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N. Leighl



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    MO05 - Prognostic and Predictive Biomarkers II (ID 95)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO05.11 - The Effect of Two BRM Promoter Polymorphisms on the Risk of Advanced Non-Small Cell Lung Cancer (NSCLC) and Small Cell Lung Cancer (SCLC) in Smokers (ID 1987)

      17:15 - 17:20  |  Author(s): N. Leighl

      • Abstract
      • Presentation
      • Slides

      Background
      BRM, an ATPase subunit of the SWI/SNF chromatin remodeling complex, is a putative tumor susceptibility gene in lung cancer. Loss of BRM expression occurs in 15% of lung cancers. Two BRM promoter insertion polymorphisms (BRM-741 and BRM-1321) lead to epigenetic silencing of BRM and highly correlate with loss of BRM expression and function in lung tumors. Pharmacologic reversal of the epigenetic changes of BRM is feasible. We previously demonstrated a strong risk association between these two polymorphisms and susceptibility to early stage NSCLC. Here, we evaluate the association between the two BRM polymorphisms and risk of developing: 1) advanced NSCLC, and 2) SCLC among smokers.

      Methods
      Genotyping for BRM promoter polymorphisms was performed using TaqMan. The cohorts analyzed were: 1) 417 stage III-IV NSCLC cases and 2) 111 SCLC cases treated at the Princess Margaret Cancer Centre (PMCC), Toronto; and 3) 43 SCLC cases from the University of Florida (U of F), all with a smoking history of ≥1 pack-year. Cases were matched to healthy controls by frequency distribution (1:2 for PMCC cases; 1:1 for U of F cases) based on age, gender, pack-year smoking history, and either current smoking status (PMCC) or ethnicity (U of F). Adjusted odds ratios (aORs) with their 95% confidence intervals (CI) of the association between polymorphisms and lung cancer risk were estimated by multiple logistic regression models.

      Results
      Of the 417 NSCLC cases, 59% were male; 41%, current smokers; 63%, adenocarcinoma; 51%, stage IV; median age, 63 years. The frequency of homozygosity was BRM-741, 21%; BRM-1321, 20%; both, 11%. The homozygous variants of BRM-741 and BRM-1321 were associated with an increased risk of advanced NSCLC compared to the wild types, with aOR’s of 1.6 (95% CI: 1.1-2.2; p=0.008) and 1.4 (95% CI: 1.0-2.0; p=0.04), respectively. Being homozygous for both BRM promoter variants carried an even greater risk (aOR 2.4 [95% CI: 1.4-4.0; p=0.0009]), with the strongest effect observed among current smokers (aOR 3.4; p=0.0005), and those with a histological diagnosis other than adenocarcinoma (aOR 3.2; p=0.0005). Among the 111 PMCC SCLC cases, 62% were male; 56%, current smokers; median age 65 years; of the 43 U of F SCLC cases, 35% were male; median age, 63 years. The presence of double homozygous variants of BRM-741 and BRM-1321 had no effect on the risk of developing SCLC in either of the two cohorts analyzed, with aOR’s of 1.1 (95% CI: 0.3-3.5; p=0.94) and 0.3 [95% CI: 0.04-2.41; p=0.27), respectively.

      Conclusion
      The presence of double homozygous variants of the BRM promoter polymorphisms, BRM-741 and BRM-1321, significantly increases the risk of advanced NSCLC among individuals with a smoking history greater than one year, with the strongest effect observed among current smokers. In contrast, the same two polymorphisms had no effect on the risk of developing SCLC in either of the two cohorts analyzed. Thus, this study offers further insight into potential mechanisms underlying the genetic susceptibility to developing advanced NSCLC among smokers. Validation in larger populations is warranted.

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    MO12 - Prognostic and Predictive Biomarkers III (ID 96)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO12.04 - Biomarker Analysis of NCIC Clinical Trials Group IND.196, a Phase I study of erlotinib plus foretinib in advanced pretreated non-small cell lung cancer patients (ID 3148)

      10:45 - 10:50  |  Author(s): N. Leighl

      • Abstract
      • Presentation
      • Slides

      Background
      Upregulation of MET and more recently AXL have been described as potential mechanisms of resistance to EGFR tyrosine kinase inhibitors in NSCLC. We explored the impact of baseline MET and AXL tumour expression and circulating hepatocyte growth factor levels, (HGF), in advanced NSCLC patients receiving erlotinib plus foretinib, an oral multi-targeted kinase inhibitor of MET, RON, AXL, TIE-2 and VEGFR.

      Methods
      Advanced NSCLC patients that previously received one or two lines of chemotherapy were treated in IND.196, a phase I dose-finding trial with an initial two-week run-in of single agent erlotinib (100-150 mg daily). If erlotinib was well tolerated, foretinib was then added (30-45 mg daily). Submission of tumour samples (archival or fresh) was mandatory, and circulating HGF levels were determined at baseline and on treatment. Tumour samples were genotyped using Sequenom MassARRAY analysis. MET and AXL expression were determined by immunohistochemistry. For AXL, the human Axl affinity purified polyclonal goat IgG antibody (R&D systems, AF154, Minneapolis MN) was scored manually. For MET, the anti-total MET (SP-44) rabbit monoclonal antibody (Ventana Medical Systems, Tucson AZ) was scored using the Benchmark XT autostainer. Staining intensity (0-3+) and percent cells stained were used to calculate the H-score; H-scores >100 were deemed positive for AXL, and >200 positive for MET.

