Erlotinib as second-line treatment in patients with advanced non-small-cell lung cancer and asymptomatic brain metastases: a phase II study (CTONG–0803)†

Y.-L. Wu 3 C. Zhou 2 Y. Cheng 1 S. Lu 6 G.-Y. Chen 5 C. Huang 4 Y.-S. Huang 3 H.-H. Yan 3 S. Ren 2 Y. Liu 1 J.-J. Yang 3 0 Data from this study were previously presented at the 47th Annual Meeting of the American Society of Clinical Oncology (ASCO) , Chicago, IL, 3-7 June 2011 , and at the 14th World Conference on Lung Cancer (WCLC) , Amsterdam , The Netherlands, 3-7 July 2011 1 Jilin Tumor Hospital , Changchun 2 Shanghai Pulmonary Hospital , Shanghai 3 Guangdong Lung Cancer Institute, Guangdong General Hospital and Guandong Academy of Medical Sciences , Guangzhou 4 Fujian Tumor Hospital , Fuzhou , China 5 The Affiliated Tumor Hospital of Harbin Medical University , Harbin 6 Shanghai Chest Hospital affiliated to Shanghai JiaoTong University , Shanghai Background: This phase II, open-label study evaluated the efficacy and safety of erlotinib as second-line therapy in non-small-cell lung cancer (NSCLC) patients with brain metastases (BM). Patients and methods: Forty-eight patients aged 18-75 years with Eastern Cooperative Oncology Group performance status 0-2, confirmed adenocarcinoma or activating epidermal growth factor receptor (EGFR) mutationpositive NSCLC, and asymptomatic BM without extracranial progressive disease after first-line platinum-doublet chemotherapy were recruited. Treatment comprised erlotinib 150 mg/day. The primary end point was progression-free survival (PFS) determined by RECIST. Results: The median PFS was 10.1 months [95% confidence interval (CI) 7.1-12.3] for intracranial progression and 9.7 months (95% CI 2.5-17.8) for intracranial and systemic progression. Patients with EGFR mutation-positive disease had significantly longer median PFS versus EGFR wild-type disease [15.2 months (95% CI 8.3-22.2) versus 4.4 months (95% CI 0.0-11.6); P = 0.02]. The median overall survival was 18.9 months (95% CI 14.4-23.4); 6-month and 1-year survival rates were 85% and 73%, respectively. Overall response rate was 58.3%. Most common adverse events were rash (77.1%), paronychia (20.8%), hyperbilirubinemia (16.7%), and diarrhea (14.6%); these were predominantly of grade 1/2. Conclusions: Single-agent erlotinib was active and well tolerated in NSCLC patients with BM. Further studies are warranted. - introduction The brain is a common site of metastases among patients with non-small-cell lung cancer (NSCLC); the prognosis for patients with brain metastases (BM) is extremely poor with 1-year survival rates around 10% despite therapy [1, 2]. Evidence suggests that the brain is the first site of disease recurrence in approximately one quarter of all patients with NSCLC and 50% of patients eventually develop BM [3, 4]. The incidence of lung cancer with BM has increased in recent years largely as a result of improvements in the diagnosis and systemic treatment of extracranial disease [5]. Available therapeutic approaches for BM include wholebrain radiotherapy (WBRT), surgery, stereotactic radiosurgery (SRS), chemotherapy, and symptomatic and supportive treatment [57]. However, despite advances in the treatment of NSCLC BM in recent years, survival rates are poor [6]. The role of systemic chemotherapy is particularly controversial because of the limited ability of most potential agents to cross the bloodbrain barrier (BBB) [8]. The epidermal growth factor receptor (EGFR) plays an important role in NSCLC and has been explored as a novel therapeutic target in lung cancer [9]. Erlotinib is an oral EGFR tyrosine kinase inhibitor (TKI) that demonstrated a significant survival benefit versus placebo in patients with advanced NSCLC after failure on chemotherapy in a pivotal trial (BR.21) [10], leading to the approval of erlotinib for patients with locally advanced or metastatic NSCLC who have failed at least one prior chemotherapy regimen [11]. Erlotinib is also approved in Europe as first-line therapy for locally advanced or metastatic NSCLC with EGFR activating mutations and as maintenance treatment in patients with stable disease (SD) after first-line standard platinum-based chemotherapy [11]. EGFR mutation status has emerged as an important predictor of response and survival benefit following treatment with EGFR TKIs [10, 1214] and consequently erlotinib is specifically recommended for the treatment of NSCLC patients with EGFR-activating mutations [11]. Optimal central nervous system (CNS) penetration is a critical issue in the treatment of patients with BM with systemic drug therapy. Recently published data showing high concentrations of erlotinib in the cerebrospinal fluid with subsequent regression of BM following erlotinib administration suggest suitable BBB permeability that warrants further investigation as a potential treatment for NSCLC-associated BM [1519]. The CTONG-0803 phase II study was designed to prospectively evaluate the efficacy and safety of erlotinib as second-line therapy in NSCLC patients with BM. study design This was a Chinese, phase II, non-randomized, open-label, multicenter, single-arm clinical trial in patients with advanced NSCLC who had progressed with asymptomatic BM after achieving SD, partial response (PR), or complete response (CR) in extracranial lesions following standard chemotherapy treatment. The trial was approved by the medical ethics committee of each participating center and was carried out in accordance with the principles of the Declaration of Helsinki and Guidelines for Good Clinical Practice. All patients provided written informed consent before any study-related procedure (ClinicalTrials.gov identifier: NCT00663689). Patients were eligible for inclusion in the study if they were aged 1875 years, of Asian origin, had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 02, confirmed adenocarcinoma or activating EGFR mutation-positive NSCLC (detected by DNA direct sequencing), asymptomatic BM (one or more lesions of 10 mm diameter or more than three lesions of <10 mm) revealed during systemic screening, without extracranial progressive disease (PD) after 26 cycles of first-line platinum-doublet chemotherapy, and a life expectancy of >3 months. BM were defined as asymptomatic if there were no signs of increased intracranial pressure, nausea or vomiting, headache, cognitive and affective disorder, epilepsy, or focal neurologic symptoms. The main exclusion criteria for the study were any unstable systemic condition (including active infection, poorly controlled hypertension, unstable angina, congestive heart failure, and hepatic, renal, or metabolic disease); prior EGFR inhibitor therapy; prior radiotherapy for BM; significant ophthalmic abnormalities; active peptic ulcer; and abnormal blood cell count, liver function tests, or creatinine clearance. During the study, patients were not permitted to receive the following drugs: phenytoin, carbamazepine, rifampicin, phenobarbital, and itraconazole because of their potential to affect the metabolism of erlotinib and reduce its plasma concentration. study treatme (...truncated)