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M. Tsao



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    MO01 - Lung Cancer Biology - Techniques and Platforms (ID 90)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO01.09 - A novel murine xenograft model using samples obtained by EBUS-TBNA (ID 773)

      11:10 - 11:15  |  Author(s): M. Tsao

      • Abstract
      • Presentation
      • Slides

      Background
      Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive approach for lymph node staging in patients with lung cancer. Although EBUS-TBNA has been utilized for various molecular testing, intrinsic characteristics of different lesions produce variability in the amount of cellular material that can be obtained. In some samples, the quantity of tumor recovered may be limited for subsequent testing. To overcome this problem, we evaluated the feasibility of establishing a murine tumor xenograft model using EBUS-TBNA samples for advanced translational research.

      Methods
      After confirmation of adequate sampling for cytopathological diagnosis during EBUS-TBNA, one additional pass was performed for this study (NCT01487603). The aspirate was stored in cell preservative solution (RPMI1640 with 10% FBS) for inoculation of the tumor for the xenograft model. The sample was transported to the laboratory on ice, then mixed with Matrigel and centrifuged. The pellet which contained tumor fragments was implanted to the subcutaneous pocket on the right flank of a NSG (NOD scid gamma) mouse. Once we confirmed the engraftment of the tumor, we passed the tumor to another mouse until 3 passages were completed. The success rate of tumor xenograft establishment was examined along with histopathology and the cellularity and cytopathologial diagnosis of the primary EBUS-TBNA samples.

      Results
      From December 2011 to June 2012, 19 patients were enrolled in this study. The cytopathological diagnoses were as follows; 12 adenocarcinoma, 3 squamous cell carcinoma, 1 large cell carcinoma NOS, and 3 small cell carcinomas. 8 out of 19 cases (42.1%) showed tumor formation. The mean duration between inoculation and tumor formation was 62.38 days (13-144 days). All engrafted tumors could be passed to the second mouse. The histological types of the engrafted tumors were 3 adenocarcinoma (3/12: 25%), 2 squamous cell carcinoma (2/3: 67%), 1 large cell carcinoma (1/1: 100%), and 2 small cell carcinomas (2/3: 67%). The tumor cellularity of primary EBUS-TBNA samples was sufficient for diagnosis and there was no correlation between engraftment and the degree of blood/lymphocyte contamination or percentage of necrosis.

      Conclusion
      EBUS-TBNA samples can be used for establishment of tumor xenograft model in immunodeficient mice. EBUS-TBNA allows minimally invasive sampling of metastatic lymph nodes in patients with advanced lung cancer which opens up possibilities for translational research. We need to continuously seek better ways to improve and standardize procurement and processing of samples obtained by minimally invasive techniques in order to optimize diagnosis and molecular analysis for improved patient care. Figure 1

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    MO08 - NSCLC - Early Stage (ID 117)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO08.08 - A cost-effectiveness analysis of the 15-gene expression signature in guiding adjuvant chemotherapy in early stage non-small cell lung cancer based on the JBR.10 trial (ID 1962)

      17:00 - 17:05  |  Author(s): M. Tsao

      • Abstract
      • Presentation
      • Slides

      Background
      The NCIC CTG JBR.10 trial demonstrated that adjuvant chemotherapy (ACT) improves survival in resected stage IB/II non-small cell lung cancer (NSCLC) compared to observation. A 15-gene expression signature was developed from the trial population and subsequently validated to stratify patients with resected NSCLC into low and high risk prognostic groups. The signature may also be predictive for greater benefit from ACT in high risk patients (Zhu et al. JCO 2010), but this has not yet been validated. This gene expression signature may offer a risk stratification strategy to identify patients most likely to benefit from ACT. We conducted an exploratory economic analysis to assess the impact of the use of this gene signature compared to current clinical staging to guide ACT decisions in resected early stage NSCLC.

