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X. Chen
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-098 - Plasma T790M Mutation Associates with Extensive Progression in Non-small Cell Lung Cancer with Acquired Resistance to EGFR Inhibitors (ID 5598)
14:30 - 15:45 | Author(s): X. Chen
- Abstract
Background:
T790M mutation is a major mechanism for clinical failure in non-small cell lung cancer (NSCLC) patients with EGFR-TKI therapy. Acknowledgement of its frequency/abundance and its correlation with clinical characteristics will be of significant importance for the management of those patients in clinical practice and future trial design. Due to the difficulty of rebiopsy, plasma ctDNA is an ideal biopsy for detection of T790M mutation.
Methods:
314 patients with advanced or recurrent NSCLC who had progressed during EGFR-TKIs treatment were enrolled prospectively. T790M mutation was determined in plasma samples by ARMS and ddPCR assay. Disease failure site was defined into three types of chest limited (CP), brain limited (BP) and extensive progression (EP). The T790M mutation status was analyzed for their correlations with failure site and clinical characteristics.
Results:
T790M mutations were detected in 30.9% and 46.8% of the patients by ARMS and ddPCR. The concordance rate was 78.3% between two methods. Compared to patients with CP and BP, EP patients showed significant higher rate for T790M[+] determined by both ARMS and ddPCR (73.8% and 54.7%, p<0.001). In T790M positive population, the median T790M abundance was 1.2% (range, 0.04%-70.3%), and the median abundance of CP, BP, and EP was 0.66%, 1.52%, and 2.61%, respectively (p＝0.062). When adjusting for TKI response, worse PFS was found correlated with the plasma T790M mutation by ddPCR.
Conclusion:
Plasma T790M status correlates the extensive progression in NSCLC patients with EGFR-TKI therapy, which may provide the important ancillary information for treatment decision-making.
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P3.02b-100 - Comparison of Three T790M Testing Methods for the Detection of Non-Small Cell Lung Cancer after Tyrosine Kinase Inhibitor Failure (ID 4958)
14:30 - 15:45 | Author(s): X. Chen
- Abstract
Background:
The third generation of TKI showed promising activities in patients with acquired T790M mutation. However, many patients in this setting are unable to undergo rebiopsy due to limited tissue availability and procedural feasibility. Mutation detection in plasma has shown promises to conquer the clinical challenging of re-biopsy, with advantage of non-invasiveness and accessibility. Here, we chose and evaluated the performance of three methods, amplification refractory mutation system (ARMS), modified amplification refractory mutation system (SuperARMS), and droplet digital PCR (ddPCR), to assess their concordance and feasibility for the detection of mutations in plasma samples.
Methods:
This study was performed between March 2015 and March 2016. Patients were considered eligible and were enrolled in this study if they met the following criteria: 1) histologically confirmed stage IIIB/IV NSCLC; 2) clinically resistant to first-generation EGFR-TKIs according to Jackman’s criteria. Blood samples were collected within 14 days after TKI resistance. Each sample was simultaneously detected by three methods.
Results:
In total, 169 patients were enrolled. 54.4% were female and 72.2% were diagnosed as stage IV; 97.6% were adenocarcinoma. The rates of patients in response to EGFR-TKI treatment were 35.5% for stable disease, 52.1% for partial response and 12.4% for complete response, respectively. T790M mutations were detected in 54 of 169 (32.0%) samples by ARMS, 33 of which simultaneously carried exon19 deletions and 21 of which carried L858R. For SuperARMS assay, 59 (34.9%) samples were detected T790M mutation and 110 (65.1%) were not detected. ddPCR results showed that 61 (36.1%) samples were with detectable T790M mutation and 108 (63.9%) samples were detected with wildtype T790M. T790M abundance ranged from 0.04% to 38.2%. The median T790M abundance was 0.15% for total samples and 2.98% for T790M mutation samples. The overall concordance was 81.1% (137/169) among ARMS, SuperARMS, and ddPCR. The crude and adjust agreement between ARMS and SuperARMS was 87.6% and 86.1%, 88.8% and 87.7% between ARMS and ddPCR, 85.8% and 84.5% between SuperARMS and ddPCR, respectively. We also found that detection of T790M with ddPCR showed a sensitivity of 94.6% (95%CI: 90%-97.5%) and a specificity of 59.9% (95%CI: 51.2%-67.9%) when took ARMS as reference.
Conclusion:
Liquid biopsy showed promises with advantage of non-invasiveness and accessibility. T790M detection based on plasma circulation tumor DNA showed high concordance. Compared with non-digital platforms, ddPCR showed higher sensitivity and provided both frequency and abundance information, which might be important for treatment decision-making.
