A phase Ib study of the highly selective MET-TKI savolitinib plus gefitinib in patients with EGFR-mutated, MET-amplified advanced non-small-cell lung cancer.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are recommended first-line treatments in EGFR-mutated (EGFRm) non-small-cell lung cancer (NSCLC). However, acquired resistance (e.g. MET amplification) is frequently observed. Savolitinib (volitinib, HMPL-504, AZD6094) is an oral, potent, and highly selective MET-TKI. In this phase Ib, open-label, multicenter study, we enrolled Chinese patients with EGFRm advanced NSCLC, whose disease progressed following prior EGFR-TKI treatment. In the safety run-in, patients received savolitinib 600 or 800 mg plus gefitinib 250 mg orally once daily, and dose-limiting toxicities were recorded. In the expansion phase, patients with MET amplification received savolitinib plus gefitinib. The primary endpoint was safety/tolerability. Secondary endpoints included antitumor activity. Thirteen patients were enrolled in the safety phase (median age 52 years, 46% female) and 51 enrolled in the expansion phase (median age 61 years, 67% female). No dose-limiting toxicities were reported in either dose group during the safety run-in. Adverse events of grade ≥ 3 in the safety run-in and expansion phases (n = 57) were reported in 21 (37%) patients. The most frequently reported adverse events (all grades) were: vomiting (n = 26, 46%), nausea (n = 23, 40%), increased aspartate aminotransferase (n = 22, 39%). Of four deaths, none were treatment-related. The objective response rates in EGFR T790M-negative, -positive, and -unknown patients were 52% (12/23), 9% (2/23), and 40% (2/5), respectively. Savolitinib 600 mg plus gefitinib 250 mg once daily had an acceptable safety profile and demonstrated promising antitumor activity in EGFRm, MET-amplified advanced NSCLC patients who had disease progression on EGFR-TKIs. NCT02374645, Date of registration: March 2nd 2015.

Survey and analysis of the nutritional status in hospitalized patients with malignant gastric tumors and its influence on the quality of life.

BACKGROUND/OBJECTIVES: The assessment of nutritional status and the quality of life in patients with gastric cancer has become one of the important goals of current clinical treatment. The purpose of this study was to assess the nutritional status in hospitalized gastric cancer patients by using patient-generated subjective global assessment (PG-SGA) and to analyze the influence of nutritional status on the patients' quality of life (QOL). METHODS: We reviewed the pathological diagnosis of gastric cancer for 2322 hospitalized patients using PG-SGA to assess their nutritional status and collected data on clinical symptoms, the anthropometric parameters (height, weight, body mass index (BMI), mid-arm circumference (MAC), triceps skin-fold thickness (TSF), and hand-grip strength (HGS). We also collected laboratory data (prealbumin, albumin, hemoglobin) within 48 h after the patient was admitted to the hospital. The 30-item European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) was used for QOL assessment in all patients. RESULTS: By using PG-SGA, we found 80.4% of the patients were malnourished (score ≥ 4) and 45.1% of the patients required urgent nutritional support (score ≥ 9). In univariate analysis, old age (> 65 years, p < 0.001), female (p = 0.007), residence in a village (p = 0.004), a lower level of education (p < 0.001), and self-paying (p < 0.001) were indicated as risk factors of patients with gastric cancer to be suffering from severe malnutrition. There was a negative correlation between PG-SGA and various nutritional parameters (p < 0.05). The quality of life was significantly different in gastric cancer patients with different nutritional status (p < 0.01). CONCLUSION: Malnutrition of hospitalized patients with gastric cancer in China is common and seriously affects the patients' quality of life. The nutritional status should be evaluated in a timely manner and reasonable nutritional intervention should be provided as soon as possible. The PG-SGA was fit for using as a clinical nutrition assessment method, being worthy of clinical application.

A multicenter survey of first-line treatment patterns and gene aberration test status of patients with unresectable Stage IIIB/IV nonsquamous non-small cell lung cancer in China (CTONG 1506).

