A Study On The Efficacy And Treatment Model Of EGFR-TKIs For Non-Small Cell Lung Cancer With Brain Metastases

Objectives Brain metastases is one of the leading causes of death from non-small cell lung cancer (NSCLC), whole-brain radiation therapy (WBRT) is a routine treatment strategy for NSCLC patients with brain metastases. The use of chemotherapy and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) to treat brain metastases remains controversial. EGFR-TKIs, such as gefitinib and erlotinib, have shown efficacy in NSCLC patients with brain metastases (BM). We retrospectively studied the efficacy of chemotherapy and/or EGFR-TKIs in NSCLC patients with BM, and we further performed a pooled analysis of published data to evaluate the efficacy of EGFR-TKI in NSCLC patients with BM, particularly for tumors with activating EGFR mutations. In addition, we conducted a prospective phase II study to evaluate the efficacy and safety of icotinib (a new first generation EGFR-TKI) in combination with WBRT in Chinese NSCLC patients with BM and investigated the cerebrospinal fluid (CSF)/plasma concentrations of icotinib.Methods We retrospectively studied solely localized treatment or localized treatment in combination with chemotherapy and/or EGFR-TKIs medication outcomes of210NSCLC patients with brain metastases; the effects of treatment modality, Karnofsky performance status (KPS), age, primary tumor histology, number of brain metastases and other factors on survival time were analyzed and the robustness of the two prognostic indices Recursive Partitioning Analysis (RPA) and Graded Prognostic Assessment (GPA) models were evaluated. In a pooled analysis, we searched several data sources, including PubMed, Web of Science and American society of clinical oncology (ASCO) Annual Meetings databases; the endpoints were intracranial overall response rate (RR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and adverse events; the pooled RR, DCR, PFS and OS with95%confidence intervals (CI) were calculated employing fixed-or random-effect models depending on the heterogeneity of the included studies. In a prospective phase II study, we included eligible patients had BM from NSCLC, regardless of EGFR status, and icotinib was administered at125mg orally3times/day (TID), until tumor progression or unacceptable toxicity, concurrently with WBRT (3.0Gy per day5days per week, to30Gy); CSF and plasma samples were collected simultaneously from10patients; icotinib concentrations in the CSF and plasma were measured by high performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS); EGFR mutation status was identified by Amplification Refractory Mutation System (ARMS).Results In the survival analysis of210NSCLC patients with BM, the median survival time (MST) of patients with systemic medication and localized treatments was higher than with localized treatments alone (11.0vs.3.0months, P=0.000); within the systemic medication group, the MST was significantly higher for EGFR-TKI than for chemotherapy treatments (12.0vs.9.0months, P=0.002); the MST of patients with mutated EGFR gene was20months vs.8months for patients with the EGFR wild type gene in the EGFR-TKI group; the MST with Pemetrexed medication was significantly higher than with other chemotherapies (13.0vs.7.0months, P=0.006); in a multivariate analysis, prognosis was significantly correlated with treatment modality (P=0.000), KPS (P=0.000), number of brain metastases (P=0.001) and tumor histological type (P=0.007); in the GPA model, the survival curves of subgroups showed clear separations. The pooled analysis included sixteen published studies, with a total of464patients enrolled, the EGRF mutational status was unknown for362(unselected group), and102had activating EGFR mutations; the pooled intracranial overall RR and DCR were51.8%(95%CI:45.8%-57.8%) and75.7%(95%CI:70.3%-80.5%), respectively; a higher response rate was ocserved in the EGFR mutation group than in the unselected group (85.0%vs.45.1%), a similar trend was observed for the DCR (94.6%vs.71.3%); the pooled median PFS and OS were7.4(95%CI,4.9-9.9) and11.9months (95%CI,7.7-16.2), respectively, with longer PFS (12.3vs.5.9months) and OS (16.2vs.10.3months) in the EGFR mutation group than in the unselected group. In the phase ? clinical study, twenty patients were enrolled, the overall response rate was80.0%and no patient experienced?grade4toxicity; the median follow-up time was20.0months; the median progression-free survival time was7.0months (95%CI,1.2-13.2months), and the median overall survival time was14.6months (95%CI,12.5-16.7months); of the18patients with known EGFR status, the MST was22.0months for those with an EGFR mutation and7.5months for those with wild-type EGFR (P=0.0001); the concentration and penetration rate of icotinib (mean±standard deviation) in the CSF were11.6±9.1ng/mL and1.4±1.1%, respectively. Conclusions NSCLC patients with BM benefited from Pemetrexed and/or TKIs along with localized treatments and the GPA index is a robust model for prognostic evaluation.EGFR.-TKI is an effective treatment for NSCLC patients with brain metastases, particularly in those patients harboring EGFR mutations. Icotinib was well tolerated in combination with WBRT and showed promising activity in patients with BM from NSCLC. This clinical benefit was related to the presence of activating EGFR mutations. The CSF penetration rate of icotinib was approximately1.4%. Larger prospective, randomized controlled clinical trials are warranted to confirm our conclusion and identify the feasibility of EGFR-TKI alone as the standard first-line therapy for NSCLC patients with BM.