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T. Vavala



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    ORAL 22 - Moving Beyond a Smoking Related-Cancer to the Young, Never-smokers and Inherited Disease (ID 117)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      ORAL22.05 - The Genomics of Young Lung Cancer Study (ID 503)

      10:45 - 12:15  |  Author(s): T. Vavala

      • Abstract
      • Presentation
      • Slides

      Background:
      Primary lung cancer is increasingly understood as a heterogeneous disease made up of genomically defined subtypes requiring distinct treatment strategies. We hypothesize young age at diagnosis (< 40 years) is a clinical characteristic associated with an increased chance for a targetable genomic alteration. Our ALCMI study prospectively characterizes the somatic and germline genomics of young lung cancer (GYLC). Our goals are to identify a genomically enriched subtype of lung cancer, facilitate delivery of targeted therapy and lay groundwork for further studies of heritable and environmental lung cancer risk factors.

      Methods:
      Accrual opened July 2014. Patients are eligible if they were diagnosed with bronchogenic lung cancer less than age 40. A study website allows for virtual consenting so patients can participate remotely from anywhere in the world; and use social media to share our trial. We have an integrated data and bio repository that allows for seamless communication and completion of study activities like remote consenting and routing of blood and tumor specimens. We have defined 7 genomic alterations of interest based on the Lung Cancer Mutational Consortium (LCMC) (EGFR, KRAS, HER2, BRAF, ALK, ROS1, RET). We aim to demonstrate that the prevalence of targetable genomic alterations will be greater in our population compared to the LCMC and have powered our study to show an increase from 35% to 50%; and an improvement in use of targeted therapy from 22% to 40%. On study subjects without a known genotype will undergo comprehensive genomic profiling with the FoundationOne test to ensure that all of these genes have been tested. Subjects with advanced adenocarcinoma who are wild type for all 7 genes will receive additional genomic profiling using the FoundationOne Heme test; with the goal of identifying novel oncogenic drivers. Additional investigational genomics will include blood for germline analysis and plasma genomics. All on study genomic analysis is at no cost to the participant.

      Results:
      Preliminary results of the first 33 subjects show: Average age at diagnosis: 33 years; Range 22-39; Histology: adenocarcinoma n=29, squamous cell n=4; Stage at diagnosis: stage 4 n=26 (79%) stages 1-3 n=7 (21%). Of those with stage 4 adenocarcinoma (n=24); 18:24 (75%) have either an ALK re arrangement n=10 (42%), an EGFR activating mutation n=5 (21%) or a ROS1 fusion n=3 (13%).

      Conclusion:
      The trial is currently accruing (NCT02273336) https://www.openmednet.org/site/alcmi-goyl. We have accrued patients from the USA, Europe and Australia. Thus far in our prospective series those diagnosed with primary NSCLC < age 40 tend to have stage 4 adenocarcinoma. Preliminary results exceed our statistical expectation with 75% of our metastatic adenocarcinoma patients having an actionable mutation. We plan on presenting data for the first time at WCLC-2015 on the first 50 subjects. (Study, supported by grants from BJALCF, Beth Longwell Foundation, Peter Barker Foundation, Genentech, Schmidt Legacy Foundation, and Upstage Lung Cancer)

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    P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      P1.01-044 - Cost-Effectiveness of Chemotherapy Based on the Tumor Genetic Profile in Elderly Patients with Advanced Non-Small-Cell Lung Cancer (ID 1656)

      09:30 - 17:00  |  Author(s): T. Vavala

      • Abstract
      • Slides

      Background:
      Platinum-Based chemotherapy is still the cornerstone in the treatment of Non-Small Cell Lung Cancer (NSCLC), in non oncogene-addicted patients (pts). Therapeutic algorithm is established on the basis of patient and disease characteristics, such as histology and radiologic features. Pharmagenomic-driven trials are investigating the role of different markers in predicting efficacy and toxicity in NSCLC pts. A better selection of a right therapy for the right patient would improve outcomes ameliorating tolerability and optimize the resources available. The aim of the present study is to carry out a cost-effectiveness analysis, in order to evaluate the economic efficiency of 1st line chemotherapy within a clinical trial (EPIC eudract N 2012-001194-81), in elderly pts affected from advanced NSCLC, looking at efficacy and tolerability.