BACKGROUND: In recent years, systemic chemotherapy and molecular targeted therapy have become standard first-line treatments for locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC). The objective of this survey was to investigate first-line anticancer treatment patterns and gene aberration test status of patients with advanced nonsquamous NSCLC in China. METHODS: Patients included in this study had unresectable Stage IIIB/IV nonsquamous NSCLC and were admitted during August 2015 to March 2016 into one of 12 tertiary hospitals throughout China for first-line anticancer treatment. Patient data (demographics, NSCLC histologic type, Eastern Cooperative Oncology Group [ECOG] Performance Status [PS], gene aberration test and results [if performed], and first-line anticancer treatment regimen) were extracted from medical charts and entered into Medical Record Abstraction Forms (MERAFs), which were collated for analysis. RESULTS: Overall, 1041 MERAFs were collected and data from 932 MERAFs were included for analysis. Patients with unresectable Stage IIIB/IV nonsquamous NSCLC had a median age of 59 years, 56.4% were male, 58.2% were never smokers, 95.0% had adenocarcinoma, and 92.9% had an ECOG PS ≤1. A total of 665 (71.4%) patients had gene aberration tests; 46.5% (309/665) had epidermal growth factor receptor (EGFR) gene mutations, 11.5% (48/416) had anaplastic lymphoma kinase (ALK) gene fusions, and 0.8% (1/128) had a c-ros oncogene 1 gene fusion. The most common first-line treatment regimen for unresectable Stage IIIB/IV nonsquamous NSCLC was chemotherapy (72.5%, 676/932), followed by tyrosine kinase inhibitors (TKIs; 26.1%, 243/932), and TKIs plus chemotherapy (1.4%, 13/932). Most chemotherapy regimens were platinum-doublet regimens (93.5%, 631/676) and pemetrexed was the most common nonplatinum chemotherapy-backbone agent (70.2%, 443/631) in platinum-doublet regimens. Most EGFR mutation-positive patients (66.3%, 205/309) were treated with EGFR-TKIs. CONCLUSIONS: Findings from our survey of 12 tertiary hospitals throughout China showed an increased rate of gene aberration testing, compared with those rates reported in previous surveys, for patients with advanced nonsquamous NSCLC. In addition, pemetrexed/platinum-doublet chemotherapy was the predominant first-line chemotherapy regimen for this population. Most patients were treated based on their gene aberration test status and results.

A randomized phase II clinical trial of nab-paclitaxel and carboplatin compared with gemcitabine and carboplatin as first-line therapy in locally advanced or metastatic squamous cell carcinoma of lung.

BACKGROUND: Recent advances have shown that histology and genetic biomarkers are important in patient selection, which have led to significantly better outcomes for lung cancer patients. However, most new treatments only apply to adenocarcinoma or non-squamous, and in squamous carcinoma there is little breakthrough. In a phase III trial nab-paclitaxel plus carboplatin showed superior response rate over paclitaxel and carboplatin. In subgroup analysis the squamous histology appeared to be a predictive factor to nab-paclitaxel treatment. METHODS/DESIGN: This is an open-label, randomized, active controlled phase II trial. A total of 120 untreated advanced squamous lung cancer patients are randomized at a 1:1 ratio to receive nab-paclitaxel (135 mg/m2, d1, 8, q3w) plus carboplatin (AUC 5, d1, q3w) or gemcitabine (1,250 mg/m2, d1, 8, q3w) and carboplatin (AUC 5, d1, q3w). The primary endpoint is objective response rate and the second endpoints are progression free survival, overall survival, safety and biomarkers associated with nab-paclitaxel. The treatment will continue up to six cycles or intolerable toxicity. DISCUSSION: This ongoing trial will be the first prospective randomized trial to explore the efficacy of nab-paclitaxel as the first-line treatment specifically in squamous carcinoma of lung. STUDY NUMBER: CTONG1002 TRIAL REGISTRATION: Clinicaltrials.gov reference: NCT01236716.

Real-world evidence of osimertinib in Chinese patients with EGFR T790M-positive non-small cell lung cancer: a subgroup analysis from ASTRIS study.