      Methods
      We developed a decision analytic model populated by the NCIC CTG JBR.10 trial cost and outcome data, including direct medical costs and overall survival (OS). Utility for each health state was estimated from quality of life data to generate quality-adjusted survival. The analysis was performed over a lifetime horizon from the perspective of the Canadian public health care system, expressed in 2013 Canadian dollars. Survival and costs were discounted at 5% per year. We determined the incremental cost-effectiveness ratio (ICER) and incremental cost-utility ratio (ICUR) of ACT versus observation in resected stage IB/II NSCLC in the following two scenarios: (1) gene signature-directed ACT, where patients classified as having high risk of recurrence receive ACT and those at low risk are observed; and (2) clinical stage-directed ACT, where gene signature profiling is not performed – those with stage IB tumours >4cm or stage II NSCLC receive ACT, and those with stage IB tumours <4cm are observed. Nonparametric bootstrapping to estimate 95% confidence intervals (CI) and multi-way sensitivity analyses were performed.

      Results
      The analysis included 52 patients in the gene signature-based strategy and 125 patients in the stage-based strategy with available direct medical costs and gene signature data. The mean survival gain of ACT versus observation was 2.28 years using gene signature-directed selection, and 1.59 years using stage-directed selection. The discounted ICER of ACT versus observation was $8,327/life-year gained (LYG; 95% CI, $395 to $19,590) using the gene signature-directed approach, and $5,623/LYG (95% CI, -$2,161 to $14,354) for the clinical approach. There was no significant difference in the ICER between the two strategies (p=0.52). The discounted ICUR was $11,315/quality-adjusted life-year (QALY; 95% CI, $211 to $27,314) using the gene signature-directed approach, and $7,728/QALY (95% CI, -$3,080 to $19,825) for the clinical approach. Sensitivity analyses showed that the ICER was most sensitive to changes in the survival hazard ratio (i.e. treatment benefit) and utility, but less sensitive to the cost of the gene signature (range $0 to $10,000 per case, with corresponding ICER $15,794 to $28,194/LYG, respectively).

      Conclusion
      This exploratory analysis suggests that use of the 15-gene expression signature to guide decisions for ACT in resected stage IB/II NSCLC patients could be highly cost-effective. Further validation of the signature’s impact on ACT outcomes is needed.

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    O04 - Molecular Pathology I (ID 126)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      O04.06 - An international standardization study using the ALK IHC antibody D5F3 and a sensitive detection kit demonstrates high concordance between ALK IHC and ALK FISH and between evaluators (ID 2875)

      11:25 - 11:35  |  Author(s): M. Tsao

      • Abstract
      • Presentation
      • Slides

      Background
      The goal of personalized medicine is treating patients with a therapy predicted to be efficacious based on the molecular characteristics of the tumor, thereby sparing the patient futile or detrimental therapy. Anaplastic lymphoma kinase (ALK) inhibitors are effective against ALK positive non-small cell lung cancer (NSCLC) tumors, but to date the only US Food and Drug Administration approved companion diagnostic is a break-apart fluorescence in situ hybridization (FISH) assay. Immunohistochemistry (IHC) is a clinically applicable cost-effective test that is sensitive and specific for ALK protein expression. The purpose of this study was to assemble an international team of expert pathologists to evaluate and standardize the interpretation of a new automated standardized ALK IHC assay.

      Methods
      Archival NSCLC tumor specimens (n=103) previously tested for ALK rearrangement by FISH were provided by the international collaborators. These specimens were stained by IHC with the anti-ALK (D5F3) primary antibody (Ventana Medical Systems, Inc) combined with OptiView DAB IHC detection and OptiView amplification (Ventana Medical Systems, Inc). The evaluators went through an interpretation training session and scored the specimens as positive, if strong granular cytoplasmic brown staining was present in tumor cells, or negative. IHC results were compared to the FISH results and inter-evaluator agreement comparisons made.

