In a 5-year follow-up to the phase III ExteNET trial of women with HER2-positive stage I-IIIc operable breast cancer, investigators found that extended adjuvant therapy with neratinib (Nerlynx) significantly reduced the proportion of clinically relevant breast cancer relapses without increasing the risk of long-term toxicity.
In results now published at Lancet Oncology, treatment with neratinib reduced the risk of invasive disease recurrence or death by 27% compared with placebo as extended adjuvant therapy for patients with HER2-positive early stage breast cancer following 12 months of trastuzumab (Herceptin).
The 5-year invasive disease-free survival (DFS) rate with neratinib was 90.2% (95% CI, 88.3-91.8) compared with 87.7% (95% CI, 85.7-89.4) with placebo. After a median follow-up of 5.2 years (IQR, 2.1-5.3), patients in the neratinib group had 116 invasive disease-free survival (DFS) events compared with 163 for those in the placebo group (HR; 0.73; 95% CI, 0.57-0.92; P = .0083).
The restricted mean invasive DFS was 56.5 months (95% CI, 55.9-57.2) in the neratinib group (mean loss of 3.5 months from a total of 60 months) compared with 55.2 months (95% CI, 54.4-55.9) in the placebo group (mean loss of 4.8 months from a total of 60 months). The betweengroup difference was 1.3 months (95% CI, 0.3-2.3; P = .0085).
The 5-year analysis was not originally planned as part of the study and was requested as part of a new drug application (NDA) for neratinib in the United States and for a marketing authorization application (MAA) in Europe. The primary endpoint of the study was the 2-year invasive DFS rate, which was 93.9% with neratinib and 91.6% with placebo (HR, 0.67; P = .009). The FDA approved neratinib (Nerlynx) for extended adjuvant treatment in July 2017.
“After a median follow-up of 5 years, a significant invasive disease-free survival benefit is evident with neratinib given for 1 year after completion of trastuzumabbased adjuvant therapy in women with earlystage HER2positive breast cancer,” first author Miguel Martin, MD, PhD, Hospital Gregorio Maranon, Universidad Complutense, Madrid, Spain, and coinvestigators wrote.
“These findings are consistent with the primary 2year analysis, and support the durability of neratinib treatment effect in the intentiontotreat population. Prospectively defined subgroup analyses indicated greater benefit with neratinib in patients with hormone receptor–positive disease,” added Martin et al.
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). The interval between receiving trastuzumab and entering the trial was approximately 4.5 months. Patients received 240 mg of neratinib daily or placebo for 12 months.
The median age of patients in the study was 52 years and approximately 23.8% had node-negative disease, with 46.6% of patients having 1 to 3 positive nodes and 29.6% having ≥4 positive nodes. Anthracyclines were administered as adjuvant chemotherapy in the majority of patients (77%). Appropriate endocrine therapy was administered to 94% of patients with HR-positive breast cancer.
While neratinib was associated with improved DFS, including for patients with ductal carcinoma in situ, that was not the case for distant DFS and time to distant recurrence. Sixteen patients (1%) in the neratinib group and 23 (2%) in the placebo group had CNS events as the first distant recurrence. The 5year cumulative incidence of CNS events was 1.3% (95% CI, 0.8-2.1) in the neratinib group and 1.8% (95% CI, 1.2-2.7). in the placebo group (P = .333). Overall survival data are not yet mature.
The safety population included 2816 patients who received at least one dose of study treatment, 1408 patients in each group. The primary safety analysis was reported at the 2year followup, but investigators saw no evidence of longterm toxicity in these updated findings.
Across the full study population, 95.4% of patients treated with neratinib experienced all-grade diarrhea, of which 40% was grade 3/4. The trial design did not mandate antidiarrhea prophylaxis.
Other gastrointestinal-related adverse events included nausea (43%), fatigue (27%), vomiting (26%), and abdominal pain (24%). In the placebo arm, 36% of patients had all-grade diarrhea, with a grade 3/4 incidence of 2.0%.
Martin M, Holmes FA, Ejlertsen B, et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017; 18:1688-700.