The results from the BRAIN GAP trial—an open-label, randomized, multicenter, phase III study—were recently published in the Journal of the American Medical Association Network Open and indicated that adding chemotherapy to first-line treatment with gefitinib enhances clinical outcomes in patients with EGFR-mutant NSCLC with brain metastases.

The researchers sought to explore the efficacy and safety of gefitinib plus chemotherapy (pemetrexed with platinum) compared with gefitinib alone in patients with untreated EGFR-mutant NSCLC brain metastases.

The primary endpoint was intracranial progression-free survival (PFS); secondary endpoints included PFS, overall survival (OS), intracranial objective response rate, overall objective response rate (ORR), and safety. Intention-to-treat analysis was conducted.

A total of 161 patients with previously untreated NSCLC, a sensitizing EGFR mutation, and brain metastases were included in the trial. The average age was 55 years; 54% of patients were women, and 25.5% of the participants were smokers.

The patients were randomly assigned 1:1 to receive gefitinib plus pemetrexed and platinum chemotherapy (n = 80) or gefitinib alone (n = 81), and the average follow-up was 21.1 months.

For patients who received gefitinib plus chemotherapy, the average intracranial PFS was significantly longer and was reported as 15.6 months in the combination arm and 9.1 months in the gefitinib monotherapy arm (hazard ratio [HR], 0.36; 95% CI, 0.25-0.53; P <.001).

The overall PFS and OS were longer with combination treatment, with the average PFS of 16.3 months in the combination arm and 9.5 months in the gefitinib monotherapy arm (HR, 0.39; 95% CI, 0.27-0.58; P <.001). Combining gefitinib plus chemotherapy had a better intracranial objective response rate (85.0 % vs. 63.0%) and overall ORR of 80.0% versus 64.2% than gefitinib alone.

At data cutoff, the average OS was also significantly longer in the gefitinib plus chemotherapy group than in the gefitinib group. The average OS was 35.0 months and 28.9 months, respectively (HR, 0.65; 95% CI, 0.43-0.99; P = .04).

In the combination group, the most common grade III or higher adverse events (AEs) included alanine aminotransferase elevation (11.3%), neutropenia (7.5%), nausea (7.5%), anorexia (5.0%), and diarrhea (5.0%). The grade III or higher AE rate was more significant with gefitinib plus chemotherapy than with gefitinib alone—40.0% and 21.0%, respectively. In the combination group, one treatment-related death was also due to pneumonia.

The authors wrote, “In this phase III randomized clinical trial, our results revealed that gefitinib plus chemotherapy significantly improved intracranial PFS, PFS, and OS in patients with untreated NSCLC EGFR mutation and asymptomatic brain metastases. To our knowledge, this is the first randomized clinical trial to compare the intracranial efficacy and safety of gefitinib plus chemotherapy with gefitinib as first-line treatment in EGFR-mutant NSCLC with brain metastases.”

Based on their findings, the authors concluded that gefitinib plus chemotherapy might be a possible first-line treatment for patients with brain metastases associated with EGFR-mutant NSCLC.

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