      Results
      Of 31 patients enrolled, 28 were evaluable for response to combination therapy, with a recommended phase II dose of erlotinib 150 mg daily for a 2-week run-in and then foretinib 30 mg daily added. The overall response rate in the intent to treat population (RECIST 1.1) was 16.1% (95% CI 5.5-33.7%), with partial responses (PR) seen in 5/31 patients and a median response duration of 17.9 months (range 3.6-17.9). Stable disease was seen in 42% (13/31), with a median duration of 4.8 months (95% CI 2.4-15.4). Tumour samples were submitted for 25 patients; 15 had sufficient tissue for genotyping, 17 for assessment of MET, and 16 for AXL expression. 2/5 responding patients had confirmed EGFR mutations, (1 wildtype, 2 unknown). Another 5 had KRAS mutations, one with >20% reduction in tumour size but SD by RECIST. Of 17 patients with MET IHC results, 71% (12/17) were positive. PR was seen in 3/12 patients with MET-positive tumours, (2 with EGFR mutations, 1 wildtype). No response was seen in those with MET-negative tumours. Of 16 samples with AXL IHC results, 9 were positive (56%). PR was seen in 2/9 with AXL-positive tumours and 2/6 with AXL-negative tumours. AXL expression was not seen in samples with EGFR mutations, but 3/5 KRAS mutant samples were AXL positive. Assessment of circulating HGF levels will be presented at the 2013 WCLC meeting.

      Conclusion
      Baseline MET expression, uncontrolled for EGFR status, may be associated with response to combination erlotinib/foretinib. No correlation between baseline AXL expression and response was seen although the sample size is small. Further study is needed to control for the impact of EGFR mutation status on response, and to assess whether combination erlotinib/foretinib can overcome resistance to EGFR TKI therapy mediated by MET and AXL.

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    MO14 - Mesothelioma II - Surgery and Multimodality (ID 121)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 1
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      MO14.09 - 5-year experience with accelerated induction hypofractionated hemithoracic intensity modulated radiation therapy (IMRT) followed by extrapleural pneumonectomy (EPP) for malignant pleural mesothelioma (MPM) (ID 2022)

      11:20 - 11:25  |  Author(s): N. Leighl

      • Abstract
      • Presentation
      • Slides

      Background
      Our experience in tri-modality therapy for MPM with induction chemotherapy followed by EPP and high dose hemithoracic radiation demonstrated that completion of EPP and radiation provided the best results. We therefore developed a new protocol of accelerated induction hypofractionated hemithoracic IMRT followed by EPP to deliver optimal radiation to the whole tumor bed in a short period of time. EPP is performed approximately one week after completion of radiation to limit the risk of pneumonitis. The results of Surgery for Mesothelioma After Radiation Therapy (SMART) was reviewed and compared to our previous cohort of patients undergoing induction chemotherapy followed by EPP and adjuvant hemithoracic radiation.

      Methods
      All patients undergoing EPP in our institution between 01/2001 and 06/2013 were reviewed. The SMART protocol (25 Gy in 5 daily fractions over 1 week delivered to the entire ipsilateral hemithorax by IMRT with concomitant boost of 5 Gy to volumes at high risk based on CT and PET scan findings) was started in 2008. EPP was performed 6±2 days after radiation therapy. The results of the SMART protocol were compared to the group of patients undergoing induction chemotherapy followed by EPP as part of a trimodality approach.

      Results
      A total of 111 patients underwent EPP between 01/2001 and 06/2013 with a hospital mortality of 4.5% (n=5). A total of 64 patients (81% men, 59±9 years old, 81% with epithelial histologic subtype) underwent induction chemotherapy, while 39 (82% men, 62±9 years old, 69% with epithelial histologic subtype) underwent SMART. Seven patients had no induction therapy and one had pre-operative chemo- and radiation therapy. Since 2008, the number of surgical patients undergoing SMART progressively increased from 14% in 2008 to 100% in 2013. None of the patients undergoing SMART died in hospital or within 30 days of surgery, while 4 of the 64 patients (6.4%) undergoing induction chemotherapy died in hospital after EPP (p=0.1). Patients undergoing SMART tended to have a greater proportion of ypN2 disease on final pathology than patients completing induction chemotherapy before EPP (58% vs 41%, respectively; p=0.09). After a median follow-up of 16 months after the start of therapy, the 3-year survival was significantly better in patients with epithelial disease undergoing SMART (n=27) compared to patients with epithelial disease undergoing induction chemotherapy and EPP (n=52) (79% 3-year survival vs 30% 3-year survival, respectively; p=0.04). In contrast, the 3-year survival of patients with biphasic disease was similar between patients undergoing SMART (n=12) or induction chemotherapy and EPP (n=12) (20% vs 8%, respectively; p=0.8). Multivariate survival analysis using Cox regression model demonstrated that epithelial histologic subtype (p=0.0003), the absence of ypN2 disease (p=0.007) and SMART (p=0.03) were predictors of better survival.

      Conclusion
      Over the past 5 years, accelerated hemithoracic IMRT followed by EPP has become our preferred approach for surgically resectable MPM. Surgery for mesothelioma after radiation therapy was feasible with no operative mortality in 39 patients. Although comparison with our historical cohort of patients has limitations, our current protocol provides very encouraging results in patients with epithelial disease with a 3 year survival of 79%.

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    MO18 - NSCLC - Targeted Therapies IV (ID 116)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO18.02 - Preliminary clinical safety and activity of MK-3475 monotherapy for the treatment of previously treated patients with non-small cell lung cancer (NSCLC) (ID 2416)

      16:20 - 16:25  |  Author(s): N. Leighl

      • Abstract
      • Presentation
      • Slides

      Background
      Currently approved cytotoxic chemotherapies for previously treated patients with NSCLC demonstrate few objective responses, which are generally of short duration, with limited impact on progression-free survival and overall survival. Programmed death-1 (PD-1) is an inhibitory T-cell co-receptor whose activation by interaction with its ligands, PD-L1 or PD-L2, can lead to suppression of antitumor immunity. Preclinical and clinical data indicate that this pathway is important in NSCLC.MK-3475 is a humanized monoclonal IgG4 antibody against PD-1.