PURPOSE: ASTRIS study aimed the largest to evaluate the effectiveness and safety of second- or higher-line osimertinib in patients with advanced/metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC) in the real-world setting. Here we report the results of Chinese patients in ASTRIS study. METHODS: Adults with EGFR T790M-positive advanced NSCLC pretreated with EGFR-tyrosine kinase inhibitor (EGFR-TKI), having a WHO performance status score of 0-2 and asymptomatic, stable central nervous system (CNS) metastases were included. All patients received once-daily osimertinib 80 mg orally. The outcomes included investigator-assessed clinical response, progression-free survival (PFS), time-to-treatment discontinuation (TTD), and safety. RESULTS: A total of 1350 patients were included. Response rate was 55.7% (95% confidence interval [CI] 0.53-0.58). The median PFS and the median TTD were 11.7 months (95% CI 11.1-12.5) and 13.9 months (95% CI 13.1-15.2), respectively. Overall, 389 patients (28.8%) had at least one protocol-specified adverse event (AE); AEs of interstitial lung diseases/pneumonitis-like events and QT prolongation were reported in 3 (0.2%) and 59 (4.4%) patients, respectively. CONCLUSION: Osimertinib was effective in Chinese patients with T790M-positive NSCLC who had progressed after first- or second-generation EGFR-TKI in real-word setting and the results were consistent with ASTRIS study overall population and AURA studies. No new safety signals or events were identified. CLINICAL TRIAL NUMBER: NCT02474355.

Bevacizumab plus erlotinib in Chinese patients with untreated, EGFR-mutated, advanced NSCLC (ARTEMIS-CTONG1509): A multicenter phase 3 study.

Dual inhibition of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways may delay therapeutic resistance in advanced non-small cell lung cancer (NSCLC). This phase 3 study investigated the efficacy and safety of an erlotinib plus bevacizumab regimen in untreated patients with advanced NSCLC. In total, 311 patients received bevacizumab plus erlotinib (n = 157) or erlotinib only (n = 154). Progression-free survival (PFS) was 17.9 months (95% confidence interval [CI], 15.2-19.9) for bevacizumab plus erlotinib and 11.2 months (95% CI, 9.7-13.8) for erlotinib only (hazard ratio [HR] = 0.55; 95% CI, 0.41-0.73; p < 0.001). A brain metastases subgroup treated with bevacizumab plus erlotinib also showed improved PFS (HR = 0.48; 95% CI, 0.27-0.84; p = 0.008). Grade ≥3 treatment-related adverse events occurred in 86 (54.8%) and 40 (26.1%) patients, respectively. Bevacizumab plus erlotinib significantly improved PFS in patients with untreated metastatic EGFR-mutated NSCLC, including those with brain metastases at baseline.

[Effects of vinorelbine on apoptosis and expression of telomerase activity in human lung adenocarcinoma cells in vitro].

OBJECTIVE: To study the effect of vinorelbine on apoptosis, telomerase activity and expression of hTERT gene in human lung adenocarcinoma cell line Anip973 cells. METHODS: Anip973 cells were cocultured with Vinorelbine at different concentrations and collected at 24 h, 48 h and 72 h after treatment, respectively. The inhibition rate of cell growth was determined by methyl thiazolyl tetrazolium (MTT) assay to evaluate the effect of vinorelbine. The percentage of apoptosis was detected by flow cytometry. The cellular morphology was observed under inverted microscope and electron microscope. Telomerase activity of Anip973 cells was determined by the method of TRAP-PAGE-silver staining. RT-PCR was used to detect the expression of hTERT mRNA. RESULTS: Vinorelbine down-regulated the telomerase activity and expression of hTERT gene mRNA, inhibited the growth of Anip973 cells, and induced cell apoptosis in a time- and concentration-dependent manner. Annexin V-FITC assay showed 0.08 µg/ml NVB group could inhibited cell proliferation in 24 hour, and apoptosis rate was (7.37 ± 0.35)%, RT-PCR detection of hTERT mRNA expression in this group was (57.01 ± 1.71), and they were very significantly different from that in the control group (P < 0.01), but telomerase activity was (6.36 ± 0.06), compared with the control group showed no significant difference(P > 0.05). The change of hTERT mRNA expression is more sensitive than telomerase activity. The apoptosis rate, telomerase activity and hTERT mRNA expression of 0.4 µg/ml group and 2.0 µg/ml group were very significantly different from that in the control group (P < 0.01). The telomerase activity of 2.0 µg/ml at 72 hour group was (1.36 ± 0.27), basically completely inhibited, while the apoptosis rate was (74.87 ± 1.88)%, showed the cell apoptosis rate was in a negative correlation with the down-regulation of the hTERT mRNA (r = -0.96046, P < 0.01). CONCLUSIONS: Vinorelbine can induce apoptosis in Anip973 cells, and its mechanism of action is related to telomerase activity. The detection of telomerase activity and expression of hTERT gene is useful in predicting prognosis of patients with lung adenocarcinoma.

