Phase III Trial Shows No Benefit of Afatinib vs Trastuzumab Plus Vinorelbine in HER2-Positive Metastatic Breast Cancer
In the phase III LUX-Breast 1 trial reported in The Lancet Oncology, Harbeck et al found no benefit of afatinib (Gilotrif)/vinorelbine vs trastuzumab (Herceptin)/vinorelbine after previous trastuzumab treatment in patients with HER2-positive metastatic breast cancer. Broader inhibition of ErbB receptors with afatinib had been hypothesized to improve outcomes.
Study Details
In this open-label trial conducted at 350 sites in 41 countries worldwide, 508 patients were randomized 2:1 between August 2010 and April 2013 to receive oral afatinib at 40 mg/d (n = 339) or intravenous trastuzumab at 2 mg/kg per week after a 4-mg/kg loading dose (n = 169), both with intravenous vinorelbine at 25 mg/m² per week. The primary endpoint was progression-free survival in the intent-to-treat population.
For patients in the afatinib and trastuzumab groups, mean age was 52 and 53 years, most were Asian (52% and 48%) or white (41% and 43%), prior trastuzumab failure had occurred in first-line metastatic treatment in 59% and 58% and adjuvant treatment in 41% and 42%, 26% and 23% were premenopausal, and 48% in both had estrogen receptor–positive disease.
Efficacy Outcomes
Recruitment was stopped in April 2013, after an independent data monitoring committee benefit-risk assessment was unfavorable for the afatinib group. Patients receiving afatinib plus vinorelbine had to switch to trastuzumab/vinorelbine, afatinib monotherapy, or vinorelbine monotherapy or receive treatment outside of the trial.
Median follow-up was 9.3 months. Median progression-free survival was 5.5 months (95% confidence interval [CI] = 5.4–5.6 months) in the afatinib group vs 5.6 months (95% CI = 5.3–7.3 months) in the trastuzumab group (hazard ratio = 1.10, P = .43). Objective response occurred in 46% vs 47% (odds ratio = 1.04, P = .85).
Adverse Events
The most common drug-related adverse events of grade ≥ 3 in the afatinib group were neutropenia (56% vs 60%), leukopenia (19% vs 20%), and diarrhea (18% vs 0%). Serious adverse events occurred in 36% vs 26% of patients. Adverse events led to dose reduction in 55% vs 3% and treatment discontinuation in 15% vs 7%; the primary reasons for dose reduction and discontinuation in the afatinib group were diarrhea (24% and 3%) and rash/acne (11% and 1%).
The investigators concluded: “Trastuzumab-based therapy remains the treatment of choice for patients with HER2-positive metastatic breast cancer who had progressed on trastuzumab.”
The study was funded by Boehringer Ingelheim.
Binghe Xu, MD, of the Chinese Academy of Medical Sciences, Beijing, is the corresponding author of The Lancet Oncology article.
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