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Park K.,Sungkyunkwan University | Tan E.-H.,National Cancer Center | O'Byrne K.,Queensland University of Technology | Zhang L.,Sun Yat Sen University | And 20 more authors.
The Lancet Oncology | Year: 2016

Background: The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and gefitinib in this setting. Methods: This multicentre, international, open-label, exploratory, randomised controlled phase 2B trial (LUX-Lung 7) was done at 64 centres in 13 countries. Treatment-naive patients with stage IIIB or IV NSCLC and a common EGFR mutation (exon 19 deletion or Leu858Arg) were randomly assigned (1:1) to receive afatinib (40 mg per day) or gefitinib (250 mg per day) until disease progression, or beyond if deemed beneficial by the investigator. Randomisation, stratified by EGFR mutation type and status of brain metastases, was done centrally using a validated number generating system implemented via an interactive voice or web-based response system with a block size of four. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. Coprimary endpoints were progression-free survival by independent central review, time-to-treatment failure, and overall survival. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01466660. Findings: Between Dec 13, 2011, and Aug 8, 2013, 319 patients were randomly assigned (160 to afatinib and 159 to gefitinib). Median follow-up was 27·3 months (IQR 15·3-33·9). Progression-free survival (median 11·0 months [95% CI 10·6-12·9] with afatinib vs 10·9 months [9·1-11·5] with gefitinib; hazard ratio [HR] 0·73 [95% CI 0·57-0·95], p=0·017) and time-to-treatment failure (median 13·7 months [95% CI 11·9-15·0] with afatinib vs 11·5 months [10·1-13·1] with gefitinib; HR 0·73 [95% CI 0·58-0·92], p=0·0073) were significantly longer with afatinib than with gefitinib. Overall survival data are not mature. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (20 [13%] of 160 patients given afatinib vs two [1%] of 159 given gefitinib) and rash or acne (15 [9%] patients given afatinib vs five [3%] of those given gefitinib) and liver enzyme elevations (no patients given afatinib vs 14 [9%] of those given gefitinib). Serious treatment-related adverse events occurred in 17 (11%) patients in the afatinib group and seven (4%) in the gefitinib group. Ten (6%) patients in each group discontinued treatment due to drug-related adverse events. 15 (9%) fatal adverse events occurred in the afatinib group and ten (6%) in the gefitinib group. All but one of these deaths were considered unrelated to treatment; one patient in the gefitinib group died from drug-related hepatic and renal failure. Interpretation: Afatinib significantly improved outcomes in treatment-naive patients with EGFR-mutated NSCLC compared with gefitinib, with a manageable tolerability profile. These data are potentially important for clinical decision making in this patient population. Funding: Boehringer Ingelheim. © 2016 Elsevier Ltd.

Yao J.,Peking Union Medical College | Yao J.,Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs | Liu L.,Beijing University of Chemical Technology | Yang M.,Beijing University of Chemical Technology
Gene | Year: 2014

Aim: Interleukin-23 (IL-23) and IL-23 receptor (IL23R) play an important role during the T-helper 17 (Th17) cell-mediated inflammatory process as well as pathogenesis of multiple cancers. Several IL-23R single nucleotide polymorphisms (SNPs), especially rs6682925, rs10889677 and rs1884444 polymorphisms, are considered to have significant impacts on susceptibility of multiple cancers. A number of case-control studies have explored the role these genetic polymorphisms in development of carcinogenesis, but the conclusions are inconsistent. Therefore, we conducted this meta-analysis to systematically investigate the associations between the three genetic variants and multiple cancer risk. Methods: A total of ten studies are eligible (12,211 patients and 14,650 controls). Pooled odds ratios (ORs) and the 95% confidence interval (95% CI) were appropriately calculated using either fixed-effect model or random-effect model. Results: Significant associations between rs6682925 or rs10889677 polymorphism and cancer risk were found (OR. = 1.11, 95% CI. = 1.03-1.21, P= 0.007; or OR. = 0.85, 95% CI. = 0.71-0.92, P= 0.001). However, there was no such association between rs1884444 genotypes and cancer susceptibility (P>. 0.05). Conclusion: These findings reveal that the IL-23R rs6682925 and rs10889677 genetic variants play a more important part in pathogenesis of multiple cancers. © 2013 Elsevier B.V.

Zhang Y.,Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs | Song Y.-Y.,Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs | Song W.-Y.,Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs | Shi Y.-K.,Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs | And 2 more authors.
Chinese Journal of New Drugs | Year: 2016