      Methods
      MK-3475 was administered at 10 mg/kg every three weeks to patients with NSCLC previously treated with two systemic regimens. At least one measurable tumor lesion, ECOG performance status of zero or one, and adequate laboratory function were required for eligibility. A new tumor biopsy no earlier than 60 days before the first dose of MK-3475 was required for study entry. Imaging assessments per investigators were performed every nine weeks until confirmed disease progression utilizing the immune-related response criteria (irRC). Independent central review of images was assessed with RECIST v1.1. PD-L1 expression on the pretreatment tumor sample was determined by immunohistochemistry. A cut-point associated with the Youden Index of the receiver-operating characteristic curve for PD-L1 staining was identified.

      Results
      Between April 2012 and September 2012, thirty-eight patients were enrolled. Median age was 63 years (range, 34-85 years), with 42% men and 42% with an ECOG performance status of zero. Previously treated, stable brain metastases were allowed and were present in 10%. Seven patients had an EGFR mutation, eight patients had a KRAS mutation, and one patient had an ALK gene rearrangement in their tumor. Fifty percent of patients experienced drug-related adverse events; the most common were fatigue, rash, and pruritus (16% each). The incidence of diarrhea was 13% (only grade 1 or 2 reported). One case of a drug-related grade 3-4 adverse event (grade 3 pulmonary edema: 3%) was seen. There were no drug-related fatalities. Using investigator-assessed irRC, the objective response rate (ORR; confirmed and unconfirmed) was 24%, including squamous and nonsquamous subtypes. Similar results were obtained using RECIST v1.1, yielding an ORR (confirmed and unconfirmed) of 21%. Most responses by irRC were observed by the time of first planned assessment at Week 9. The median duration of response by irRC has not been reached, with a median duration of follow-up of 9 months (minimum, 6 months). As of June 2013, seven of the nine responding patients by irRC continue on therapy. Pretreatment tumor PD-L1 expression was a statistically significant predictor of response. In patients with evaluable tumor PD-L1 expression, all confirmed responses by RECIST v1.1 (and irRC) occurred in patients with tumors strongly positive for PD-L1.

      Conclusion
      MK-3475 is generally well tolerated in previously treated patients with advanced NSCLC and provides durable objective responses. An additional cohort of patients whose tumors express PD-L1 is enrolling; preliminary safety and efficacy data, including PFS and OS, will be reported further at the World Conference on Lung Cancer 2013.

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    MO27 - Patient Centred Care (ID 141)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Nurses
    • Presentations: 1
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      MO27.08 - Needs assessment of advanced lung cancer patients - evolution over a decade? (ID 2914)

      11:15 - 11:20  |  Author(s): N. Leighl

      • Abstract
      • Presentation
      • Slides

      Background
      Lung cancer patients continue to experience higher symptom distress than others with different cancer types. We assessed changes in the needs and symptoms of advanced lung cancer patients over a 10 year period.

      Methods
      Consecutive outpatients with advanced lung cancer attending thoracic oncology clinics at a major Canadian cancer centre were invited to complete a 25-item self-administered questionnaire assessing physical and psychosocial symptoms, functional impairment, cancer knowledge and information preferences. Patients were surveyed over 6 months in 2002, and a second cohort surveyed over 3 months in 2012. Summary data and relevant changes over time are presented here.

      Results
      108 advanced lung cancer patients were surveyed in 2002, and 100 in 2012. Fatigue, cough, and shortness of breath are the most common physical symptoms, affecting over one-third of patients on a frequent or constant basis. Significant anxiety was reported by 27% in 2002, 20% in 2012, and 15% reported depression, unchanged over time. Lung cancer or treatment-related symptoms impair daily activities in approximately two-thirds of patients. More than a third experience significant financial hardship, and 62% believe their lung cancer imposed significant hardship on their family. More patients in 2012 reported receiving advice on symptom management, information on the goals and benefits of cancer therapy, and an understanding of clinical trials. However a quarter of patients still perceived that they received little to no advice on symptom management, and 19% felt uninformed about treatment goals for their advanced lung cancer. Despite advances in palliative care, less than 20% discussed their end-of-life care wishes with their healthcare team, even though ~40% had specific wishes or plans, with no change over 10 years. In 2002, most advanced lung cancer patients preferred to receive information in print media. In 2012, while most would still be interested in print media, significantly more were interested in a telephone helpline (~60%). Half of patients indicated they would not use internet-based resources even if readily available in 2002, but this number did not change over time (46% in 2012).

      Conclusion
      Advanced lung cancer patients continue to experience a significant burden of physical and psychosocial symptoms, with no decrease in this burden over time despite perceived advances in treatment and support. Patients are more informed about symptom management and treatment goals than a decade ago, although a significant number still require more information. Patients with advanced lung cancer also need greater empowerment and support from their oncology team in advanced care planning. Printed information continues to be preferable to internet-based resources for the majority of advanced lung cancer patients, and a growing number are interested in telephone help-line support.

