This article is more than 5 years old. Information may no longer be current.
Neratinib fails to extend PFS in ERBB2–positive metastatic breast cancer
First-line neratinib plus paclitaxel did not prolong PFS compared with trastuzumab and paclitaxel in patients with metastatic ERBB2–positive breast cancer, according to results of the randomized, open-label NEfERT-T trial.
Although the neratinib (PB272, Puma Biotechnology) and paclitaxel combination increased incidence of diarrhea, it also delayed the onset and reduced the frequency of central nervous system progression, results showed.
Mark D. Pegram
“The NEfERT-T study ... suggests that neratinib is no more effective than trastuzumab [Herceptin, Genentech] in unselected ERBB2–positive breast cancer,” Ahmed Awada, MD, PhD, head of the Medical Oncology Clinic at Jules Bordet Institute in Brussels, Belgium and colleagues wrote. “But, [neratinib] may have a potential role in patients at risk for central nervous system metastatic events and has more side effects (particularly diarrhea).”
Therapies directed against ERBB2 have improved OS in patients with early-stage and metastatic ERBB2–positive breast cancer. However, mortality is common 2 to 5 years after relapse in patients with stage IV disease.
Awada and colleagues sought to determine the efficacy of neratinib — an oral small-molecule tyrosine kinase inhibitor of ERBB1, ERBB2 and ERBB4 — as first-line treatment for patients with metastatic disease.
Researchers randomly assigned 479 women with previously untreated recurrent or metastatic ERBB2–positive breast cancer to receive 80 mg/m2 paclitaxel (days 1, 8 and 15 every 28 days) with neratinib (n = 242; 240 mg daily) or trastuzumab (n = 237; 4 mg/kg followed by 2 mg/kg weekly). Researchers stratified randomization by prior trastuzumab and lapatinib (Tykerb, Novartis) exposure, hormone-receptor status and region.
Median follow-up was 23 months.
PFS served as the primary endpoint. Secondary endpoint included response rate, clinical benefit rate, duration of response, frequency and time to CNS lesions, and safety.
Overall, 167 (69%) women in the neratinib arm experienced a PFS event, and median PFS in this cohort was 12.9 months (95% CI, 11.1-14.9). In the trastuzumab arm, 156 (65.8%) women experienced a PFS event, with a median PFS of 12.9 (95% CI, 11.1-14.8). These data suggested PFS was comparable between the two cohorts (HR = 1.02, 95% CI, 0.81-1.27).
Objective response rate (neratinib, 74.8%; trastuzumab, 77.6%) and median duration of response (13.4 months vs. 12.9 months) also were comparable between the cohorts.
However, fewer symptomatic or progressive CNS recurrences occurred in the neratinib arm compared with the trastuzumab arm (8.3% vs. 17.3%; RR = 0.48; 95% CI, 0.29-0.79).
The estimated 2-year incidence of CNS recurrence was 16.3% in the neratinib arm and 32.1% in the trastuzumab arm (HR = 0.45, 95% CI, 0.226-0.78).
The most common adverse events in the neratinib and trastuzumab arms included diarrhea (92.5% vs. 33.3%), alopecia (52.1% vs. 56.4%) and nausea (44.2% vs. 30.3%). Grade 3 diarrhea occurred in 73 patients (30.4%) in the neratinib arm compared with nine patients (3.8%) in the trastuzumab arm (P < .001); however, no grade 4 diarrhea occurred.
Researchers acknowledged limitations to these results, including changes to the study protocol and smaller-than-expected enrollment. These limitations mean the data give a preliminary understanding of neratinib–paclitaxel efficacy and safety rather than a definitive understanding of treatment effects, researchers wrote.
Identifying which patients with ERBB2–positive breast cancer are most likely to develop brain metastases would enable clinicians to select an appropriate patient population for treatment with neratinib, Mark D. Pegram, MD, associate director for clinical research at Stanford Cancer Institute of Stanford University School of Medicine, wrote in an accompanying editorial.
“The results presented herein by Awada et al are of sufficient interest to merit father investigation, preferably prospectively (with antidiarrheal prophylaxis), and in principle coupled with an extensive companion biomarker campaign designed to further characterize and classify those patients at highest risk for development of brain metastasis,” Pegram wrote. “Only through focused clinical and/or translational research will important advances be made that exploit new insights into the tumor biology of ERBB2–positive brain metastasis.” – by Nick Andrews
Disclosure : Awada reports honoraria from Wyeth in relation to this study. Please see the full study for a list of all other researchers’ relevant financial disclosures. Pegram reports consultant roles with Genentech/Roche and Pfizer. He also served on the data and safety monitoring committee for a phase 2 trial of neratinib compared with lapatinib plus capecitabine for ERBB2–positive advanced breast cancer.