GEMSTONE-301: a phase III clinical trial of CS1001 as consolidation therapy in patients with locally advanced/unresectable (stage III) non-small cell lung cancer (NSCLC) who did not have disease progression after prior concurrent/sequential chemoradiotherapy.

BACKGROUND: In China, platinum-based doublet chemotherapy is the standard treatment for patients who have unresectable stage III non-small cell lung cancer (NSCLC), administered with radiotherapy on either a concurrent or sequential basis. However, NSCLC patients who undergo this treatment can expect poor median progression-free survival (PFS) of around 8-10 months and a dismal 5-year overall survival (OS) rate of about 15%. In the recent PACIFIC trial, durvalumab was demonstrated to hold significant clinical benefit for patients with locally advanced/unresectable NSCLC who experienced no disease progression after definitive concurrent chemoradiotherapy (cCRT). CS1001 is the first full-length, fully human immunoglobin G4 (IgG4) monoclonal antibody (mAb) that targets programmed death ligand-1 (PD-L1) created through the OMT transgenic rat platform. The phase Ia/Ib study indicated CS1001 was well tolerated and exhibited anti-tumor potential with a range of tumors. GEMSTONE-301 is a phase III randomized, double-blind, study to explore the efficacy and safety of CS1001 compared with a placebo as consolidation therapy for stage III unresectable NSCLC patients. METHODS: In this trial, eligible patients will be randomized to receive CS1001 1,200 mg or placebo, every 3 weeks (Q3W). The primary endpoint will be investigator-assessed PFS, based on the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The secondary endpoints will include OS, PFS assessment based on Blinded Independent Center Review (BICR), objective response rate (ORR), other efficacy measurements, safety, and tolerability. DISCUSSION: This phase III trial will determine the efficacy and safety of CS1001 as consolidation therapy in patients with locally advanced/unresectable (stage III) NSCLC who did not have disease progression after prior concurrent/sequential chemoradiotherapy (cCRT or sCRT), and is the first phase III trial on an anti-PD-L1 mAb initiated in China for this indication. PROTOCOL VERSION: Version 3.0/September 12, 2019.

Inhibition of c-MET upregulates PD-L1 expression in lung adenocarcinoma.

Non-small cell lung cancer (NSCLC) patients with c-MET dysregulation may benefit from c-MET inhibitors therapy as inhibition of c-MET activity has emerged as a therapeutic approach against this disease. Although several c-MET inhibitors have been evaluated in multiple clinical trials in lung cancer, their benefits so far have been modest. Thus, furthering our understanding of the mechanisms contributing to the lack of success of c-MET inhibitors in clinical trials is essential toward the development of rational and effective combination strategies. Here we show that exposure of NCSLC cell lines to c-MET inhibitor tivantinib increases their expression of PD-L1, which in turn causes cells to become more resistant to T-cell killing. Mechanistically, inhibition of c-MET suppresses p-GSK3ß, leading to the stabilization of PD-L1 similar to that observed in liver cancer cells. Collectively, our findings suggest a potential crosstalk between c-MET inhibition and immune escape and provide a rationale for the combination therapy of c-MET inhibitors and immune checkpoint blockade in NSCLC.

Survival Benefit and Genetic Profile of Pemetrexed as Initial Chemotherapy in Selected Chinese Patients With Advanced Lung Adenocarcinoma.

Objective: This study investigated survival in selected Chinese patients with advanced lung adenocarcinoma who received initial chemotherapy with pemetrexed. We also explored the relationship between genetic biomarkers and pemetrexed efficacy. Methods: We retrospectively collected patients (n = 1,047) enrolled in the Chinese Patient Assistance Program from multiple centers who received pemetrexed alone or combined with platinum as initial chemotherapy and continued pemetrexed maintenance therapy for advanced lung adenocarcinoma from November 2014 to June 2017. The outcomes were duration of treatment (DOT) and overall survival (OS). Clinical features were analyzed for their influence on the treatment effect and prognosis. Next-generation sequencing (NGS) was performed to identify genetic biomarkers associated with the efficacy of pemetrexed. Results: The median DOT was 9.1 months (95% CI: 8.5-9.8), and the median OS was 26.2 months (95% CI: 24.2-28.1). OS was positively correlated with DOT (r = 0.403, P < 0.001). Multivariable analysis showed that smoking status and Eastern Cooperative Oncology Group (ECOG) performance status (PS) were independently associated with DOT; smoking status, ECOG PS, targeted therapy, and EGFR/ALK/ROS1 status were independently associated with OS. NGS in 22 patients with available samples showed genes with high mutation rates were: TP53 (54.5%), EGFR (50.0%), MYC (18.2%), and PIK3CA (13.6%). When grouped based on progression-free survival (PFS) reported in the PARAMOUNT study, the DOT > 6.9 months set was associated with PIK3CA, ALK, BRINP3, CDKN2A, CSMD3, EPHA3, KRAS, and RB1 mutations, while ERBB2 mutation was observed only in the DOT ≤ 6.9 months set. Conclusion: This study shows that initial chemotherapy with pemetrexed is an effective regimen for advanced lung adenocarcinoma in selected Chinese patients. There is no specific genetic profile predicting the benefit of pemetrexed found by NGS. Biomarkers predicting the efficacy of pemetrexed need further exploration.