      Results
      Overall for the 100 evaluable cases the ALK IHC assay was highly sensitive (90%), specific (95%) and accurate (93%) relative to the ALK FISH results. Similar results were observed using a majority score. For the discrepant cases IHC negativity was scored by 7/7 on 3 FISH positive cases and 6/7 evaluators on 2 additional FISH positive cases. IHC positivity was scored on 2 FISH negative cases by 7/7 readers. There was agreement among 7/7 and 6/7 readers on 88% and 96%% of the cases before a consensus review, respectively, and following a review there was agreement among 7/7 and 6/7 on 95% and 97% of the cases, respectively.

      Conclusion
      Based on expert evaluation the ALK IHC assay using the D5F3 antibody combined with Optiview Detction and Optiview amplification is sensitive, specific and accurate, relative to FISH, and a majority score of multiple readers does not improve these results over an individual reader’s score. Excellent inter-reader agreement was observed for the IHC assay. These data support the algorithmic use of ALK IHC as a screening procedure for ALK protein expression in NSCLC.

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    O08 - Preclinical Therapeutic Models I (ID 92)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      O08.07 - Patient-derived primary non-small cell lung carcinoma (NSCLC) xenograft models for mechanistic studies of resistance to EGFR tyrosine kinase inhibitor therapy (ID 2380)

      17:10 - 17:20  |  Author(s): M. Tsao

      • Abstract
      • Presentation
      • Slides

      Background
      Non-small cell lung cancer (NSCLC) patients with tumors bearing “driver” mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase (TK) domain have very high response rates to small molecule EGFR TK inhibitors (TKIs). However, all patients eventually develop resistance to the TKIs, and more recent reports have shown that patients who have stopped TKI therapy may be sensitive again upon re-treatment. While several genetic mechanisms of resistance have been documented, including the gate keeper T790M mutation and Met amplification, cell line studies in vitro have also implicated alternate epigenetic mechanisms that may explain the clinical progression observed in patients with EGFR mutations treated by TKIs. Studies in vivo using patient-derived primary lung tumor xenograft models have not been reported.

      Methods
      Patient-derived primary tumor xenografts were established from surgically resected early stage NSCLC implanted subcutaneously in non-obese diabetic severe combined immune deficient (NOD-SCID) mice. Tumors were passaged after reaching the humane endpoint 1.5 cm maximum diameter. EGFR TKI therapy was initiated when tumors reached ~6 mm diameter. Treatment included daily oral gavage for erlotinib (50 mg/Kg) and dacomitinib (3 mg/Kg). Cetuximab was administered weekly intraperitoneally (50 mg/Kg).

      Results
      Among 33 tumors with EGFR mutations engrafted into the mice, only 6 (18.2 %) formed tumors that could be propagated beyond first passage. Three models have been studied for their responses to EGFR TKIs. Model 148 with L858R mutation showed intrinsic pan-resistance to erlotinib and dacomitinib, as well as to cetuximab. This model was derived from a patient who received pre-operative erlotinib in a window of opportunity trial and did not respond. The patient relapsed after surgery and did not receive additional TKI therapy. Model 137 with exon19 E746-A750 deletion mutation demonstrated complete response to both erlotinib and dacomitinib. However, microscopic examination of tissue from the implantation site revealed viable tumor cells, consistent with the inability of TKI to completely eradicate tumor cells even when complete response is observed clinically. The patient subsequently developed disease recurrence and responded to third line gefitinib treatment. Model 164 has double exon19 L747-T751 deletion/T790M mutations. As anticipated, the xenograft failed to respond to erlotinib but responded dramatically to cetuximab alone. Importantly, model 164 xenograft showed transient stabilization of the tumor growth when treated by dacomitinib, but eventually developed progressive growth after 2 weeks of treatment. Resistance was reversible each time the dacomitinib-resistant tumor was propagated, without drug in new mice. The reversibility of resistance observed upon re-initiation of dacomitinib treatment suggests an epigenetic mechanism for TKI resistance. This patient developed recurrence after surgery and failed to respond to second line erlotinib treatment.