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    MS25 - Translating Research into Practice (Applied Statistics) (ID 42)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Statistics
    • Presentations: 1
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      MS25.3 - Cost-Effectiveness of Modern Therapies (ID 581)

      14:45 - 15:05  |  Author(s): N. Leighl

      • Abstract
      • Presentation
      • Slides

      Abstract
      The growing number and rising costs of modern lung cancer therapies have brought the issue of cost and cost effectiveness to the forefront of clinical practice. While personalized medicine improves outcomes in specific subgroups, sparing others from ineffective costly treatment and toxicity, it can be challenging to incorporate into economic analyses. Defining the target population for the new treatment is key, and then evaluating the costs and benefits of the new intervention compared to the previous standard. However, the definition of molecular populations for targeted therapies has emerged as an important consideration when considering whether or not to adopt a new targeted therapy. The cost of biomarker testing can have a major impact on healthcare costs, and many countries are struggling with how to best incorporate the "hidden" costs of personalized medicine into adopting new targeted therapies. Focusing only on the target population, comparing the new treatment with standard comparators does not incorporate the costs of biomarker testing, or need for repeat biopsies for successful testing, but will be a better reflection of the benefit of the new treatment in that population. Comparing a test-and-treat strategy to a strategy without testing or the new therapy allows incorporation of the costs of testing, but has some important challenges. Biomarker frequency is a key driver in these analyses, with smaller populations as a particular challenge, such as ALK positive nonsmall cell lung cancer. Presenting the cost of both a test-and-treat strategy alongside an evaluation of the cost effectiveness of therapy in the target population may be a better way to illustrate the impact of a novel treatment, especially when the target population is small, while acknowledging the incremental financial burden of biomarker testing in cancer. This may allow new therapies to compete with current alternatives on a comparable footing, and not underestimate the impact of a new treatment in a small subgroup. It would also permit the development of more effective and cost-efficient screening methods for the desired target population. It is important to recall that technological methods and costs involved in biomarker testing and molecular analysis are rapidly changing, and should be revisited over time. The technological methods used to identify molecular abnormalities in cancer, such as sequencing and antibody development, are changing rapidly along with associated costs. Thus less expensive or more efficient methods (e.g. multiplex testing) may be more affordable compared to more labor-intensive methods used in initial clinical trials. For example, immunohistochemical techniques may replace more expensive methods, allowing more jurisdictions to take up testing and treatment of new therapies.

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    O01 - Prognostic and Predictive Biomarkers I (ID 94)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 2
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      O01.01 - Genetic polymorphisms of inflammatory and DNA repair pathways, radiation-related esophagitis and pneumonitis in definitive chemoradiation treated non-small cell lung cancer patients. (ID 2997)

      10:30 - 10:40  |  Author(s): N. Leighl

      • Abstract
      • Presentation
      • Slides

      Background
      The benefits of concurrent chemoradiotherapy in locally advanced non-small cell lung cancer (NSCLC) are tempered by treatment toxicity. Germline genetic variants have been associated with intrinsic radiosensitivity and radiotoxicity in various cancer settings. We investigated whether variants in genes involved in inflammation response and DNA repair pathways independently influence radiation-induced phenotypes of esophagitis and pneumonitis. From 19 candidate genes, 52 polymorphisms, directed by literature and by tagging procedures, were systematically selected for assessment. The candidate genes were involved in DNA repair (double-strand breaks, homology directed, nucleotide excision) and pro/anti-inflammatory signaling. The this investigation sought to evaluate the association of genetic sequence markers for two clinically significant radiation-induced toxicities - esophagitis and pneumonitis – seen in NSCLC patients treated with a curative intent.

      Methods
      From 312 patients treated at PMCC between 2005-12, a training cohort was defined consisting of 92 definitive concurrent chemoradiation/radiation-treated NSCLC patients with genotype information on the 52 polymorphisms. A second, validation cohort consisted of 209 patients. Multivariate logistic regression was performed for each polymorphism of interest, adjusting for known clinical and dosimetric prognostic factors on the dichotomized outcomes of radiation esophagitis (Grades 0-2 vs 3-5) and pneumonitis (Grades 0-1 vs 2-5). The CTCAEv4.03 grading criteria were used. Additive genetic models were used for genetic association analysis. In the training set, genetic variants, genotyped by IlluminaGoldenGate, with p<=0.05 were identified for validation; HWE was set at p>0.01, a criteria met by all polymorphisms with statistical significance.

      Results
      In the combined training and validation datasets, 63% were males, with median age of 65 years. Specifically in the training dataset, 65% were male, with median age of 62, median mean lung doses of 15.9, median max esophageal dose of 67.1 and median V20 of 27.6. For esophagitis, the final models were adjusted for concurrent chemotherapy, V20 and max esophageal dose. Five genetic variants linked to TNF and IL6 were significantly associated with outcome (each using wild-type genotype as reference) (Table 1). For pneumonitis, the final models adjusted for V20 and smoking status. Eight genetic variants found within four genes (ATM, BRCA2, IL1alpha, IL1RN) were associated with significant pneumonitis (Table 1).

      ESOPHAGITIS
      Function / Pathway Gene refSNP OR 95% CI P value
      pro-inflammatory cytokine TNF rs3093662 3.54 1.9-10.6 0.02
      pro-inflammatory cytokine TNF rs3093664 3.42 1.2-10.2 0.03
      pro-inflammatory cytokine TNF rs3093665 4.95 1.2-21.1 0.03
      anti-inflammatory cytokine IL6 rs1800797 2.53 1.0-6.2 0.04
      anti-inflammatory cytokine IL6 rs1800795 2.45 1.0-5.9 0.046
      PNEUMONITIS
      Function / Pathway Gene refSNP OR 95% CI P value
      double-strand break repair ATM rs664143 2.67 1.3-5.6 0.01
      double-strand break repair ATM rs664677 2.37 1.2-4.7 0.01
      homology-directed repair BRCA2 rs1799955 2.59 1.3-5.3 0.01
      homology-directed repair BRCA2 rs1801406 2.42 1.2-4.8 0.01
      homology-directed repair BRCA2 rs1799943 2.09 1.0-4.2 0.04
      anti-inflammatory cytokine IL1alpha rs17561 2.63 1.2-5.7 0.01
      anti-inflammatory cytokine IL1alpha rs2856863 2.60 1.1-5.9 0.02
      anti-inflammatory cytokine IL1RN rs3087263 0.17 0.04-0.8 0.04

      Conclusion
      In our 92 patient training set, genetic variations in TNF and IL6 are associated with radiation esophagitis, while genetic variations in ATM, BRCA2, IL1alpha and IL1RN are associated with pneumonitis. Results from the 209 patients in the validation dataset will be presented at the meeting (A.H. and G. L are co-senior authors).

