Development of treatment for EGFR-mutated non-small-cell lung cancer (NSCLC) had been focused on monotherapy of gefitinib, erlotinib, or afatinib. However, more than half patients treated with EGFR-TKI monotherapy experience recurrence or progression of disease within a year. Some different strategies have been expected to overcome this efficacy limitations of EGFR-TKIs. One of these strategies is combination of EGFR-TKIs and VEGF inhibitors. A phase II study named JO25567 comparing between erlotinib alone and erlotinib with bevacizumab as first-line therapy in patients with advanced non-squamous NSCLC harboring EGFR mutations was conducted in Japan. This study showed that the combined treatment had extremely prolonged progression free survival as a primary endpoint than the monotherapy (Hazard ratio 0.54, p = 0.0015). Consequently, we conducted a phase III study comparing combination with erlotinib plus bevacizumab with erlotinib monotherapy.
Chemotherapy-naïve patients with advanced non-squamous, EGFR-mutant NSCLC are randomly assigned to receive either erlotinib (150 mg) (E arm) or a combination with erlotinib (150 mg) plus bevacizumab (15 mg/kg) (EB arm) intravenously every 3 weeks. The doublet of platinum plus pemetrexed in EB arm and the triplet of platinum, pemetrexed, and bevacizumab in E arm are recommended as second-line therapy. Status of EGFR mutations in plasma samples are analyzed routinely from pretreatment of the first-line therapy until PD of the second-line therapy. The primary endpoint is PFS. Secondary endpoints are OS, response, safety, and patient oriented outcome. Exploratory endpoints are duration from initiation of first-line treatment to PD of second-line, detection rate of plasma EGFR mutations, association between status of plasma EGFR mutation and efficacy of 1st or 2nd-line treatment, and OS analysis combined with the JO25567 study. We hypothesized that hazard ratio of PFS is 0.63. We estimated that 147 events would be needed for the study to have a power of 80% and a two-sided significance level of 5% and planned to enroll total 214 patients. The enrollment was initiated in June 2015.
Clinical trial identification
Legal entity responsible for the study
M. Maemondo: Lecture fees from Chugai, AstraZeneca, Boehringer. S. Sugawara, A. Inoue, A. Gemma: Lecture fee from Chugai. Y. Takiguchi: Lecture fee from Chugai Pharmaceutical Co., AstraZeneca KK, and Boehringer Ingerheim Co. S. Oizumi: Lecture fee from AstraZeneca and Eli Lilly. S. Morita: Honorarium from Chugai and AstraZeneca. K. Kobayashi: Lecture fee from Chugai and AstraZeneca. T. Nukiwa: Lecture fee from Boehringer Ingelheim. All other authors have declared no conflicts of interest.