The oral pan-HER TKI neratinib continued to show similar rates of disease-free survival for patients with HER2-positive early-stage breast cancer at a 3-year analysis of the phase III ExteNET trial.
Arlene Chan, MD
The oral pan-HER TKI neratinib continued to show similar rates of disease-free survival (DFS) for patients with HER2-positive early-stage breast cancer, according to a 3-year exploratory analysis of the ExteNET trial presented at the 2015 San Antonio Breast Cancer Symposium.
The updated 3-year invasive DFS rate was 92% with neratinib versus 89.9% for placebo (HR, 0.74; 95% CI, 0.56-0.96; P = .023). In those specifically with centrally confirmed HER2-positive/HR-positive breast cancer, the 3-year DFS rate was 94.4% versus 88%, for neratinib and placebo, respectively (HR, 0.43; 95% CI, 0.26-0.70; P <.001).
“The 3-year exploratory analysis is consistent with and supports the 2-year primary analysis results—that neratinib improved invasive disease-free survival," said lead investigator Arlene Chan, MD, director of the Breast Cancer Clinical Trials Unit at Mount Hospital in Perth. “Diarrhea is the most common adverse event, although this usually happens within the first 30 days. Typically the frequency and severity of this side effect will abate with ongoing treatment.”
In the phase III study, 2840 patients who remained disease-free following 1 year of treatment with adjuvant trastuzumab and chemotherapy were randomized to neratinib (n = 1420) or placebo (n = 1420). Neratinib was administered for 12 months at 240 mg per day.
Following the initiation of the study in 2009, the trial underwent several protocol adjustments, including changes to the patient population, primary endpoints, and the number of enrolled patients. Throughout these various alterations, which were accompanied by new trial sponsors, the independent data monitoring committee remained the same.
During these changes, the trial duration had been restricted to 2 years. In order to gather additional data, an exploratory analysis was initiated and patients were readmitted into the study for an additional 3- and 5-year follow-up. At this point, there were 856 patients in the neratinib arm and 922 in the placebo group.
In the exploratory group, the median age in the neratinib arm was 52 years. Overall, 19.9% of patients had node-negative disease in the neratinib arm versus 23.6% in the placebo group. HR-positive disease was seen in 57.7% and 57.3% of patients and the median number of prior therapies was 4.2 and 4.3, for the neratinib and placebo arms, respectively. By central testing, only 84% of patients were found to be HER2-positive.
At the data cutoff for the 3-year analysis of November 30, 2015, those with centrally confirmed HER2-positive disease (n = 1709) had an invasive DFS rate with neratinib of 91.8% versus 89.6% with placebo (HR, 0.70; P = .037). In patients who received ≤1 year of trastuzumab, the invasive DFS rate was 91.5% with neratinib versus 88.9% with placebo (HR, 0.72; 95% CI, 0.54-0.95; P = .020).
“For patients at higher risk, those patients who entered the trial within 12 months of completing trastuzumab, these patients demonstrated a consistent benefit with the receipt of neratinib,” said Chan.
A greater benefit was seen with neratinib in those with HR-positive and HER2-positive breast cancer. In this group, the 3-year invasive DFS rate with neratinib was 93.6% versus 89.3% in the placebo arm (HR, 0.57, P = .003). In patients with HER2/HR-positive breast cancer who received ≤1 year of trastuzumab, the 3-year invasive DFS rates were 93.3% versus 88.6%, for neratinib and placebo, respectively (HR, 0.57; P = .004).
In the HR-negative group, there was no improvement seen between the neratinib group and the placebo arm, suggesting a distinct population that benefits from the TKI. In the HR-negative group, invasive DFS rate with neratinib was 88.1% versus 89.5% with placebo (HR, 0.98; 95% CI, 0.67-1.45; P = .938).
“The population of patients who are hormone receptor-positive continued to derive benefit with the two curves remaining separate well through 48 months while the patients with hormone receptor-negative disease did not appear to benefit,” explained Chan.
In the 2-year analysis, which was the primary endpoint of the study, the 2-year invasive DFS rate was 93.9% in the neratinib arm versus 91.6% with placebo (HR, 0.67; 95% CI, 0.50-0.91; P = .009). In patients with HER2-positive/HR-positive breast cancer (n = 1631), the 2-year invasive DFS rate with neratinib was 95.4% compared with 91.2% with placebo (HR, 0.51; P = .001).
In the earlier analysis, 95.4% of patients treated with neratinib experienced all-grade diarrhea (39.9% was grade 3). The median duration of grade 3 diarrhea was 5 days and 1.4% of patients required hospitalization.
Quality of life scores by FACT-B were distinctly worse during the first 30 days in the neratinib arm, related to diarrhea; however, after 30 days, the two groups reported similar scores.
“The occurrence of grade 3 diarrhea clearly had an impact on quality of life, as demonstrated by the FACT-B,” Chan said. “Inline with the typical abatement of diarrhea, we can see the quality of life is pretty much identical for both the placebo and neratinib groups beyond the first 30 days.”
Within the initial protocol of the trial, prophylactic treatment with loperamide was not given, Chan noted. In other studies assessing neratinib, proper diarrhea prophylaxis successfully reduced the rate of grade 3 events to between 0 and 17%, she said.
Other gastrointestinal-related side effects included nausea (43%), fatigue (27%), vomiting (26.2%), and abdominal pain (24.1%). In the placebo arm, 35.4% of patients had all-grade diarrhea, with a grade 3/4 incidence of 1.6%.
Other adverse events of special interest included QT prolongation, which was less common in the neratinib arm (3.5% vs 6.6%). Left ventricular ejection fraction abnormalities of grade ≥2 were 1.3% with neratinib versus 1.1% with placebo.
“There are ongoing trials in progress to confirm the efficacy of loperamide prophylaxis. We hope to report findings from a phase II study, which is currently ongoing, to evaluate the efficacy of loperamide prophylaxis in patients receiving adjuvant neratinib,” Chan said.
Chan A, Delaloge S, Holmes FA, et al. Neratinib after trastuzumab-based adjuvant therapy in early-stage HER2+ breast cancer: 3-year analysis from a phase 3 randomized, placebo-controlled, double-blind trial (ExteNET). Presented at: San Antonio Breast Cancer Symposium; December 8-12, 2015; San Antonio, TX. Abstract S5-02.