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      O01.03 - BRM Promoter Variants and Survival Outcomes of Advanced Non-Small Cell Lung Cancer (NSCLC) Patients: A Validation Study in the NCIC Clinical Trials Group (NCIC-CTG) BR24 Clinical Trial (ID 1999)

      10:50 - 11:00  |  Author(s): N. Leighl

      • Abstract
      • Presentation
      • Slides

      Background
      BRM, an ATPase subunit of the SWI/SNF chromatin remodeling complex, is a putative tumor susceptibility gene in NSCLC. Loss of BRM expression occurs in 15% of NSCLC, and has been linked to adverse outcome. Two BRM promoter insertion variants (BRM-741 and BRM-1321) result in epigenetic silencing of BRM through recruitment of histone deacetylases. The presence of double homozygous BRM variants is linked to loss of BRM expression and function in lung tumors, and double the risk of lung cancer. Pharmacological reversal of the epigenetic changes of BRM is feasible. In this study we evaluated the association between the BRM promoter variants and survival outcomes of advanced NSCLC patients.

      Methods
      The training cohort consisted of 564 stage III-IV NSCLC patients treated at the Princess Margaret Cancer Centre, Toronto 2006-2010. The validation cohort comprised 219 stage IIIb-IV NSCLC patients from the NCIC-CTG BR24 clinical trial, a phase II/III double-blind randomized trial of cediranib versus placebo in patients receiving carboplatin/paclitaxel for the treatment of advanced or metastatic NSCLC. Genotyping for the BRM promoter variants was performed using Taqman. Associations of BRM promoter variants and overall (OS) and progression free survival (PFS) were assessed using Cox proportional hazard models adjusted for clinically relevant variables, and in the case of the BR24 population, stratified by treatment arm.

      Results
      Among the training cohort, 73% were Caucasian, 52% male, median age 63 yrs, 55% stage IV disease, and 67% adenocarcinoma. Median OS was 1.6yrs; median follow up, 3.6yrs. The frequency of homozygosity was BRM-741, 23%; BRM-1321, 21%; both 12%. Homozygous variants of BRM-741 were strongly associated with worse OS (adjusted HR [aHR] 2.5 [95% CI: 1.9-3.3; p=6x10E-10]) and PFS (aHR 2.0 [95% CI: 1.6-2.6; p=9x10E-8]) compared to the wild types. Similar findings were observed for the BRM-1321 homozygous variants (aHR for OS of 2.0 [95% CI: 1.5-2.6; p=2x10E-6]; aHR for PFS of 1.8 [95% CI: 1.4-2.4; p=3x10E-6]). The presence of double homozygous BRM-741 and BRM-1321 variants was strongly associated with worse OS (aHR 2.8 [95% CI: 1.9-4.0; p=7x10E-8]) and PFS (aHR 2.7 [95% CI: 1.9-3.8; p=1x10E-8]). Genotyping was possible for 219/296 BR24 participants. Of these, 59% were male, median age 59 yrs, 83% stage IV, 46% adenocarcinoma, with 50% receiving cediranib. Individuals carrying the homozygous variants of both BRM-741 and BRM-1321 (13% of cases) had a substantially worse OS (aHR 9.0 [95% CI: 4.3-18.5; p=1x10E-9]) and PFS (aHR 3.8 [95% CI: 1.9-7.3; p=3x10E-5]) compared to the wild types, irrespective of whether they were treated with cediranib (aHR for OS of 6.4; p=1x10E-4; aHR for PFS of 2.1; p=0.02) or placebo (aHR for OS of 16.8; p=2x10E-7; aHR for PFS of 8.3; p=1x10E-4).

      Conclusion
      The same two homozygous BRM promoter variants that are associated with increased risk of NSCLC are also strongly associated with adverse OS and PFS in this study of advanced NSCLC patients. We are completing additional studies focusing on the relationship between the BRM promoter variants and BRM protein expression; results will be presented at the meeting.

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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): N. Leighl

      • 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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    O24 - Cancer Control and Epidemiology III (ID 134)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      O24.05 - The impact of body mass index on survival in stage 3 and 4 lung cancer (ID 663)

      16:55 - 17:05  |  Author(s): N. Leighl

      • Abstract
      • Presentation
      • Slides

      Background
      Obesity has been shown to be an adverse prognostic factor in several cancers, including breast, colorectal, endometrial, ovarian, pancreatic and prostate. However, studies of body mass index (BMI) and outcomes in lung cancer are lacking. Understanding the clinical impact of body weight on cancer outcomes is important given the high prevalence of obesity globally. We retrospectively evaluated the distribution of BMI at diagnosis and its effects on survival in stage 3 and 4 lung cancer patients.

      Methods
      1,121 patients with stage 3 or 4 lung cancer from a single institution were analyzed. Clinicopathologic data were collected retrospectively. Adjusted hazard ratios (aHR) for overall survival (OS) and progression-free survival (PFS) were generated by Cox regression for each BMI (kg/m[2]) category (underweight: <18.5, normal: 18.5-24.9, overweight: 25.0-29.9, obese: ≥30), after adjusting for age, gender, Charlson Comorbidity Index, performance status (PS), clinical stage and treatment regimen.

