Safety and efficacy of neratinib in combination with weekly paclitaxel and trastuzumab in women with metastatic HER2-positive breast cancer: an NSABP Foundation Research Program phase I study

Abstract

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).

Pharmacodynamics, pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations

“…Although the precise loperamide regimen varies from study to study, it typically involves administering loperamide 16 mg on day 1, with dose tapering to 12 mg/day and then 6-8 mg/day over the first cycle of treatment [80]. Preliminary data from trials including an intensive loperamide prophylaxis regimen show a marked reduction in the incidence of grade 3 diarrhea (ranging from 0 to 17%) [72,73,81] compared with the ExteNET trial (40%), in which diarrhea was managed only after the development of symptoms [75]. The effectiveness of loperamide prophylaxis in the prevention of neratinibassociated diarrhea is currently being investigated in a prospective multicenter phase II trial (Table 4).…”

Neratinib in HER-2-positive breast cancer: results to date and clinical usefulness

“…Of 15 patients allocated to dosing cohorts 120 mg, 160 mg or 240 mg, eight patients (53.3%, 4 in the 120 mg cohort and 4 in the 160 mg and 240 mg cohorts) experienced grade 3 diarrhea either during cycles one or two (n = 6) or subsequent to cycle two (n = 2). With the implementation of a mandatory loperamide prophylaxis regimen (4 mg with the first dose of neratinib, followed by 2 mg every 4 hours during days 1-3, and 2 mg every 6-8 hours during days 4-21) in patients allocated to the 200 mg cohort, there were no observed episodes of grade 3 or 4 diarrhea and four of six patients experienced grade 1 or 2 diarrhea at some time during study treatment [Jankowitz et al 2013]. A transient decline of ⩾10% in left-ventricular ejection fraction from baseline was seen in two patients, with only one patient experiencing asymptomatic decline in ejection fraction below 50%, which recovered without treatment modification.…”

New protein kinase inhibitors in breast cancer: afatinib and neratinib

“…Clinical benefit rate is defined as complete response plus partial response plus stable disease (CBR = CR + PR + SD). The combination therapy was well tolerated [62]. A Phase III trial of neratinib plus paclitaxel compared with trastuzumab plus paclitaxel is ongoing.…”