Gefitinib Plus Chemotherapy vs Gefitinib Alone in Untreated EGFR-Mutant Non–Small Cell Lung Cancer in Patients With Brain Metastases

Abstract

ImportanceUse 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.ObjectiveTo 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 ParticipantsThis 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.InterventionsThe eligible patients were randomly assigned (1:1) to receive gefitinib plus chemotherapy or gefitinib alone.Main Outcomes and MeasuresThe 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.ResultsA 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 RelevanceIn 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 RegistrationClinicalTrials.gov Identifier: NCT01951469

CNS Efficacy of Osimertinib With or Without Chemotherapy in Epidermal Growth Factor Receptor–Mutated Advanced Non–Small-Cell Lung Cancer

“…22,23 The GAP BRAIN phase III trial, conducted in China, showed improved intracranial efficacy for platinum-pemetrexed plus gefitinib versus gefitinib alone as a first-line treatment for patients with EGFR -mutated NSCLC with brain metastases. 24 These data support the possibility that adding chemotherapy to osimertinib may further improve outcomes compared with osimertinib monotherapy, including in patients with baseline CNS metastases.…”

“…22,23 The GAP BRAIN phase III trial, conducted in China, showed improved intracranial efficacy for platinum-pemetrexed plus gefitinib versus gefitinib alone as a first-line treatment for patients with EGFR-mutated NSCLC with brain metastases. 24 These data support the possibility that adding chemotherapy to osimertinib may further improve outcomes compared with osimertinib monotherapy, including in patients with baseline CNS metastases. FLAURA2, a phase III randomized trial in patients with EGFRmutated advanced NSCLC, showed that first-line osimertinib plus platinum-pemetrexed was associated with a statistically significant and clinically meaningful improvement in investigator-assessed systemic progression-free survival (PFS) compared with osimertinib monotherapy (hazard ratio [HR], 0.62 [95% CI, 0.49 to 0.79]; P < .001).…”

“…Intracranial median PFS was 15.6 months with gefitinib plus platinum-pemetrexed and 9.1 months with gefitinib alone. 24…”

ESCRT-III Component CHMP4C Attenuates Cardiac Hypertrophy by Targeting the Endo-Lysosomal Degradation of EGFR

“…Notably, EGFR signaling is essential for numerous cellular functions, complete inhibition of EGFR may lead to unintended consequences. 40,41 Hence, curbing EGFR overactivation by targeting CHMP4C might offer a more nuanced and beneficial therapeutic strategy than targeting EGFR directly.…”

Management of Brain Metastases: A Review of Novel Therapies

“…A phase II study prospectively evaluated EGFR mutant NSCLC patients treated with erlotinib or gefitinib and noted that 83% achieved a PR and 11% achieved a SD without a statistically significant difference in PFS or OS. [47][48][49][50][51][52] Anaplastic Lymphoma Kinase…”