      Results
      In this cohort (n=1,121), the frequencies of stage 3A, 3B and 4 lung cancers were 35%, 32% and 33%, respectively. There were 633 (57%) adenocarcinomas, 238 (21%) squamous cell carcinomas, 38 (3%) small cell lung cancers, and 210 (19%) other histologies. Patients had variable BMI: 82 (7%) underweight, 550 (49%) normal weight, 333 (30%) overweight, 156 (14%) obese. Being overweight/obese was associated with older age (p=0.002) and stage 3A disease (p=0.001); underweight patients were more likely current smokers (p<0.001). OS was significantly decreased with age ≥65, males, PS 2-3, stage 4, and lack of systemic treatment (p<0.001). Median OS in underweight, normal weight, overweight and obese patients were 14, 23, 24 and 26 months, respectively. Compared with BMI ≥18.5, being underweight was associated with significantly poorer OS (aHR 1.33, 95% CI 1.01-1.77, p=0.045), but not PFS (aHR 1.12, 95% CI 0.86-1.46, p=0.414). The magnitude of this association was greatest among those aged less than 65 years (aHR 1.57, 95% CI 1.11-2.22, p=0.011).

      Conclusion
      In stage 3 and 4 lung cancer, being underweight at diagnosis is associated with significantly poorer OS, especially in patients younger than 65 years of age. Lower BMI is mostly observed in current smokers, while above normal BMI is seen in older patients and stage 3A disease. Unlike other malignancies, obesity does not increase mortality in this population. The BMI-survival relationship in lung cancer requires further study.

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    P3.07 - Poster Session 3 - Surgery (ID 193)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Surgery
    • Presentations: 1
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      P3.07-038 - Long-term outcome after resection of non-small cell lung cancer invading the thoracic inlet (ID 2929)

      09:30 - 09:30  |  Author(s): N. Leighl

      • Abstract

      Background
      Non-small cell lung cancer (NSCLC) of the thoracic inlet accounts for less than 5% of all lung cancers. Due to the lack of efficient treatment and the complexity of the anatomical structures commonly invaded, these tumors were deemed historically unresectable and fatal. In this study, we reviewed our surgical experience and long-term outcome after resection of NSCLC invading the thoracic inlet

      Methods
      All consecutive patients from a single center who underwent resection of NSCLC invading the thoracic inlet were reviewed with data retrieved retrospectively from the charts.

      Results
      A total of 65 consecutive patients with a median age of 61 years (range 32 to 76) underwent resection of NSCLC invading the thoracic inlet from 1991 to 2011. Tumors were located in the previously described (Reference) five zones of the thoracic inlet as follows: zone 1 or anterolateral (n=5, 8%), zone 2 or anterocentral (n=7, 11%), zone 3 or posterosuperior (n=12, 18%), zone 4 or posteroinferior (n=22, 34%) and zone 5 or inferolateral (n=7, 11%). Fifty-two (80%) patients had induction therapy, mostly two cycles of cisplatin-etoposide and 45 Gy of concurrent radiation. All patients underwent en bloc resection of the lung and chest wall. Lobectomy was performed in 60 patients (92%). A median of three ribs were resected (range 1 to 5) and included the first rib in all patients. Twenty-four patients (37%) had an additional vertebral resection of up to five levels (median 3). Considering the most extended vertebral resection, total vertebrectomy with anterior-posterior spinal stabilization was required in 6 patients (25%), hemi-vertebrectomy with posterior spinal stabilization in 15 (62%), and partial vertebrectomy without stabilization in 3 (13%). Arterial resections were performed in seven patients (11%) and included subclavian artery (n=5), vertebral artery (n=1) and combination of sublclavian and carotid arteries (n=1).The median postoperative length of stay was 11 days (range 4 to 173). Postoperative morbidity and mortality were 46% and 6%, respectively. Pathologic response to induction treatment was complete (n=19) or near complete (n=12) in 31 patients (49%). Pathologic stages were 0 in 19 patients (29%), IB in 1 (2%), IIB in 28 (43%), IIIA in 15 (23%) and IIIB in 2 (3%) patients. After a median follow-up of 20 months (range 0 to 193), 34 patients were alive without recurrence. The overall 3- and 5-year survivals reached 58% and 52%, respectively. Results of the Cox regression and log-rank/Breslow tests identified the site of tumor (zone 1/3 vs 2/4/5, p=0.050) and the response rate to induction treatment (complete/near complete vs partial, p=0.004) as significant predictors of survivals. A trend toward shorter survival was found in case of arterial resection (p=0.063).

      Conclusion
      Survival after resection of NSCLC invading the thoracic inlet in highly selected patients reached 52% after five years. Tumor location within the thoracic inlet and pathologic response to induction therapy were significant predictors of survivals. Reference: de Perrot M, Rampersaud R. Surgical approaches to apical thoracic malignancies. J Thorac Cardiovasc Surg. 2012 Jul;144(1):72-80.

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 2
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      P3.11-027 - A randomised, open-label phase II trial of volasertib as monotherapy and in combination with standard dose pemetrexed compared with pemetrexed monotherapy in second-line non-small cell lung cancer (NSCLC) (ID 2307)

      09:30 - 09:30  |  Author(s): N. Leighl

      • Abstract

      Background
      Polo-like kinases (Plks) are overexpressed in many cancers including NSCLC. Volasertib (BI 6727; an investigational drug) is a selective and potent Plk inhibitor, which induces mitotic arrest and apoptosis. This 3-arm trial compared the efficacy, safety and pharmacokinetics of volasertib monotherapy, volasertib combined with pemetrexed and single-agent pemetrexed as second-line therapy in patients with advanced/metastatic NSCLC (NCT00824408).

