), with a clinical benefit of CR + PR+ stable disease (SD) ≥24 weeks in 11 patients (52 %). Median time-to-disease progression was 3.7 months. CONCLUSIONS: Dual anti-HER blockade with neratinib and trastuzumab resulted in significant clinical benefit despite prior exposure to trastuzumab, lapatinib, T-DM1, a taxane, and multiple lines of chemotherapy. In selected populations, inhibiting multiple ErbB-family receptors may be more advantageous than single-agent inhibition. Based on favorable tolerance and efficacy, this three-drug combination will be further assessed in a randomized phase II neoadjuvant trial (NSABP FB-7:NCT01008150).
Authors: John W Park; Minetta C Liu; Douglas Yee; Christina Yau; Laura J van 't Veer; W Fraser Symmans; Melissa Paoloni; Jane Perlmutter; Nola M Hylton; Michael Hogarth; Angela DeMichele; Meredith B Buxton; A Jo Chien; Anne M Wallace; Judy C Boughey; Tufia C Haddad; Stephen Y Chui; Kathleen A Kemmer; Henry G Kaplan; Claudine Isaacs; Rita Nanda; Debasish Tripathy; Kathy S Albain; Kirsten K Edmiston; Anthony D Elias; Donald W Northfelt; Lajos Pusztai; Stacy L Moulder; Julie E Lang; Rebecca K Viscusi; David M Euhus; Barbara B Haley; Qamar J Khan; William C Wood; Michelle Melisko; Richard Schwab; Teresa Helsten; Julia Lyandres; Sarah E Davis; Gillian L Hirst; Ashish Sanil; Laura J Esserman; Donald A Berry Journal: N Engl J Med Date: 2016-07-07 Impact factor: 91.245
Authors: Carlton L Schwab; Diana P English; Jonathan Black; Stefania Bellone; Salvatore Lopez; Emiliano Cocco; Elena Bonazzoli; Beatrice Bussi; Federica Predolini; Francesca Ferrari; Elena Ratner; Dan-Arin Silasi; Masoud Azodi; Thomas Rutherford; Peter E Schwartz; Alessandro D Santin Journal: Gynecol Oncol Date: 2015-08-08 Impact factor: 5.482
Authors: Mariana Segovia-Mendoza; María E González-González; David Barrera; Lorenza Díaz; Rocío García-Becerra Journal: Am J Cancer Res Date: 2015-08-15 Impact factor: 6.166