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N. Pavlakis
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OA22 - Novel Trials and Biomarkers in Malignant Pleural Mesothelioma (ID 403)
- Event: WCLC 2016
- Type: Oral Session
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:H. Pass, N. Van Zandwijk
- Coordinates: 12/07/2016, 14:20 - 15:50, Strauss 3
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OA22.02 - Nintedanib plus Pemetrexed/Cisplatin in Patients with MPM: Phase II Findings from the Placebo-Controlled LUME-Meso Trial (ID 4191)
14:20 - 15:50 | Author(s): N. Pavlakis
- Abstract
- Presentation
Background:
Standard first-line treatment for patients with unresectable malignant pleural mesothelioma (MPM) is pemetrexed/cisplatin, yielding a median overall survival (OS) of only ~1 year, thus new approaches are required. As demonstrated by the bevacizumab MAPS study, inhibition of the VEGF pathway is of interest as a treatment approach for MPM. Nintedanib is an oral, triple angiokinase inhibitor of VEGFR, PDGFR and FGFR. This study will evaluate the efficacy and safety of nintedanib plus pemetrexed/cisplatin in patients with advanced MPM.
Methods:
Patients with unresectable MPM (chemo-naïve, ECOG PS 0–1) were stratified by histology (epithelioid/biphasic) and randomised (1:1) to receive up to 6 cycles of pemetrexed (500 mg/m[2])/cisplatin (75 mg/m[2]) on Day 1 plus nintedanib (200 mg bid)/placebo on Days 2–21. Patients without disease progression received maintenance treatment with nintedanib/placebo. The primary endpoint was progression-free survival (PFS).
Results:
87 patients were randomised to receive pemetrexed/cisplatin, plus nintedanib/placebo. Patient characteristics were comparable between the groups. PFS was longer in the nintedanib vs the placebo arm, in both the overall study population and in epithelioid patients (Table 1). Preliminary OS data also favour nintedanib. All patients experienced at least one adverse event (AE, any grade), with 7% of patients in the nintedanib arm discontinuing due to AEs, vs 15% with placebo. Serious AEs occurred in 36% vs 42% of patients in the nintedanib and placebo arms, respectively. The most common ≥grade 3 AEs occurring in nintedanib vs placebo patients were neutropenia (34% vs 10%), ALT increase (14% vs 2%) and gamma glutamyltransferase increase (14% vs 0%).
Conclusion:
Nintedanib plus pemetrexed/cisplatin demonstrated clinical efficacy with improved PFS and a tolerable safety profile in patients with unresectable MPM. Based on these promising findings, this Phase II study was extended to a confirmatory Phase III trial, which is currently enrolling patients. Clinical trial identifier: NCT01907100.
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P2.01 - Poster Session with Presenters Present (ID 461)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.01-012 - Acquired Chemotherapy Resistance in vitro: miRNA Profiles of Chemotherapy Resistant Squamous Lung Cancer Cell Lines (ID 4160)
14:30 - 15:45 | Author(s): N. Pavlakis
- Abstract
Background:
Lung cancer is the leading cause of cancer death worldwide. 25 -30% of lung cancers are histologically squamous cell carcinomas (SCC). Despite recent advances in immunotherapy for lung SCC, traditional cytotoxic chemotherapies currently remain the mainstay of treatment. However, over the course of treatment, patients with lung SCC inevitably acquire chemotherapy resistance. This results in poor overall survival of advanced stage lung SCC of only 9 to 11 months. Repetitive exposure of lung cancer cell lines to chemotherapeutic drugs enables investigation of molecular mechanisms of acquired chemotherapy resistance in vitro. We are studying the role of miRNAs in this process. MiRNAs are small non-coding nucleic acids that regulate gene expression. They are involved in numerous cellular pathways, including therapy resistance. MiRNA serve as biomarkers and have recently become therapeutic targets or therapeutics themselves.
Methods:
We induced chemotherapy resistance in lung SCC cell lines LUDLU-1, Calu-1, SK-MES-1 in vitro by repetitive drug treatment over a period of 6 – 12 months. Agents used to develop resistance included Cisplatin, Gemcitabine, Paclitaxel and Vinorelbine. Cell viability after 3 days of chemotherapy treatment was measured by MTT assay and drug dose causing a 50% growth inhibition (IC~50~) was calculated. Total RNA including miRNA was extracted. Expression of 754 miRNA was measured by TaqMan OpenArray Human MicroRNA array.
Results:
After 15 -25 cycles of chemotherapy lung SCC resistant cells showed a statistically significant increase in IC~50~ values: Cisplatin up to 12.4 (n-fold); Gemcitabine 40.2 – absolute resistance (n-fold); Paclitaxel 30.9 – 110.1 (n-fold); Vinorelbine 4.8 -19.3 (n-fold). Resistance was stable and passed on to daughter cells. MiRNA expression of resistant cells was compared to parental, drug sensitive cells and is illustrated by heatmaps and volcano plots. Analysis of expression patterns revealed upregulation and downregulation of specific miRNAs in drug resistant cells. We are currently investigating the function of these dysregulated miRNAs in promoting chemotherapy resistance. Further, we are testing if certain miRNA are suitable targets to improve chemotherapy response.
Conclusion:
We identified changes of miRNA expression patterns after induction of chemotherapy resistance with various drugs used for lung SCC treatment. These findings may lead to development of new predictive biomarkers and to new miRNA-based drugs.