      Conclusion
      Patient-derived primary lung cancer xenografts may provide important patient-like models to study mechanisms of resistance to targeted therapies, and to test novel treatment strategies that may improve further treatment efficacy.

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    O17 - Anatomical Pathology I (ID 128)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      O17.01 - Prognostic and predictive value of a new IASLC/ATS/ERS lung adenocarcinoma classification in a pooled analysis of four adjuvant chemotherapy trials: a LACE-Bio study (ID 3255)

      10:30 - 10:40  |  Author(s): M. Tsao

      • Abstract
      • Presentation
      • Slides

      Background
      A new IASLC/ATS/ERS classification for lung adenocarcinoma has been proposed to classify invasive lung adenocarcinoma patients according to the predominant growth pattern present in the tumor: lepidic (LEP), papillary (PAP), acinar (ACN), micropapillary (MPP) and solid (SOL). Several studies have reported consistently that early stage resectable lung adenocarcinoma patients with LEP predominant pattern have a better prognosis, while MPP and SOL predominant patterns have a significantly poorer prognosis. However, the prognostic significance of these histological patterns has not been tested in clinical trials. Furthermore, the clinical utility of this new classification for predicting benefit from adjuvant chemotherapy is unknown.

      Methods
      The representative single H&E slide of 1766 non-small cell lung cancer patients from IALT, JBR.10, CALGB 9633 and ANITA adjuvant chemotherapy trials who participated in the LACE-Bio study were reviewed to confirm the histological diagnosis. These cases were independently assessed by two pathologists involved in the development of this new IASLC/ATS/ERS classification for subtyping. Discordant cases were resolved by consensus. Clinical outcomes were overall survival (OS, main outcome), disease-free survival (DFS) and specific disease-free survival (SDFS) (DFS with censoring deaths not related to cancer). Multivariable Cox models stratified by trial were used for prognostic analyses and the interaction between treatment (chemotherapy / control) and histology subtypes added for predictive analyses. The five histology subtypes were first analysed separately and 3 groups (LEP, PAP+ACN and MPP+SOL) were considered.

      Results
      573 patients were classified as 23 (4%) as LEP, 148 (26%) as ACN, 99 (17%) as PAP, 39 (7%) as MPP and 264 (46%) as SOL. The distribution of histology subtypes was different across trials (p=0.02) but not related with standard prognostic variables. The number of deaths, events and cancer-related events were 269, 320 and 292 respectively. No significant difference was observed between the survival curves of 5 subtypes whatever the endpoint. No prognostic value of 3 histological subtypes was observed for OS (p=0.21 in the control arm) contrary to DFS (p=0.04) and SDFS (p=0.03). These last 2 results were explained by the difference between PAP+ACN and MPP+SOL with hazard ratio (HR)~ACN+PAP vs. MPP+SOL~=0.66 95% confidence interval (CI)=[0.47-0.91] and HR~ACN+PAP vs. MPP+SOL~=0.67 [0.44-0.89] for DFS and SDFS, respectively. Due to the small number of patients with LEP predominant pattern, the predictive value was assessed after excluding this subtype. MPP+SOL patients reported significant DFS benefit from adjuvant chemotherapy (HR=0.58 [0.43-0.80], p<0.001) compared to ACN+PAP patients (HR=1.12 [0.79-1.59], p=0.53; p interaction < 0.01). A similar result was observed for SDFS with HR=0.58 [0.42-0.80], p<0.005 in MPP+SOL compared to HR=1.13 [0.78-1.63], p=0.52 in ACN+PAP (p interaction <0.01) while no predictive effect for OS.