A randomised phase II clinical trial of nab-paclitaxel and carboplatin compared with gemcitabine and carboplatin as first-line therapy in advanced squamous cell lung carcinoma (C-TONG1002).

BACKGROUND: Nab-paclitaxel/carboplatin (nab-PC) and gemcitabine/carboplatin (GC) are the standard first-line chemotherapy in non-small cell lung carcinoma. Up to now, there is no head to head trial to compare nab-PC with GC in advanced squamous cell lung carcinoma. PATIENTS AND METHODS: A multicentre randomised phase II trial was performed to compare the efficacy and safety for nab-PC with GC in previously untreated patients with advanced squamous cell lung carcinoma. The primary end-point was objective response rate (ORR). Progression-free survival (PFS), overall survival (OS), treatment-related adverse events and quality of life (QoL) were also analysed. RESULTS: Totally 127 participants were eligible for this study (62/65 nab-PC/GC). Nab-PC has higher ORR than GC without statistical significance (42% versus 27%, P > 0.05). After a median follow-up of 14.5 months, both PFS and OS had no difference between the two arms (6.7 versus 5.8 months, hazard ratio [HR] 0.75, P = 0.143; 11.6 versus 14.4 months, HR 0.92, P = 0.846). Both regimens were well tolerated; however, more dose reduction occurred after cycle 2 in GC (27%) than in nab-PC (12%) (P < 0.05). Significant QoL improvement measured by trial outcome index was seen in nab-PC than in GC (P < 0.05). CONCLUSIONS: The first-line nab-PC and GC had the same response, PFS, and OS in patients with advanced squamous cell lung carcinoma. Nab-PCM has advantage over GC in QoL improvement. TRIAL REGISTRATION NUMBER: NCT01236716.

Factors associated with gene aberration test status and treatment decision in patients with unresectable Stage IIIB/IV nonsquamous non-small cell lung cancer: A multicenter survey in China (CTONG 1506).

OBJECTIVES: This study investigated factors associated with (i) the likelihood of receiving a gene aberration test and (ii) the choice of treatment between chemotherapy and targeted therapy in patients with non-small cell lung cancer (NSCLC) in China. MATERIALS AND METHODS: This cross-sectional study analyzed data previously extracted from the medical charts of patients with unresectable Stage IIIB/IV nonsquamous NSCLC discharged from one of 12 tertiary hospitals in China between August 2015 and March 2016. Logistic regressions were applied to investigate factors associated with receiving a gene aberration test and the treatment decision. RESULTS: Data from 932 patients were analyzed. Patients were less likely to have a gene aberration test if they had a histologic subtype other than adenocarcinoma or a hospital waiting time for test results of >5 days. Patients were more likely to receive tyrosine kinase inhibitor (TKI) treatment than chemotherapy if they had a positive result for epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase gene aberration testing. EGFR positive patients were more likely to receive TKI treatment than chemotherapy if they did not have insurance for TKI or pemetrexed treatment, and more likely to receive chemotherapy than TKI treatment if they had a waiting time for test results of >5 days. EGFR wild-type/unknown patients receiving chemotherapy were more likely to receive pemetrexed if they attended a hospital in a developed area or had insurance for pemetrexed. CONCLUSION: In this real-world setting in China, the choice of first-line treatment for advanced NSCLC was appropriately guided by gene aberration testing for most patients. However, gene aberration testing and the treatment decision were influenced by practical factors such as hospital location, the waiting time for test results, and insurance coverage, which should be addressed to ensure optimal patient care.

