A phase II study of first-line low-dose afatinib in patients with EGFR mutated non-small-cell lung cancer (KTORG1402)

Background: Exploratory analyses of phase III afatinib trials (LUX-Lung 3 and 6) suggest that reducing afatinib dose can decrease treatment-related adverse events without affecting its efficacy. Methods: This study was a multi-center, single-arm, open-label phase II trial. Treatment-naïve patients with common epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) were treated with afatinib starting at a dose of 20 mg/day. If tolerated, the dose is increased by 10 mg increments up to 50 mg/day. The primary endpoint was progression-free survival (PFS). A sample size of 44 patients was required on the assumption that threshold and expected PFS would be 9 and 14 months, respectively (α error of 0.10 (one sided) and ß error of 0.20). Results: From February 2015 to March 2016, 46 patients were enrolled. Median age was 73 years (range, 43-86). Eighteen patients (39%) had central nervous system (CNS) metastasis at study entry. Most patients showed performance status 0 or 1 (91%) and adenocarcinoma histology (98%). As of the data cut-off date of June 2017, the median follow-up was 18.9 months. Median PFS of entire population was 15.2 months (95% confident interval (CI): 13.2-not estimable [NE]), and 1-year PFS rate was 69.3% (95% CI, 57.1-84.1), meaning the study met its primary endpoint. Subset analyses of PFS revealed no significant differences by EGFR mutation subtype (exon 19 deletion (n = 25) vs. L858R point mutation (n = 21), p = 0.111), age ( > =75 (n = 18) vs. <75 (n = 28), p = 0.192), or CNS metastasis (present (n = 18) or absent (n = 28), p = 0.226). One-year overall survival rate was 95.6% (95%CI: 89.7-100). Objective response rate of patients with measurable lesion(s) (n = 44 (96%)) was 81.8% (95%CI, 81.3-98.6). Adverse events of grade 3 or worse occurred in 14 patients (30%). Conclusions: Low-dose afatinib therapy demonstrated promising clinical efficacy and was well tolerated. Further investigation is warranted.