      Conclusion
      Resectable lung adenocarcinoma patients with micropapillary and solid predominant patterns showed a trend for poorer DFS and SDFS compared to patients with the other subtypes, and they show a significantly higher benefit from adjuvant chemotherapy on these outcomes. Histological subtypes according to the IASLC/ATS/ERS classification may be proposed as a stratification factor in design of future adjuvant chemotherapy trials.

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    P1.03 - Poster Session 1 - Technology and Novel Development (ID 150)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.03-004 - Robust Global microRNA Expression Profiling Using Next-Generation Sequencing Technologies (ID 2063)

      09:30 - 09:30  |  Author(s): M. Tsao

      • Abstract

      Background
      MicroRNAs (miRNA) are endogenous, small regulatory nucleotides that negatively regulate gene expression post-transcriptionally. They are involved in a wide range of cellular functions, including growth, development, and apoptosis. Given their widespread roles in biological processes, changes in their expression are likely to be associated with the development and progression of diseases. Understanding their patterns of expression could provide new insights into complex biological processes and the possible clinical implications of miRNA dysfunction. As such, global miRNA expression profiling of human malignancies is increasingly performed, but to date, the majority of such analyses have used microarrays and quantitative real-time PCR (qRT-PCR). With the introduction of digital count technologies, such as next-generation sequencing (NGS) and the NanoString nCounter System, we have at our disposal, many more options.

      Methods
      To compare the attributes of different profiling methodologies, five pairs of non-small cell lung cancer cell lines and their corresponding xenograft models were analysed using a microarray platform (Illumina Human microRNA Expression Profiling v2), NGS (Applied Biosystems SOLiD™ 3 Plus and 4 Systems and Illumina HiSeq2500), and the NanoString nCounter System (Human miRNA Expression Assay v1). The platforms were evaluated according to the following criteria: (i) inter-platform concordance, (ii) concordance with an independent validation method, qRT-PCR, and (iii) detection of differentially expressed miRNAs in a biologically relevant setting.

      Results
      Inter-platform correlations ranged from 0.62 – 0.80, while correlations with qRT-PCR, the current gold standard for validating expression profiling studies, was highly statistically significant for all platforms, with Spearman’s ρ ranging from 0.79 – 0.86. The accuracy in detecting differential expression was the highest for NGS (88%). Overall, sequencing technologies had the greatest detection sensitivity, along with the largest dynamic range of detection, and highest concordance with qRT-PCR. To assess the technical reproducibility of NGS, the same set of samples was profiled in duplicates. Using unsupervised hierarchical clustering, technical replicates for each biological sample clustered together, with Spearman’s ρ > 0.93 in all cases. miRNA analysis of formalin-fixed paraffin-embedded tissue (FFPE) was also evaluated. FFPE samples represent a rich source of archived specimen for retrospective studies of human disease. The feasibility of miRNA analysis with FFPE tissues would offer many opportunities to evaluate such large banks of archival materials. Three pairs of matched frozen and FFPE xenografts tumors were profiled using the Illumina HiSeq2000 platform. Hierarchical clustering showed similarity between expression profiles of paired frozen and FFPE samples (Spearman’s ρ > 0.88); whereas, samples of different biological origin were less correlated (Spearman’s ρ < 0.81).

      Conclusion
      These results show the superior sensitivity, accuracy and robustness of NGS for global miRNA profiling in both frozen and FFPE tissue. Although microarrays and qRT-PCR have been used more extensively for expression profiling and are highly reproducible, they are limited to the detection of only known targets identified at the time of assay development and manufacturing. With the rapid increase in miRNAs being discovered and deposited in public databases, sequencing will offer a more comprehensive view of the miRNA transcriptome.