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P3.05 - Poster Session with Presenters Present (ID 475)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Palliative Care/Ethics
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.05-016 - Mitochondial Pathway Mediated Apoptosis is Involved in Erlotinib-Induced Cytoxicity in Hepatic Cells (ID 4299)
14:30 - 15:45 | Author(s): X. Chen
- Abstract
Background:
For advanced non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor(EGFR) mutations, EGFR tyrosine kinase inhibitors(TKIs) including erlotinib are indicated for the first-line treatment. Liver injury is one of many limited toxicities of erlotinib and can greatly affect its safety. This study explored the mechanism of erlotinib-induced hepatotoxicity in vitro and provide experimental evidence for screening potential hepatoprotectors.
Methods:
L02 cells, human hepatocytes were cultured for investigating mechanism of erlotinib-induced hepatotoxicity in vitro. The cell inhibition rate was detected by sulforhodamine B (SRB) colorimetric assay and IC50 value was calculated. Apoptosis was evaluated by DAPI staining and Annexin V-FITC/PI staining for flow cytometry, moreover, the variation of mitochondrial membrane potential (△Ψm) was examined using JC-1 staining. The expressions of apoptosis related protein including cleavage of poly-ADP-ribose polymerase (PARP), c-caspase-3, Bcl-2 and Bax were detected with West blotting.
Results:
We found that erlotinib induced dose-dependent cytotoxicity in human L02 hepatic cells 72 h after treatment. In other experiments, L02 cells were treated with erlotinib for 48 h and displayed typical features of apoptosis. Erlotinib caused alteration of nucleus morphology such as chromatin condensation and karyopyknosis. It also induced a raise in the fraction of late apoptotic cells and regulation of apoptosis protein expression including activation of c-caspase-3 as well as c-PARP. Furthermore, 48 h exposure to erlotinib disturbed mitochondrial functions by reducing both the ratio of Bcl-2 to Bax proteins and mitochondrial membrane potential.
Conclusion:
The results of this in vitro study suggested that erlotinib-induced hepatotoxicity may occur through mitochondrial-pathway mediated apoptosis.
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P3.06 - Poster Session with Presenters Present (ID 492)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Trial Design/Statistics
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.06-011 - Concurrent Nab-Paclitaxel/Carboplatin Combined with Thoracic Radiotherapy in Locally Advanced Squamous Cell Lung Cancer (NCT01494415) (ID 5118)
14:30 - 15:45 | Author(s): X. Chen
- Abstract
Background:
Chemoradiotherapy is the standard treatment for locally advanced squamous cell lung cancer, however, treatment development is urgently needed due to poor prognosis and significant toxicity. Combination therapy of carboplatin and nab-paclitaxel is a useful choice as first-line therapy for patients with advanced non-small cell lung cancer, especially for squamous cell cancer. This prospective phase Ⅱ study was conducted to explore the efficacy and toxicity of concurrent chemoradiotherapy with nab-paclitaxel, carboplatin and thoracic radiotherapy in unresectable locally advanced squamous cell lung cancer.
Methods:
Patients with unresectable Stage Ⅲ squamous cell lung cancer were eligible. Patients received nab-paclitaxel weekly at a dose of 60mg/m[2], in combination with carboplatin (area under the plasma concentration time curve (AUC) 2) weekly during concurrent chemoradiotherapy. Thoracic radiation was administered at a dose of 66Gy/33 fractions, both three dimensional conformal and intensity modulated radiation therapy were allowed. The consolidation phase chemotherapy consisted of full dose nab-paclitaxel (260 mg/m[2] on day 1) and carboplatin (AUC 6 on day 1) every 21 days was administered in two cycles after the concurrent chemoradiotherapy. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), acute radiation esophagitis and pneumonitis.(Clinical trial registration: NCT01494415).
Results:
Initially, enrollment of 21 patients was planned; however, the trial was prematurely closed due to slow recruitment. Finally, a total of 8 patients were enrolled between January 2012 and July 2015 from one institute. All patients completed concurrent chemoradiotherapy and 6 patients (75.0%) received consolidation chemoradiotherapy. The objective response rate was 62.5%, with partial remission 5 (62.5%), stable disease 2 (25.0%), progressive disease 1 (12.5%), respectively. After a median follow-up of 11.6 (range, 2.0–29.2) months, 5 patients were dead, 3 were alive. The median progression-free survival and overall survival were 12.1 months and 15.2 months, respectively. According to Common Terminology Criteria for Adverse Events (CTCAE) version.4.0, 6 patients (75.0%) experienced acute radiation esophagitis, 4 (50.0%) were grade 2 (G2), 2 (25.0%) were G3; 4 patients (50%) experienced acute radiation pneumonitis, 3 (37.5%) were G2, 1 (12.5%) were G3. No late radiation-induced esophageal and pulmonary toxicity was observed after 1-year follow-up.
Conclusion:
Concurrent nab-paclitaxel, carboplatin and thoracic radiotherapy is showed to be an effective regimen for patients with unresectable locally advanced squamous cell lung cancer. However, further study should exercise caution due to the severe toxicity of radiation tissue injury especially acute radiation esophagitis.