[Establishment of a multi drug-resistant human lung adenocarcinoma cell line and biological characteristics there of].

OBJECTIVE: To establish a multidrug-resistant human lung adenocarcinoma cell line and to investigate its biologic characteristics. METHODS: NBV of the terminal concentration of 0.02 mg/L was co-cultured with the human lung adenocarcinoma cells of the line Anip973. When the cells got a stable growth and generation the concentration of NVB was increased gradually till the 65 th generation. Thus a drug-resistant line Anip973/NVB that could grow under the NVB of the concentration of 2.0 mg/L was established. Anip973 and Anip973/NVB cells were co-cultured with 10 anti-cancer drugs: NVB, cisplatin, fluorouracil, gemcitabine, paclitaxel, etoposide, irinotecan, dacarbazine, ifosfamide, and pharmorubicin of different concentrations respectively. Forty-eight hours later MTT method was used to detect the 50% inhibition concentration (IC50) values of different drugs. The doubling times of the Anip973 and Anip973/NVB cells were calculated. Inverted microscopy and electron microscopy were used to observe the morphology of the cells. Flow cytometry was conducted to observe the cell cycle. The cells were cultured in the medium with NVB of the concentration of 2.0 mg/L. High efficiency fluid chromatography was used to observe the drug concentration in the cells. RESULTS: Anip973/NVB cells showed resistance at different degrees to 8 drugs (all P<0.05), except to gemcitabine and irinotecan. The doubling time of the Anip973 cells was 23.45 h, not significantly different from that of the Anip973/NVB cells The percentage of the cells in the phase G0 approximately G1 was 62.90% in the Anip973 cells, significantly higher than in the Anip973 cells (53.73%, P=0.014), and the proportion of the cells in the phase S 28.32% in the Anip973/NVB cells, significantly lower than that in the Anip793 cells (38.25%, P=0.035) NVB could be detected in the Anip973 cells with a concentration of 0.22 mg/L+/-0.05 mg/L, however, could not be detected in the Anip973/NVB cells. MTT assay showed that the IC50 of Anip973/NVB cells was 21.81 times higher than Anip973 cells. Microscopy showed that the structure, especially the ultramicrostructure, of the Anip973/NVB cells was more irregular than that of the Anip973 cells, and there were significant difference in ultramicrostructure. CONCLUSION: A reliable multi-drug resistant human lung adenocarcinoma cell line Anip973/NVB has been successfully established.

A consensus on liquid biopsy from the 2016 Chinese Lung Cancer Summit expert panel.

The diagnosis and treatment of lung cancer have evolved into the era of precision medicine. Liquid biopsy, a minimally invasive approach, has emerged as a promising practice in genetic profiling and monitoring of lung cancer. Translating liquid biopsy from bench to bedside has encountered various challenges, including technique selection, protocol standardisation, data analysis and cost management. Regarding these challenges, the 2016 Chinese Lung Cancer Summit expert panel organised a trilateral forum involving oncologists, clinicians, clinical researchers, and industrial expertise on the 13th Chinese Lung Cancer Summit to formally discuss these controversies. Six consensuses were reached to guide the use of liquid biopsy and perform precision medicine in both clinic and research.

MCM2 is a therapeutic target of lovastatin in human non-small cell lung carcinomas.

Human non-small cell lung carcinoma (NSCLC) is one of the most common cancer worldwide. In previous studies, lovastatin, acting as an inhibitor of 3-hydroxy-3-methylglutaryl Co A (HMG-CoA) reductase, exhibited significant antitumor activity during tumorigenesis. However, whether or not this effect is mediated through changes in minichromosome maintenance (MCM) 2 expression remains unclear. The present study investigated whether lovastatin inhibits proliferation due to MCM2 in NSCLCs. We first assessed the effects of lovastatin on cell anti-proliferation, cell cycle progression and apoptosis in NSCLC cells. We found, by quantitative RT-PCR and western blot analysis, that lovastatin treatment markedly and consistently inhibited the expression of MCM2. Then, to further explore the anticancer mechanism of lovastatin involving MCM2, we silenced MCM2 by siRNA in two cell lines (A549 and GLC-82). Silencing of MCM2 triggered G1/S arrest. Following further examination of cell cycle-related factors, MCM2 knockdown inhibited protein retinoblastoma (Rb), cyclin D1 and CDK4 expression, but increased p21 and p53 expression, suggesting that siMCM2 indeed triggered cell cycle arrest. In addition, siMCM2 induced apoptosis. Finally, lovastatin treatment increased p-JNK, which is involved in the downregulation of MCM2. In conclusion, our data suggest that MCM2 may be a novel therapeutic target of lovastatin treatment in NSCLCs.

