MA08.01 Phase 3 Trial of Whole Brain Radiotherapy with Concurrent Erlotinib Versus WBRT Alone for NSCLC with Brain Metastases (ENTER)

Abstract

Brain metastasis (BM) is a leading cause of death for non-small cell lung cancer (NSCLC). Whole Brain Radiotherapy (WBRT) is a standard-of-care treatment for NSCLC patients with multiple brain metastases. Elevated EGFR expression and activity are important causes of tumor resistance to radiotherapy. This phase 3 trial sought to determine if concurrent erlotinib with WBRT will benefit patients with multiple BM compared with WBRT alone. In this open-label, randomised, multicenter phase 3 study in China (NCT01887795), we enrolled NSCLC patients with at least two metastatic brain lesions who were naive to brain radiation and free from any EGFR-TKI for at least 4 weeks. Participants were randomly assigned (1:1) to receive either WBRT (2.0 Gy per day, 5 days per week, to 40 Gy) or WBRT plus concurrent oral erlotinib 150 mg daily (Erlotinib was given for 6 days then concurrently with WBRT). Subsequent treatments were maintenance therapy of erlotinib for EGFR-positive patients or standard chemotherapy for EGFR-negative patients until unacceptable adverse events or disease progression. The primary endpoint was intracranial progression-free survival (iPFS), defined as time from randomisation to either intracranial disease progression or death for any cause. Between August 7, 2013 and November 25, 2016, in total 222 patients from 11 centers across China were randomized to treatments: 115 with WBRT alone and 107 with WBRT and concurrent erlotinib. Median follow-up was 11.2 months (IQR 4.6-18.2). Median iPFS was 11.2 months (95% CI: 7.2-13.7) with WBRT and concurrent erlotinib versus 9.2 months (95% CI: 6.7-10.9) with WBRT alone (HR 0.926; 95% CI: 0.695-1.234; P=0.601). In the subgroup of 109 patients who were positive for the EGFR mutation, iPFS was not significantly longer among those who received WBRT with concurrent erlotinib than WBRT with sequential erlotinib (14.6 [95% CI 11.8-17.7] vs 12.8 [7.9-14.9] months; HR 0.743; 95% CI: 0.489-1.129; P=0.164). Median PFS of concurrent erlotinib arm was 5.3 months versus 4.0 of WBRT alone (HR 0.969; 95% CI: 0.735-1.277; P=0.825) and median overall survival (OS) was 12.9 versus 10.0 months (HR 0.913; 95% CI: 0.680-1.226; P=0.545). This multi-institutional study demonstrated WBRT with concurrent erlotinib improved neither iPFS significantly than WBRT alone in the intention-to-treat population and the EGFR-positive subgroup, nor improved PFS or OS in intention-to-treat population, indicating that erlotinib played limited role when concurrently used with WBRT and for EGFR-positive NSCLC patients, WBRT with concurrent erlotinib was not significantly superior to WBRT with sequential erlotinib.