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    P1.05 - Poster Session 1 - Preclinical Models of Therapeutics/Imaging (ID 156)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.05-007 - Large scale establishment of genetically diverse patient-derived primary tumor xenografts from resected early stage non-small cell lung cancer (NSCLC) patients (ID 1539)

      09:30 - 09:30  |  Author(s): M. Tsao

      • Abstract

      Background
      The fidelity of established NSCLC cell line models to reflect patient tumors has been challenged. Patient-derived primary tumor xenografts (PTXGs) established directly from patient tumors in immunodeficient mice reproduce closely the histology of the primary tumors, thus are potentially better preclinical models to investigate novel therapies. We previously reported that early stage NSCLC patients whose tumors form PTXGs have significantly greater risk of relapse after surgery (Clin Cancer Res 2011; 17: 134-141). We report here a more extended analysis of clinical-molecular-pathological features of early stage NSCLC that are associated with engraftment and its impact on patient outcome.

      Methods
      Resected NSCLC tumors were harvested within 30 minutes after surgery and were implanted into severely immunodeficient mice to establish PTXGs. Tumors that grew were propagated for up to 3 passages. The mutational profiles of the primary tumors were assessed by the MassARRAY platform that included 133 mutations with ‘putative’ driver function, which have been reported in COSMIC database as recurrent in NSCLC. All identified mutations were verified by direct sequencing in both the primary and PTXG tumors. Engraftment rate among clinical factors were tested using the Fisher’s exact or Mann-Whitney tests. The Kaplan-Meier method was used to estimate 3-year overall (OS) and disease-free survival (DFS) probabilities. The effect of engraftment on OS and DFS adjusting for clinical variables was assessed using a Cox proportional hazards model.

      Results
      From April 2005 to December 2010, 261 rigorously verified resected primary non-carcinoid NSCLCs were engrafted; 38 xenografts that were lymphoma were excluded from further analysis. For the remaining 223 primaries, 101 (45.3%) successfully engrafted and formed PTXG lines. Engraftment rates were 33.8% (48/142) for adenocarcinoma (AdC), 67.7% (42/62) for squamous cell carcinoma (SqCC), 66.7% (4/6) for large cell neuroendocrine carcinoma, and 53.8% (7/13) for others. The tumors forming PTXGs were more likely to be poorly differentiated (p=0.00012) and of larger tumor size and higher pT stage (p<0.0001), but were not correlated with the pN stage. Among 95/101 (94.1%) PTXG cases profiled for mutations, 6 had mutations in the EGFR tyrosine kinase domain, 18 in KRAS/HRAS, 5 in PIK3CA, 2 in paxillin and 1 in STK11/LKB gene; 56 (62.2%) were negative for mutations. The median follow-up time was 2.7 years (range 0.04 – 7.5 years). Patients whose tumors engrafted had decreased DFS (HR 2.68, 95% CI 1.16-4.60, Wald p<0.0001) and OS (HR 3.14, 95% CI 1.56-6.33, Wald p=0.0014). Significantly poorer survival was maintained in AdC. Among 33 patients with EGFR mutation, only 6 (18.2%) engrafted. Engraftment was associated with significantly poorer DFS (HR 4.76; 1.43-15.86, log-rank p=0.005) and OS (HR 8.55, 95% CI 0.77-94.3, log-rank p=0.035) in this population.

      Conclusion
      The ability to form PTXGs of early stage NSCLC is confirmed as a very strong poor prognostic marker. Although EGFR mutant tumors usually do not engraft, engraftment of EGFR mutant tumors is associated with poor patient survival. PTXGs appear to represent biologically aggressive NSCLC.

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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.11-020 - Economic Analysis of TORCH: Erlotinib versus Cisplatin and Gemcitabine as First-Line Therapy for Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 1645)

      09:30 - 09:30  |  Author(s): M. Tsao

      • Abstract

      Background
      The TORCH (“Tarceva or Chemotherapy”) randomized phase III trial demonstrated that first-line erlotinib followed by second-line cisplatin-gemcitabine (N=380) compared to cisplatin/gemcitabine followed by erlotinib (N=380) in unselected advanced NSCLC patients yielded inferior survival, without major differences in first-line global quality of life. We determined the incremental costs and utility between arms, including in the EGFR mutation positive subgroup (N=39).

