Int J Clin Exp Med 2015;8(9):16140-16148 www.ijcem.com /ISSN:1940-5901/IJCEM0012202 Original Article Cetuximab combined with chemotherapy is beneficial for patients with advanced non-small cell lung cancer after EGFR-tyrosine kinase inhibitors failure Feng Zhang1*, You Yu2*, Lina Xing1, Min Chen1 1Department of Radiation Oncology, The Second Affiliated Hospital, Harbin Medical University, Harbin, China; 2Department of Pediatric Surgery, The First Affiliated Hospital, Harbin Medical University, Harbin, China.* Equal contributors. Received July 1, 2015; Accepted August 27, 2015; Epub September 15, 2015; Published September 30, 2015 Abstract: To determine if cetuximab combined with chemotherapy is beneficial for patients with advanced NSCLC af- ter failure of first-line chemotherapy and EGFR-tyrosine kinase inhibitors (TKI). Twenty patients were treated with ce- tuximab in combination with pemetrexed, and 14 patients were treated with cetuximab in combination with docetax- el. Short-term response rates and long-term survival after salvage therapy were evaluated. Partial response (PR) occurred in 4 patients, stable disease (SD) occurred in 13 patients, and progressive disease (PD) occurred in 17 patients. No patient achieved a complete response (CR). The objective response rate (ORR) was 11.8% (4/34) and the disease control rate (DCR) was 50.0% (17/34). The disease progression rate (DPR) was 50% (17/34). Further analyses showed that the DCR was significantly higher in patients treated with EGFR-TKI for ≥6 months compared to patients treated with EGFR-TKI for <6 months (P=0.031). The median follow-up time was 5.5 months. The median progression-free survival (PFS) was 4.1 months. PFS was significantly longer in patients treated with EGFR-TKI for ≥ 6 months compared to those treated <6 months with EGFR-TKI (5.9 vs. 3.0 months; P=0.004). In general, however, patients tolerated this therapy well and there were no therapy-related deaths. As a salvage therapy, cetuximab combined with chemotherapy is indeed beneficial for patients with advanced NSCLC after first-line chemotherapy and subsequent EGFR-TKI treatment failure. In particular, this salvage regimen is beneficial for patients who were treated with EGFR-TKI for ≥6 months, and is well tolerated in these patients. Keywords: Lung cancer, cetuximab, chemotherapy, salvage therapy, EGFR Introduction cellular processes, including promotion of cell proliferation, angiogenesis induction, and apop- Non-small cell lung cancer (NSCLC) accounts tosis inhibition [12-14]. for 80%-85% of newly diagnosed lung cancers. Approximately 65% of NSCLC patients are in EGFR tyrosine kinase inhibitors (EGFR-TKI) are advanced stages at the time of diagnosis, and a group of inhibitors that target EGFR tyrosine therefore, the opportunity for surgical resection kinase activity. Gefitinib and erlotinib are two is lost [1-3]. Epidermal growth factor receptor widely used EGFR-TKIs. These inhibitors are (EGFR)-targeted therapy has been widely used selective EGFR tyrosine kinase inhibitors and to treated lung cancer and has achieved mea- have specific effects on cancer cell growth, surable effects in these patients [4-6]. EGFR is metastasis, and angiogenesis by blocking EGFR a 170 kDa transmembrane protein that is wide- tyrosine kinase phosphorylation [15-18]. A vari- ly expressed in many malignancies, including ety of cancer treatment guidelines have recom- lung, colon, and breast cancers [7-11]. EGFR mended EGFR-TKI therapy as first-line, second- signaling is one of the most studied pathways line, or third-line agents to treat NSCLC and to in cancer progression. Phosphorylation of EGFR maintain chemotherapy. Most advanced NSCLC leads to activation of its downstream target patients receive EGFR-TKI therapy at certain genes. These genes are involved in a variety of stages during the disease process. Acquired Cetuximab in TKI-resistant advanced NSCLC resistance to EGFR-TKI therapy is common dur- conducted in accordance with the guidelines of ing the treatment course [19-21]. Subsequent Clinical Research Ethics Board at our hospital. treatment in patients with advanced NSCLC Written informed consent was obtained from all after acquiring EGFR-TIK-resistance is a signifi- patients before the inclusion in the study. Our cant concern. hospital approved this study. Currently, antibody therapy combined with che- Study design motherapy is an important alternative treat- ment strategy for cancer patients. It is becom- All patients received salvage therapy. Salvage ing more widely accepted, particularly as a sal- treatment consisted of cetuximab combined vage therapy for those patients resisting first- with either pemetrexed (regimen A) or docetax- line chemotherapy. Cetuximab (Erbitux) is the el (regimen B). An initial loading dose of cetux- first approved monoclonal antibody (IgG1) imab at 400 mg/m2 was administered over 2 against EGFR. It binds to the EGFR ligand and hours. Cetuximab was intravenously injected blocks downstream pathways of EGFR signal weekly at a dose of 250 mg/m2. The delivery transduction, thereby inhibiting cancer cell pro- speed did not exceed 5 ml/min. In addition to liferation and growth [22-24]. The combination cetuximab, 20 patients (58.8%) in regimen A of cetuximab and chemotherapeutic agents to were concurrently given 500 mg/m2 peme- treat stage I-II NSCLC after failed EGFR-TKI trexed on day 1, continuing once every 3 weeks. treatment has been reported, and cetuximab Fourteen patients (41.2%) in regimen B were can sensitize early stage NSCLC to subsequent concurrently given 75 mg/m2 docetaxel on day chemotherapy [7, 25]. However, whether a simi- 1, continuing once every 3 weeks. Standard lar outcome occurs in EGFR-TKI-resistant ad- premedications consisted of 0.4 g cimetidine, vanced NSCLC is not yet known. 