Objective: To investigate the influence of EDTA-K2 or lithium heparin anticoagulant plasma, different extraction agents and liquid chromatograph methods on matrix effects of sabarubicin and M3 during analysis by high performance liquid chromatography mass spectrometry. Methods: Prepared plasma samples of sabarubicin and M3 at 3 concentrations in plasmas containing different anticoagulants were extracted by ethyl-acetate or chloroform. Gradient elution or isocratic elution composed of A: 0.1% formic acid water and B:acetonitrile were adopted, and a gradient elute were developed. Detection was performed by electrospray ionization (ESI) in the positive ionization mode by multiple reaction monitoring (MRM) of the transitions at m/z 644→130 for sabarubicin, m/z 646→333.2 for M3 and m/z 544→360 for internal standard doxorubicin. Post-extraction spiking method was adopted to investigate the impacts of these conditions on matrix effects of sabarubicin and M3. Results: At lower concentration, the matrix effects of sabarubicin and M3 in EDTA-K2 anticoagulant plasma were respectively 123% and 110%, while it is 143% and 160% in in lithium heparin anticoagulant plasma. There was a statistically significant difference between anticoagulant plasmas (sabarubixin:P<0.05, M3:P<0.05). Matrix effects for chloroform extracted sabarubicin and M3 at 3 concentrations in lithium heparin anticoagulant plasma were 142%, 94% and 78% for sabarubicin, and 123%, 102% and 89% for M3, respectively. After adoption of gradient elute, the matrix effects were 108%, 81% and 73% for sabarubicin, and 93%, 83% and 73% for M3, at 3 concentrations. The matrix effects in ultimate method were 85.4% and 98.7% for sabarubicin and M3 at low concentration, and 88.5% and 96.0% at high concentration. Conclusion: The matrix effects are more serious for sabarubicin and M3 in lithium heparin anticoagulant plasma, which have large difference in multi-concentration. Improvement of pretreatment method and liquid chromatograph method could decrease matrix effects. © 2016, Chinese Journal of New Drugs Co. Ltd. All right reserved.

Worden F.,University of Michigan | Fassnacht M.,University of Wurzburg | Shi Y.,Peking Union Medical College | Shi Y.,Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs | And 15 more authors.
Endocrine-Related Cancer | Year: 2015

Effective adverse event (AE) management is critical to maintaining patients on anticancer therapies. The DECISION trial was a multicenter, randomized, double-blind, placebo-controlled, Phase 3 trial which investigated sorafenib for treatment of progressive, advanced, or metastatic radioactive iodine-refractory, differentiated thyroid carcinoma. Four hundred and seventeen adult patients were randomized (1:1) to receive oral sorafenib (400 mg, twice daily) or placebo, until progression, unacceptable toxicity, noncompliance, or withdrawal. Progression-free survival, the primary endpoint of DECISION, was reported previously. To elucidate the patterns and management of AEs in sorafenib-treated patients in the DECISION trial, this report describes detailed, by-treatment-cycle analyses of the incidence, prevalence, and severity of hand-foot skin reaction (HFSR), rash/desquamation, hypertension, diarrhea, fatigue, weight loss, increased serum thyroid stimulating hormone, and hypocalcemia, as well as the interventions used to manage these AEs. By-cycle incidence of the above-selected AEs with sorafenib was generally highest in cycle 1 or 2 then decreased. AE prevalence generally increased over cycles 2-6 then stabilized or declined. Among these AEs, only weight loss tended to increase in severity (from grade 1 to 2) over time; severity of HFSR and rash/desquamation declined over time. AEs were mostly grade 1 or 2, and were generally managed with dose interruptions/reductions, and concomitant medications (e.g. antidiarrheals, antihypertensives, dermatologic preparations). Most dose interruptions/reductions occurred in early cycles. In conclusion, AEs with sorafenib in DECISION were typically grade 1 or 2, occurred early during the treatment course, and were manageable over time. © 2015 Society for Endocrinology.

Shi Y.,Peking Union Medical College | Shi Y.,National Center for Anticancer Drugs Clinical Study | Shi Y.,Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs | Xing P.,Peking Union Medical College | And 13 more authors.
Thoracic Cancer | Year: 2015

Background: The treatment status of small cell lung cancer (SCLC) in Mainland China has never been reported; therefore, this study is the first multicenter survey investigating the status of epidemiology and treatment options of SCLC in Mainland China. Methods: Two questionnaires were designed to obtain information in 12 medical centers in five major Chinese cities. The hospital information questionnaire was designed to outline SCLC patients' characteristics and treatment preferences in each medical institution, and the patient information questionnaire collected detailed treatment information of 298 SCLC cases in these hospitals. Results: SCLC represented 13.7% and 18.3% of all lung cancer patients in 2005 and 2010, respectively. Clinical management of SCLC follows mainstream clinical guidelines in general. The most widely applied first-line treatment mode for limited-stage patients was combined chemoradiotherapy (66.2%), while 77.0% of the extensive-stage patients received chemotherapy alone as initial treatment. Etoposide with cisplatin or carboplatin were the most accepted first-line chemotherapy regimens. The objective response rate was 58.3% after first-line chemotherapy and 23% of the patients who responded well to first-line treatment received prophylactic cranial irradiation. As for second-line chemotherapy, single regimen topotecan or a combined regimen containing topotecan were preferred (53.0%). Conclusions: The treatment options indicated in our study are in accordance with the international clinical guidelines, which is valuable for the improvement of future guidelines, health care standard, and even the better distribution of health care resources in China. © 2015 The Authors. Thoracic Cancer published by Tianjin Lung Cancer Institute and Wiley Publishing Asia Pty Ltd.

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