Erlotinib plus capecitabine as first-line treatment for older Chinese patients with advanced adenocarcinoma of the lung (C-TONG0807): an open-label, single arm, multicenter phase II study.

Preclinical studies have shown synergism between epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and antifolates in solid tumors. This study is to investigate the efficacy and tolerability of erlotinib plus capecitabine as first-line treatment in older Chinese patients (≥ 65 years) with lung adenocarcinoma. This is an open-label, single arm, multicenter phase II clinical trial. Sixty- two patients with previously untreated stage IIIB/IV adenocarcinoma and age 65 years or above were enrolled at four tertiary teaching hospitals and 2 provincial hospitals in China; 58 patients fulfilled the study requirements. Erlotinib (150 mg/day) and capecitabine (1000 mg/m2 twice daily on days 1-14) were administered during every 21-day cycle. The primary endpoint was the non-progression rate at 12 weeks. EGFR and K-ras mutation rates were determined using PCR. Tumor expression of different biomarkers was assessed using immunohistochemistry. In a cohort of 58 patients, 34 patients had no disease progression at 12 weeks following treatment. The objective response rate was 29.3%, and the disease control rate was 75.9%. The objective response rate was significantly higher in patients with EGFR mutations than in those with wild-type EGFR. Patients with thymidine phosphorylase-negative tumors had significantly longer overall survival after one year than patients with thymidine phosphorylase-positive tumors. Forty-four patients had at least one primary adverse events (AEs), including skin rash (n = 30), grade 3 AEs (n = 17), and grade 4 AEs (n = 7). This is the first phase II clinical trial to assess erlotinib plus capecitabine combination therapy as first-line treatment in older patients with lung adenocarcinoma. Erlotinib/capecitabine chemotherapy was significantly better in patients with EGFR mutations and in those with thymidine phosphorylase-negative tumors. The use of fluorouracil derivatives for the treatment of lung adenocarcinoma warrants further study.

A multicenter phase II study of sorafenib monotherapy in clinically selected patients with advanced lung adenocarcinoma after failure of EGFR-TKI therapy (Chinese Thoracic Oncology Group, CTONG 0805).

OBJECTIVES: Aim of the study was to investigate efficacy and safety of sorafenib in patients with advanced lung adenocarcinoma after failure of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) therapy. PATIENTS AND METHODS: Patients who were diagnosed with stage IIIB or stage IV lung adenocarcinoma, and benefited from one prior EGFR-TKI therapy and then failed, were eligible. No more than one previous chemotherapy regimen was permitted. Patients received oral sorafenib 400mg twice daily continuously until disease progression or intolerable toxicity. Primary endpoint was disease control rate (DCR). Secondary endpoints included safety, progression-free survival (PFS) and overall survival (OS). For patients who agreed to provide peripheral blood or tumor tissue, we analyzed the genotype of Bcl-2-interacting mediator of cell death (BIM) deletion polymorphism and EGFR mutation status. RESULTS: Of 65 enrolled patients, 64 were evaluable. The DCR was 32.8%, which did not meet the predefined statistical hypothesis of 38.4%. The median PFS and OS were 3.7 months [95% (confidence interval), 3.5-3.9 months] and 7.4 months (95% CI, 5.7-9.2 months), respectively. Logistic regression analysis showed no correlation between DCR and age, gender, smoking status and performance status. Hand-foot syndrome (HFS) was the predominant toxicity occurring in 71.9% of patients. Fourteen patients (21.9%) had ≥ grade 2 dermatologic reactions that resulted sorafenib dose reduction in three patients (4.7%). Of 36 patients, the BIM deletion polymorphism was found in 3, and no response to sorafenib was observed. In 30 tumor tissues, 22 EGFR active mutations were found. The DCR had no significant difference between mutation-positive and wild-type patients (31.8% vs. 42.9%, respectively; HR, 0.622; p=0.665). CONCLUSION: Sorafenib monotherapy did not achieve positive result in patients defined in our trial and we need better biomarker to determine the population who can benefit from sorafenib treatment (ClinicalTrials.gov number: NCT00922584).

