Adding chemotherapy to first-line treatment with gefitinib improves outcomes in patients who have EGFR-mutant non-small cell lung cancer (NSCLC) with brain metastases, according to results from the BRAIN GAP trial published in JAMA Network Open.

In this phase 3 trial, chemotherapy improved the objective response rate (ORR), intracranial ORR, progression-free survival (PFS), intracranial PFS, and overall survival (OS). Adverse events (AEs) with chemotherapy and gefitinib were considered manageable.

The BRAIN GAP trial ( Identifier: NCT01951469) included 161 patients with previously untreated NSCLC, a sensitizing EGFR mutation, and brain metastases. At baseline, the mean age was 55 years, 54% of patients were women, and 25.5% were smokers. 

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Most patients (95%) had adenocarcinoma, 52.8% had exon 19 deletion, 43.5% had an L858R mutation at exon 21, and 3.7% had an uncommon mutation in EGFR. TP53 mutations were present in 73.8% of patients. A majority of patients (60.9%) had 4 or more intracranial lesions, and 39.1% had 1 to 3. 

Patients were randomly assigned to receive gefitinib plus pemetrexed and platinum chemotherapy (n=80) or gefitinib alone (n=81). The median follow-up was 21.1 months.

Intracranial PFS was significantly longer for patients who received gefitinib plus chemotherapy. The median intracranial PFS was 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 as well. The median PFS was 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). The median OS was 35.0 months and 28.9 months, respectively (HR, 0.65; 95% CI, 0.43-0.99; P =.04).

The ORR was significantly higher in the combination arm than in the monotherapy arm — 80.0% and 64.2%, respectively (P =.03). The intracranial ORR was 85.0% and 63.0%, respectively (P =.002).

The rate of grade 3 or higher AEs was higher with gefitinib plus chemotherapy than with gefitinib alone — 40.0% and 21.0%, respectively. 

The most common grade 3 or higher AEs in the combination group were alanine aminotransferase elevation (11.3%), neutropenia (7.5%), nausea (7.5%), anorexia (5.0%), and diarrhea (5.0%). There was 1 treatment-related death in the combination group due to pneumonia. 

“[G]efitinib plus chemotherapy significantly improved intracranial PFS, PFS, and OS compared with gefitinib alone in asymptomatic patients with untreated EGFR-mutant NSCLC brain metastases, with manageable adverse events,” the researchers concluded.


Hou X, Li M, Wu G, et al. 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. JAMA Netw Open. Published online February 8, 2023. doi:10.1001/jamanetworkopen.2022.55050