      Methods
      Direct medical resource utilization data and EQ5D scores were collected prospectively during the trial. Mean survival and quality-adjusted survival per arm were calculated for the entire study population and the subgroup with documented EGFR mutations. The analysis was conducted from the Canadian public health perspective, using a lifetime horizon. Costs for medications, outpatient visits, investigations and toxicity management including hospitalization were determined, and presented in 2012 Canadian dollars (CAD). The primary outcomes of the analysis included costs and outcomes per treatment arm, and the incremental cost per quality-adjusted life-year (QALY) gained in the EGFR mutation positive subgroup.

      Results
      The costs per patient in the chemotherapy were higher than in the erlotinib arm, with an incremental mean cost of $4,190 CAD. This was related to longer duration of chemotherapy treatment, associated with higher drug and outpatient visit costs. Higher costs from hospitalization and adverse event management were seen in the erlotinib arm, likely related to disease progression. Mean overall survival in the entire study population was longer in the chemotherapy arm , although mean quality-adjusted survival was similar (0.82 QALY in chemotherapy arm and 0.87 in erlotinib arm). In the EGFR mutation positive subgroup, mean survival was slightly higher in the chemotherapy arm, but quality-adjusted survival was longer in the erlotinib arm (1.19 QALYs versus 1.08 QALYs with chemotherapy). The incremental cost-effectiveness ratio for first-line erlotinib compared to chemotherapy in the EGFR mutation positive subgroup was $32,916 CAD per QALY.

      Conclusion
      While first-line platinum doublet chemotherapy remains the standard for unselected advanced NSCLC patients, first-line erlotinib appears to be cost effective in the EGFR mutation positive subgroup. This supports routine EGFR genotyping to select first-line therapy in advanced NSCLC, and targeted EGFR TKI therapy for those with EGFR mutation positive NSCLC.

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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.11-044 - Clinical impact of EGFR mutation fraction and tumour cellularity in EGFR mutation positive NSCLC (ID 2982)

      09:30 - 09:30  |  Author(s): M. Tsao

      • Abstract

      Background
      We investigated the impact of mutation fraction, tumour sample cellularity, and diagnostic specimen type on EGFR TKI response, time to treatment failure (TTF) and overall survival (OS), as well as patterns of treatment in a population-based cohort of advanced EGFR mutation positive NSCLC patients.

      Methods
      From March 2010 to May 2012, EGFR testing in the province of Ontario (Canada) was conducted at a single centre, using fragment analysis for exon 19 deletion and Sau961 restriction enzyme digest for exon 21 mutations. Patients with EGFR mutation positive samples were identified and tumour sample cellularity, mutation fraction (percent of tumour cells mutated), demographic, treatment and outcome data were collected. Regression analysis was undertaken to assess the association between demographic variables, mutation fraction, tumour sample cellularity and sample type on clinical outcomes.

      Results
      Among 293 patients identified with EGFR mutation positive NSCLC, 253 received EGFR TKIs and are included in this analysis. Most are female (72%), never smokers (59%), have exon 19 deletions (53%; 47% exon21 L858R), and median age 65 years (range 26 to 96). Tumour specimens tested include resection (32%), cytology (30%), and core biopsies (38%). Median EGFR mutation fraction is 30% (range 0.4% to 96%); 24% had a low (≤10%) mutation fraction, and 13% had a mutation fraction ≤5%. Responses (any tumour reduction) were seen in 62%, mixed response or stable disease in 25%, and progression as the best response in 13%. Median TTF from the start of EGFR TKI therapy is 13.2 months (range 0-43.7 months). Median OS from TKI start is 22.3 months (95% CI: 19.5-28.2 months), with 1-, 2- and 3-year survival rates of 72%, 49% and 37%. In multivariable analysis, factors associated with TTF included female sex (HR 0.69, p=0.03) and sample type (resection HR 0.56, cytology HR 0.82, core biopsy as reference, p=0.01). Age at metastatic diagnosis (p=0.01), sample cellularity (p=0.01) and sample type were significantly associated with OS, (resection HR 0.51, cytology HR 0.70, core biopsy as reference, p=0.04). Proportional odds logistic regression identified that mutation frequency and age at metastatic diagnosis were significantly associated with the odds of response, (p=0.047, p=0.04 respectively). Responses were seen even in those with lower EGFR mutation fraction, 48% (24/50) at a mutation frequency of ≤10% and 33% (9/27) at a mutation frequency of ≤5%. The average cellularity in the high (>10%) mutation fraction group was 53% (95%CI 50– 56%), and 36% (95%CI 29 – 43%) in those with a low mutation fraction (p<.0001).