      Methods:
      The study population consisted in Elderly Patients Individualized Chemotherapy (EPIC) trial enrolled at San Luigi Hospital (Orbassano-Italy, coordinating centre) from July 2012 to August 2014. Main recruitment criteria: chemotherapy-naïve pts diagnosed with stage IV NSCLC, aged≥70 years, no activating EGFR mutations. We evaluated 48 pts randomised (2:1 ratio) to receive pharmacogenomics-driven chemotherapy assessed according to the genetic profile of primary tumours based on expression of ERCC1, RRM1 and TS evaluated by “Real-Time PCR” (arm A) or standard chemotherapy (arm B). Costs of treatments were calculated using National Health System (NHS) direct costs and 12 months time-horizon. Effectiveness was estimated as Progression Free Survival (PFS). The Incremental Cost-Effectiveness Ratio (ICER) was calculated and pharma-economic analysis was performed setting the Willingness To Pay (WTP) threshold value at 40,000€ per free-disease month gained. The reliability of results was assessed by a probabilistic sensitivity analysis based on “Monte Carlo” method (10,000 simulations) changing the costs and effectiveness variables simultaneously. Number and grade of adverse events were used to determine the tolerability profile.

      Results:
      The average cost per patient was 10,278.38€ (arm A) and 8,659.53€ (arm B). Related ICER was 4,496.80€ per free-disease month gained and 53,961.73€ per year gained (over the WTP threshold). The scatterplot generated in the sensitivity analysis indicated that higher densities of ICERs, calculated for each simulation, took place at the cross over of the Cartesian axes indicating that there is no clear prevalence of treatment cost-effectiveness. Moreover, the Cost-Effectiveness Acceptability Curve (CEAC) was calculated. This curve demonstrated that treatment A had 35% of probability to be cost-effectiveness.

      Conclusion:
      This preliminary evaluation, conducted in a subgroup of pts, suggests the relevance of pharmacoeconomic analysis within a clinical trial looking at the best way to identify a tailored treatment in non-oncogene addicted NSCLC pts. Further data will be collected in a larger simple size. Personalised chemotherapy is a potential method addressing both the optimisation of the effectiveness of therapeutic agents and the minimisation of adverse events, objectives even more relevant for elderly and fragile patients, given the possibility to optimize the use of scarce resources available.

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    P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P3.04-060 - Non Small Cell Lung Cancer in Women: Identification of Molecular Biomarkers Towards Sex Specific Tailored Treatments (ID 1272)

      09:30 - 17:00  |  Author(s): T. Vavala

      • Abstract
      • Slides

      Background:
      Lung cancer is the leading cause of cancer mortality in both men and women in more developed countries, with a four-fold increase in lung cancer in women in US over the past 30 years. This was confirmed in Europe where, in the last 5 years, lung cancer mortality fell in men (−6%) and increased in women (+7%). Several studies documented sex differences in lung cancer in terms of clinical presentation, survival, pathological patterns and treatment related toxicities; younger age at diagnosis, higher frequency of adenocarcinoma histology, different metabolism of tobacco-related carcinogens, differential gene expression are commonly seen in women. Furthermore, previous studies showed in female gender the expression of functional aromatase enzyme in lung tumor tissues as well as the interaction between Estrogen Receptors (ERs) and Epidermal Growth factor Receptor (EGFR) pathways in lung cancer cells. The aim of this study is to collect a prospective series of advanced stage non small cell lung cancers (NSCLC), to identify, through the Next Generation Sequencing (NGS) technology, potential gender sex differences of selected tumor-associated genes, assessing their both mutational status and gene expression levels.

      Methods:
      One hundred patients, including 50 women and 50 men, with newly diagnosed stage IV NSCLC will be prospectively enrolled. Smoking history, clinical and anamnestical data will be collected for all patients. Female patients will also provide obstetrical-gynecological anamnesis, while men will provide urological one, if present. Formalin fixed, paraffin embedded diagnostic sample of each patient will be collected and sectioned to obtain: a DNA genomic library to define the mutational profile of a selected panel including 50 tumor-associated genes, a mRNA library to obtain gene expression levels of the corresponding transcripts and protein expression of estrogen receptor Beta (ERß) and DNA repair enzyme ERCC1. Immunohistochemistry reaction, for both ERCC1 and ERβ, will be scored according to the H-score method. NGS analyses will be performed by means of the Ion Torrent Personal Genome Machine (PGM, Life Technologies, Grand Island, NE). Tumor tissues will be tested with commercial library kits: Ion AmpliSeq Cancer Hotspot Panel v.2 to investigate 50 cancer-associated genes and significant gene variations will be further confirmed using Sanger Sequencing method; Ion AmpliSeq™ RNA Cancer Panel to define also gene expression of the same 50 cancer-associated genes (Life Technologies). Correlations among mutational profile, transcriptional pattern, protein levels and clinico-pathological characteristics will be assessed.

      Results:
      Not Applicable

      Conclusion:
      Lung cancer incidence in women is increasing worldwide and genetic predisposition, sex hormones or specific molecular features could all account for the clinical differences observed between females and males. Up to the current date, the clinical approach to lung cancer treatment does not rely on gender. The identification of differential status of specific biomarkers can deepen knowledge on the molecular basis of this disease, guiding clinicians towards sex-based treatments.

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