Gefitinib Plus Chemotherapy vs Gefitinib Alone in Untreated EGFR-Mutant Non-Small Cell Lung Cancer in Patients With Brain Metastases: The GAP BRAIN Open-Label, Randomized, Multicenter, Phase 3 Study.

Importance: Use of tyrosine kinase inhibitors (TKIs) is the standard therapy for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) with brain metastases. Several studies have shown that adding chemotherapy to EGFR-TKIs could improve progression-free survival (PFS) in patients with EGFR-mutant advanced NSCLC; however, the efficacy of these agents in patients with brain metastases remains unclear. Objective: To investigate the efficacy and safety of gefitinib plus chemotherapy (pemetrexed with platinum) compared with gefitinib alone in patients with untreated EGFR-mutant NSCLC brain metastases. Design, Setting, and Participants: This open-label prospective, multicenter, phase 3 randomized clinical trial was conducted in 6 centers in China from January 13, 2016, to August 27, 2021. The median follow-up time was 21.1 months (IQR, 13.5-31.8 months). Patients with untreated confirmed brain metastases and EGFR-sensitive mutated NSCLC were enrolled. Interventions: The eligible patients were randomly assigned (1:1) to receive gefitinib plus chemotherapy or gefitinib alone. Main Outcomes and Measures: The primary end point was intracranial PFS; secondary end points included PFS, overall survival (OS), intracranial objective response rate, overall objective response rate, and safety. Intention-to-treat analysis was performed. Results: A total of 161 patients (87 [54.0%] women; mean [SD] age, 55 [9.8] years; range, 26-80 years) were enrolled and randomized to receive gefitinib (n = 81) or gefitinib plus chemotherapy (n = 80). The median intracranial PFS was 15.6 months (95% CI, 14.3-16.9 months) in the gefitinib plus chemotherapy group vs 9.1 months (95% CI, 8.0-10.2 months) in the gefitinib group (hazard ratio, 0.36; 95% CI, 0.25-0.53; P < .001). Similarly, the median PFS was significantly longer with gefitinib plus chemotherapy than gefitinib alone (16.3; 95% CI, 14.4-18.2 months vs 9.5; 95% CI, 8.3-10.8 months; P < .001). Gefitinib plus chemotherapy had a better intracranial objective response rate (85.0%; 95% CI, 77.0%-93.0% vs 63.0%; 95% CI, 52.2%-73.7%; P = .002) and overall objective response rate (80.0%; 95% CI, 71.0%-89.0% vs 64.2%; 95% CI, 53.5%-74.9%; P = .03) than gefitinib alone. At data cutoff, the median OS was also significantly longer in the gefitinib plus chemotherapy group vs the gefitinib group (35.0 vs 28.9 months; hazard ratio, 0.65; 95% CI, 0.43-0.99; P = .04). Grade 3 or worse adverse events were more common with gefitinib plus chemotherapy, most of which were manageable. Conclusions and Relevance: In this randomized clinical trial, gefitinib plus chemotherapy significantly improved intracranial PFS, PFS, and OS compared with gefitinib alone in patients with untreated EGFR-mutant NSCLC brain metastases and could be an optional first-line treatment for these patients. Trial Registration: ClinicalTrials.gov Identifier: NCT01951469.