      Conclusion
      Pathologic features may be relevant to clinical outcomes in EGFR mutation positive NSCLC, including mutation fraction, sample cellularity, and specimen tested. The clinical relevance of sample tumour cellularity and sample type tested remains unclear. In particular, initial stage and prognosis may be confounders in the association between resected specimens and favourable outcomes. Given that those with mutation fractions ≤5% may have significant response from EGFR TKI therapy, treatment should not be withheld on the basis of mutation frequency alone.

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    P3.12 - Poster Session 3 - NSCLC Early Stage (ID 206)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.12-015 - Surgery for Early Non-Small Cell Lung Cancer with Preoperative Erlotinib (SELECT): A Correlative Biomarker Study (ID 2529)

      09:30 - 09:30  |  Author(s): M. Tsao

      • Abstract

      Background
      Erlotinib has demonstrated major activity in EGFR mutation positive NSCLC, but may also benefit those with wild type tumours. We conducted a single-arm trial of pre-operative erlotinib in early stage NSCLC to assess radiologic and functional response as well as correlation with known and investigational biomarkers.

      Methods
      Patients with clinical stage IA-IIB NSCLC received erlotinib 150 mg daily for 4 weeks followed by surgical resection. Tumor response was assessed using pre- and post-treatment CT and PET imaging. Tumor genotype was established using Sequenom MassARRAY analysis. EGFR, PTEN, cMET and AXL expression levels were determined by immunohistochemistry. Pre- and post-treatment circulating markers/ligands for EGFR activation (TGF-α, amphiregulin, epiregulin, EGFR ECD) were measured by ELISA. Tumor MET copy number by FISH and VeriStrat® analysis of pre-treatment serum samples is ongoing. Secondary endpoints included pathological response, toxicity and progression-free survival.

      Results
      Twenty-five patients were enrolled; 22 received erlotinib treatment with a median follow up of 4.4 years (range 2.2 to 6.4 years). Histology was predominantly adenocarcinoma (15) with smaller numbers of squamous cell carcinoma (7). PET response (25% SUV reduction) was observed in 2 patients (9%), both with confirmed squamous carcinoma histology. All patients met criteria for stable disease by RECIST and several experienced minor radiographic regression with histologic findings of fibrosis/necrosis, including 2 with squamous histology. The presence of an EGFR activating mutation was detected in two adenocarcinoma cases; one patient experienced minor radiographic response to treatment (exon 19 deletion) and the other stable disease (L858R). High pre-treatment serum levels of TGF- α correlated with tumor growth or primary resistance to erlotinib therapy (p=0.04), whereas high post-treatment soluble EGFR levels correlated with tumor response (p=0.02). Expression of EGFR, PTEN, cMET and AXL did not correlate significantly with tumor response.

      Conclusion
      Erlotinib appears to demonstrate some activity in EGFR wild-type tumors including those with squamous histology. These findings support that certain EGFR wild-type patients may respond to EGFR TKIs. Further research is needed to characterize these patients and elucidate the predictive ability of potential biomarkers such as TGF- α, EGFR copy number and others.