5 mg diphenhydramine, and 5 mg dexametha- sone. Patients participated in the study until The primary objective of this study was to deter- the disease progressed, unacceptable toxicity, mine if salvage therapy based on combining death, or withdrawal of consent. Two patients cetuximab with chemotherapeutic agents can experienced disease progression after one improve the therapeutic efficacy in patients treatment cycle. The remaining 32 patients with advanced NSCLC after resistance to initial were treated for at least two cycles. The medi- first-line chemotherapy and subsequent EGFR- an number of treatment cycles was three cycles TKI treatments. For this purpose, we conducted (1-6 cycles). a retrospective study in 34 patients with ad- vanced NSCLC whose first-line platinum-based Patient baseline information chemotherapy and EGFR-TKI failed. Baseline clinical and pathological characteris- Materials and methods tics of patients were collected, including sex, age, pathological classification, tumor stage, Eligibility criteria smoking status, PS score, first-line chemother- apy, and duration of EGFR-TKI treatment. Ad- For inclusion in this study, all patients satisfi- ditionally, physical examinations, weight mea- ed the following criteria: 1) Pathologically con- surements, hematology and chemistry tests, firmed advanced NSCLC according to the 2009 urinalyses, electrocardiograms, and Eastern International Association for the Study of Lung Cooperative Oncology Group (ECOG) perfor- Cancer staging system [26]; 2) Refractory to mance status were assessed at baseline. first-line standard chemotherapy containing Imaging studies (computed tomography or platinum and resistant to subsequent erlotinib magnetic resonance imaging) were performed or gefitinib treatment; 3) An Eastern Cooperative at baseline and every 6 weeks or longer. Oncology Group (ECOG) performance status score of ≤2 [27]; 4) Predicted survival time was Treatment assessments longer than three months; and (5) Normal bone marrow, liver, and kidney function. A total of 34 The lung cancer remission rate (RR) was as- patients was collected from March 2007 to sessed according to a modified version of the May 2013. This study and all treatments were Response Evaluation Criteria in Solid Tumors 16141 Int J Clin Exp Med 2015;8(9):16140-16148 Cetuximab in TKI-resistant advanced NSCLC Table 1. Baseline characteristics of the study Cancer Institute (NCI) Common Terminology population Criteria for Adverse Events version 3.0]. Parameters No. of patients % Statistical analyses Sex Male 23 67.6 SPSS 15.0 statistical software was used to Female 11 32.4 analyze all data in this study. P<0.05 is consid- PS score ered statistically significant. The participating 0-1 22 64.7 investigators determined PFS. Adverse events 2 12 35.3 were assessed according to the NCI Common Pathological diagnosis Terminology Criteria for Adverse Events (CTCAE) version 3.0. Only events that were reported as Adenocarcinoma 24 70.6 possibly, probably, or definitely related to treat- Squamous cell carcinoma 6 17.6 ment protocols were included in these analy- Unknown 4 11.8 ses. Progression-free survival was estimated Smoking status using the Kaplan-Meier product-limit method Smoker 14 41.2 [29]. Non-smoker 20 58.8 EGFR-TKI agent Results Gefitinib 19 55.9 Patient characteristics Erlotinib 15 44.1 EGFR-TKI preference A total of 34 patients participated in this retro- Second-line 18 52 spective study. The majority of patients were Above second-line 16 48 male (67.6%), were treated with EGFR-TKI for EGFR-TKI duration less than 6 months (64.7%), had PS scores of ≥6 Months 12 35.3 0-1 (64.7%), and had histological diagnoses of <6 Months 22 64.7 adenocarcinoma (70.6%). The percentage of Note: EGFR-TKI, epidermal growth factor receptor tyro- patients who smoked (either currently or in the sine kinase inhibitor. past) was similar to patients who did not smoke or never smoked (41.2% vs. 58.8%). EGFR-TKI was given as second-line treatment in 52% of 1.0 guidelines [28], and were divided into com- patients, and as first-line treatment in 48% of plete remission (complete response, CR), par- patients. The majority of patients (55.9%) re- tial remission (partial response, PR), stable ceived gefitinib treatment, whereas 44.1% of (stable disease, SD), and progression (progres- patients received erlotinib treatment.