Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer

Abstract

Introduction:Neratinib is a potent irreversible pan-ErbB tyrosine kinase inhibitor that has demonstrated antitumour activity and an acceptable safety profile in patients with human epidermal growth factor receptor (HER)-2-positive breast cancer and other solid tumours.Methods:This was a phase I/II, open-label, two-part study. Part 1 was a dose-escalation study to determine the maximum tolerated dose (MTD) of neratinib plus paclitaxel in patients with solid tumours. Part 2 evaluated the safety, efficacy, and pharmacokinetics of the combination at the MTD in patients with HER2-positive breast cancer.Results:Eight patients were included in the dose-escalation study; no dose-limiting toxicities were observed, and an MTD of oral neratinib 240 mg once daily plus intravenous paclitaxel 80 mg m−2 on days 1, 8, and 15 of each 28-day cycle was determined. A total of 102 patients with HER2-positive breast cancer were enrolled in part 2. The overall median treatment duration was 47.9 weeks (range: 0.1–147.3 weeks). Common treatment-emergent adverse events (all grades/grade ⩾3) included diarrhoea (92%/29% none grade 4), peripheral sensory neuropathy (51%/3%), neutropenia (50%/20%), alopecia (46%/0%), leukopenia (41%/18%), anaemia (37%/8%), and nausea (34%/1%). Three (3%) patients discontinued treatment due to an adverse event (mouth ulceration, left ventricular ejection fraction reduction, and acute renal failure). Among the 99 evaluable patients in part 2 of the study, the overall response rate (ORR) was 73% (95% confidence interval (CI): 62.9–81.2%), including 7 (7%) patients who achieved a complete response; an additional 9 (9%) patients achieved stable disease for at least 24 weeks. ORR was 71% among patients with 0/1 prior chemotherapy regimen for metastatic disease and no prior lapatinib, and 77% among those with 2/3 prior chemotherapy regimens for metastatic disease with prior lapatinib permitted. Kaplan–Meier median progression-free survival was 57.0 weeks (95% CI: 47.7–81.6 weeks). Pharmacokinetic analyses indicated no interaction between neratinib and paclitaxel.Conclusion:The combination of neratinib and paclitaxel was associated with higher toxicity than that of neratinib as a single agent, but was manageable with antidiarrhoeal agents and dose reductions in general. The combination therapy also demonstrated a high rate of response in patients with HER2-positive breast cancer. A phase III trial is ongoing to assess the benefit and risk of this combination in the first-line setting.

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

“…Neratinib exposure, when given in combination with vinorelbine, paclitaxel or temsirolimus [63][64][65], was similar to that observed after neratinib monotherapy [61] ( Table 2). The potential for interactions between neratinib and other chemotherapeutic or targeted agents (i.e.…”

“…Considerably higher overall response rates were observed when neratinib was combined with chemotherapeutic agents, notably paclitaxel (73%) [64] and capecitabine (63%) [70] (Table 3), findings that have prompted larger randomized trials of these combinations. The results from the first of these studies -NEfERT-T -have recently been reported [69] (Table 3).…”

CNS Metastases in Breast Cancer: Old Challenge, New Frontiers

“…Neratinib is an irreversible inhibitor of EGFR and HER2. Phase II data in patients with HER2-positive metastatic breast cancer have been encouraging with respect to single-agent activity, as well as activity in combination with chemotherapy (63)(64)(65). A prospective, phase II study evaluating neratinib monotherapy enrolling patients with progressing breast cancer brain metastases has recently completed accrual (NCT01494662) and plans are ongoing to further study the effects of neratinib in the brain when given in conjunction with capecitabine (R. Freedman, Dana-Farber Cancer Institute; personal communication).…”

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

“…In SKBR-3 cells, the use of paclitaxel or vinblastine together with neratinib led to greater antiproliferative effect than with either chemotherapy or neratinib alone. This preclinical data led to the development of a phase I/ II study of neratinib and paclitaxel (NP) [Chow et al 2013]. In part one of this study, eight patients with advanced solid malignancy were treated in a dose-escalation study using a standard 3 + 3 cohort design to determine the maximal tolerated dose (MTD).…”