Significance of survivin expression: Prognostic value and survival in stage III non-small cell lung cancer.

This study was designed to determine the levels of survivin expression and identify its clinical significance as a prognostic factor for stage III non-small cell lung cancer (NSCLC). A total of 210 cases of stage III NSCLC were collected and the expression levels of survivin and vascular endothelial growth factor A (VEGF-A) in tumor tissues were investigated using immunohistochemistry (IHC). The medical records of the patients were reviewed to determine the association with clinical course. Of the 210 NSCLC tissues, 112 (53.3%) cases demonstrated positive expression of survivin protein. Coexpression of survivin and VEGF-A was identified. The 5-year survival rate of patients with positive survivin expression was significantly lower compared with the survivin-negative cancer patients (P<0.05). The expression of survivin in NSCLC correlated with tumor size. Survivin and VEGF-A were independent prognostic factors of stage III NSCLC. Survivin protein is a valuable marker of prognosis in stage III NSCLC patients.

Significance of CXCR4, phosphorylated STAT3 and VEGF-A expression in resected non-small cell lung cancer.

C-X-C chemokine receptor type 4 (CXCR4) plays an important role in determining the metastatic potential of non-small cell lung cancer. In order to elucidate the effect and mechanism of CXCR4 in tumor angiogenesis we evaluated the clinical significance of CXCR4, phosphorylated signal transducer and activator of transcription 3 (P-STAT3), and vascular endothelial growth factor (VEGF) expression in patients with completely resected non-small cell lung cancer (NSCLC). A total of 208 cases of resected NSCLC were collected, and expression of CXCR4, P-STAT3 and VEGF-A in tumor tissue was investigated using immunohistochemistry (IHC). We reviewed the patient clinical records to determine the association of the expression of these proteins with the clinical course of the disease. Expression of CXCR4, P-STAT3 and VEGF-A was detected in 56.3, 46.2 and 51.9% of the samples, respectively. We observed co-expression between CXCR4, P-STAT3 and VEGF-A. Using multivariate analysis, the expression levels of CXCR4 and VEGF-A were identified as independent prognostic factors that affected overall survival. In conclusion, the results of this study suggest that CXCR4, P-STAT3 and VEGF-A expression may play a role in tumor progression and angiogenesis of NSCLC. However, further studies are needed to uncover the detailed mechanism that underlies the role of these proteins in NSCLC.

Multidrug resistance-associated protein 3 and Bcl-2 contribute to multidrug resistance by vinorelbine in lung adenocarcinoma.

Although cancer cells initially respond to vinorelbine (NVB), the acquisition of resistance to the treatment is the main cause of chemotherapeutic failure in lung cancer. The intrinsic mechanism of drug resistance induced by NVB in lung cancer is not clear and tumor cell models to study NVB resistance have not been widely studied. We previously established a NVB resistant cell line, Anip973/NVB, derived from the Anip973 lung adenocarcinoma cell line. The aim of this study was to investigate the molecular mechanisms involved in the resistance to NVB in lung adenocarcinoma. Genetic profiles of Anip973/NVB and Anip973 cells were compared by microarray analysis and qRT-PCR. Tumor xenografts were obtained by grafting Anip973/NVB and Anip973 cells into nude mice and the xenograft response to NVB or control treatment was evaluated. Morphological assessment of xenograft tissues was performed by transmission electron microscopy (TEM). Immunohistochemistry (IHC) was used to compare Bcl-2 and MRP3 protein expression in xenografts. Fifty-five up-regulated genes and 88 down-regulated genes in Anip973/NVB cells compared with Anip973 cells were identified by cDNA microarray analysis. Up-regulation of MRP3 and Bcl-2 was confirmed by qRT-PCR. NVB inhibits xenografts of Anip973 growth but did not affect xenografts of Anip973/NVB growth. Ultrastructural changes observed by TEM showed that NVB induces apoptosis in the Anip973-treated group but not in the Anip973/NVB-treated group. Higher expression rates of Bcl-2 and MRP3 were observed in Anip973/NVB xenograft cells compared with Anip973 xenograft cells by IHC. In conclusion, in the present study, we identified a set of genes responsible for multidrug resistance in Anip973/NVB cells. Among them, MRP3 and Bcl-2 may participate in lung adenocarcinoma multidrug resistance induced by NVB.