      Methods
      An initial run-in phase was conducted to determine the tolerability and dose of volasertib combined with pemetrexed 500mg/m[2]. Subsequent patients were randomised to one of three arms: (A) volasertib 300mg, (B) volasertib 300mg plus pemetrexed 500mg/m[2], or (C) pemetrexed 500mg/m[2]. Both drugs were administered on Day 1 every 21 days. Eligible patients had advanced/metastatic NSCLC, ECOG PS 0–2, adequate organ function and prior platinum-based chemotherapy. The primary endpoint was progression-free survival (PFS) evaluated using a stratified one-sided log-rank test (Arms B versus C); an exploratory analysis was performed for Arms A versus C. Secondary endpoints included objective response rate (ORR), overall survival (OS), safety and pharmacokinetics.

      Results
      Twelve patients were included in the run-in phase; the volasertib dose selected for the randomised phase was 300mg. 131 patients were then randomised to the three arms (A: n=37, B: n=47, C: n=47). Arm A recruitment was stopped early due to an increased rate of early progression. Demographic data were balanced between the arms. One patient per arm did not receive treatment. The median number (range) of treatment cycles in Arms A, B and C was 2 (1–49), 4 (1–36) and 5.5 (1–38), respectively. Median PFS (Arms A/B/C) was 1.4/3.3/5.3 months (HR B versus C =1.141 [95% CI: 0.735–1.771; p=0.2804]; HR A versus C =2.045 [95% CI: 1.271–3.292; two-sided p=0.0030]). ORR (Arms A/B/C) was 8%/21%/9%; no complete responses were observed. Disease control rates (Arms A/B/C) were 27%/66%/68%. Median OS (Arms A/B/C) was 22.9/17.1/17.4 months. Median relative dose intensity was 100% for both volasertib and pemetrexed in all arms with a range of 80.6–111.1% in Arm A and 83.3–100.0% in Arm B for volasertib, and 87.5–100% in Arm B and 81.3–100% in Arm C for pemetrexed. The most common all-grade adverse events (AEs) were (Arms A/B/C): fatigue (56%/74%/70%), nausea (14%/48%/54%), decreased appetite (8%/44%/41%), constipation (17%/37%/22%), dyspnoea (17%/28%/30%) and vomiting (19%/33%/24%). Most common grade 3/4 AEs (>5%) were (Arms A/B/C): fatigue (8%/13%/17%), neutropenia (14%/11%/4%) and dyspnoea (3%/9% /13%). Grade 3/4 febrile neutropenia was seen in 2 (4%) patients in Arm B and 1 (2%) patient in Arm C. One fatal AE of septic shock (Arm B) was considered drug-related; 22%/22%/26% of patients experienced a serious AE. Pharmacokinetic analysis of volasertib in Arms A and B, together with historical pharmacokinetic data for pemetrexed, did not reveal any evidence of pharmacokinetic interactions between volasertib and pemetrexed.

      Conclusion
      Volasertib and pemetrexed could be combined at full single-agent doses, with generally acceptable toxicities, and demonstrated modest antitumour activity. However, the addition of volasertib did not improve PFS compared to single-agent pemetrexed in patients with relapsed or refractory NSCLC after platinum-based first-line therapy.

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      P3.11-049 - Afatinib in advanced pretreated NSCLC - a Canadian experience (ID 3460)

      09:30 - 09:30  |  Author(s): N. Leighl

      • Abstract

      Background
      Afatinib is an oral, irreversible pan-EGFR inhibitor with demonstrated superiority over first-line chemotherapy in advanced EGFR mutation positive NSCLC. It is also active after failure of chemotherapy and reversible EGFR tyrosine kinase inhibitor (TKI) therapy, with higher response rate and better progression-free survival than placebo (LUX-Lung 1, Miller et al. Lancet Oncol. 2012). Through a national special access program (SAP), Canadian patients with advanced NSCLC, similar to those in the LUX-Lung 1 trial, may access afatinib after exhausting all other available therapies. We report our Canadian experience with afatinib at the two largest centres participating in the SAP.

      Methods
      Retrospective chart review of SAP participants was undertaken at 2 major Canadian cancer centres, the British Columbia Cancer Agency (Vancouver) and Princess Margaret Cancer Centre (Toronto). Demographic, disease and treatment data were abstracted, including toxicity, response (clinically documented tumour reduction), treatment duration and overall survival.

      Results
      From July 2010 to the present, 54 patients at the two sites were treated with afatinib through the SAP. Median age was 59.5 (range 37 to 88 years), 57% were female, 52% were never smokers (7% current, 35% former smokers), 67% had adenocarcinoma histology and 28% were East Asian. 26% had known EGFR mutations (7% wild type, 67% unknown), most commonly exon 19 deletions. Patients received a median of 3 previous therapies (range 2 to 5). All had received prior EGFR TKI therapy (81% erlotinib, 11% gefitinib, 6% both, 2% dacomitinib). Half (47%) had a response to prior EGFR TKI therapy, and 37% experienced grade ≥2 rash and 9% grade ≥2 diarrhea on prior EGFR TKI. The median time from metastatic diagnosis to starting afatinib was 23.1 months. The median treatment duration was 2 months (range 0 – 26). 21% of patients had a response (tumour reduction) to afatinib, 20% stable disease and 50% disease progression as their best response. Median survival from the time of afatinib start was 5 months (95% CI: 2-12 months). The average starting dose of afatinib was 40 mg (6% 50 mg, 94% 40 mg), with 11% requiring dose reduction. One third of patients (34%) stopped treatment for disease progression, 17% for toxicity, 30% for clinical deterioration and 19% for other or unknown reasons. The rate of grade ≥2 diarrhea, rash, paronychia, or stomatitis with afatinib was 17%, 20%, 9%, and 9% respectively (grade ≥3 in 10%, 11%, 5% and 5%). Response (non-RECIST) to afatinib was seen in EGFR wild type (2/4) and mutation positive (3/13) patients. Response to erlotinib or gefitinib was non-significantly associated with response to afatinib (OR 3.3, p=0.22). A similar non-significant association was seen with rash (OR 1.7, p=0.22), but not with diarrhea, (OR 0.37, p=0.45).

      Conclusion
      Afatinib demonstrates activity in clinical practice similar to that reported in LUX-Lung 1. While some required dose reduction, toxicity from afatinib appeared manageable for the majority. Although not significant, there was a propensity to experience response or rash on afatinib if seen with prior EGFR TKI, although this was not seen with diarrhea.

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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): N. Leighl

      • 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.

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    P3.24 - Poster Session 3 - Supportive Care (ID 160)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Supportive Care
    • Presentations: 1
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      P3.24-037 - The cost-effectiveness of second-line crizotinib in EML4-ALK rearranged advanced non-small cell lung cancer (ID 2637)

      09:30 - 09:30  |  Author(s): N. Leighl

      • Abstract

      Background
      The management of non-small cell lung cancer (NSCLC) has changed markedly over last decade with the discovery of distinct molecular and genetic changes within the lung cancer genome and the availability of new therapeutic agents to target these genetic aberrations. However, the clinical benefits observed are not without significant financial costs. These include diagnostic testing to identify molecular targets and an increasing cost of cancer treatment. Chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) are predictive for clinical response to crizotinib, a first-in-class oral ALK inhibitor. In a recent phase 3 trial, crizotinib was associated with a higher response rate, improved progression-free survival and improved quality of life when compared with docetaxel or pemetrexed as second-line chemotherapy for advanced NSCLC following platinum-based chemotherapy. We performed an analysis to estimate the cost-effectiveness of ALK testing and crizotinib treatment in the second-line setting for patients with stage IV ALK-rearranged NSCLC in the province of Ontario, Canada.

      Methods
      We developed a Markov state-transition model to compare the costs and effectiveness of ALK testing and treatment with crizotinib in positive cases with the current standard of care (docetaxel or pemetrexed chemotherapy). Patients had stage IV NSCLC with non-squamous histology and were previously treated with a platinum-based regimen. The analysis was conducted from the Canadian public health perspective (Ontario) and a “lifetime” time horizon was used. Transition probabilities, mortality rates and costs were calculated from the Ontario Registry, Cancer Care Ontario New Drug Funding Program, Ontario Case Costing Initiative, University Health Network and published literature, including a recent second-line randomized trial of crizotinib versus chemotherapy (Shaw et al. New Engl J Med 2013). Population-based ALK testing included initial immunohistochemical (IHC) staining followed by fluorescent in-situ hybridization (FISH) for positive cases. The outcome of the analysis was incremental cost per quality-adjusted life-years (QALY). The survival impact of crizotinib in ALK-positive NSCLC was derived from a retrospective study (Shaw et al. J Clin Oncol 2012), as the second-line randomized trial of crizotinib versus chemotherapy permitted >80% crossover from the standard chemotherapy arm to crizotinib.

      Results
      The use of crizotinib compared to pemetrexed and docetaxel in ALK-rearranged NSCLC, based on our preliminary model, could yield as much as +0.309 QALY and +0.433 QALY respectively, assuming no crossover from chemotherapy to crizotinib. Incremental costs based on the preliminary model are estimated at CAD $88,446 for pemetrexed and $102,764 for docetaxel, with incremental cost-effectiveness ratios of $286,198/QALY ($162,814/life-year) and $237,575/QALY ($136,707/life-year) gained respectively. Major drivers of cost-effectiveness included the cost of drug therapy and incremental survival. Data on the impact of ALK testing on the overall cost-effectiveness ratio will be presented at the 2013 WCLC meeting, as will refined cost estimates after further model calibration.

      Conclusion
      While crizotinib therapy 2[nd] line for advanced ALK-rearranged NSCLC is clearly superior to chemotherapy, the cost-effectiveness ratio is higher than traditionally accepted thresholds, driven largely by drug cost. Payors and manufacturers should collaborate to ensure that highly effective NSCLC treatments are available and affordable to patients with NSCLC.

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    Y - Young Investigator & First Time Attendee Session (ID 77)

    • Event: WCLC 2013
    • Type: Other Sessions
    • Track: Other Topics
    • Presentations: 1
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      Y.1 - Planning an Academic Career in Lung Cancer (ID 642)

      08:00 - 08:20  |  Author(s): N. Leighl

      • Abstract
      • Presentation
      • Slides

      Abstract
      There are many academic career opportunities for the young oncologist. Examples of career tracks include basic, translational and clinical research, education and administration. Finding a niche, or an unique area of contribution, is essential. Key elements for success include: 1. Finding a mentor - you can have more than one, and s/he doesn't need to be at your institution; 2. Spending time in academic training, such as pursuing formal research methodology training, administration or education training (e.g. Masters of Public Health, Business Administration or Education, and higher); 3. Developing a team to support you - include clinical support, research support or the personnel you need to achieve your career goals; 4. Build strategic partnerships and build a collaborative network - for example if you're not a scientist and wish to do translational research, partner with scientists. Engage statisticians, methods experts, and remember that collaboration is a two-way street; 5. Challenge yourself to ask important questions in your area of study, and focus on key issues - aim high and trust yourself; 6. Be a mentor to junior trainees - this is your best investment; 7. Publish your work; 8. Apply for grants (and don't give up - you will get some!); 9. Focus on your areas of interest - your areas of priority may not be where you spend most of your time, but they should be; 10. Keep your passion for your career alive - have a life outside academic oncology, enjoy your work and keep it fun. 11. Take advantage of opportunities for development - presentation skills, teaching skills, grant writing, paper writing, research methods - essential for a successful career, and not taught in medical school. 12. If you pursue a career in clinical research, join a cooperative group. Accrual is one way that young investigators can get themselves noticed, in addition to new ideas.

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