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A. Bearz



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    O01 - Prognostic and Predictive Biomarkers I (ID 94)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O01.07 - Randomized Proteomic Stratified Phase III Study of Second Line Erlotinib (E) versus Chemotherapy (CT) in Patients with Inoperable Non-Small Cell Lung Cancer (PROSE): Secondary Endpoint Analysis (ID 3276)

      10:30 - 12:00  |  Author(s): A. Bearz

      • Abstract
      • Presentation
      • Slides

      Background
      EGFR-TKis are more effective in NSCLC patients with EGFR activating mutations. However, about 90% of non-Asian patients are EGFR wild type, and a test for optimizing treatment in pts with wild-type or in patients with undetectable EGFR mutation status or squamous histology is of clinical value. VeriStrat (VS) is a serum protein test that assigns "good" (VSG) or "poor" (VSP) classification and has demonstrated prognostic and predictive utility in retrospective studies. PROSE is the first completed multicenter prospective randomized biomarker validation trial, designed to evaluate the ability of VS to predict survival in 2[nd]- line NSCLC pts treated with E or CT. As reported at 2013 ASCO[1], VSG pts derived similar overall survival (OS) benefit from both agents (hazard ratio (HR) for E=1.06; p=0.71) whereas CT was the superior option for VSP pts (HR for E=1.72; p=0.02). PROSE met its primary endpoint of demonstrating significant treatment*VS interaction with a p-value of 0.031. The present report discusses the results for the secondary endpoints, PFS.

      Methods
      285 pts, stratified by ECOG-PS, smoking, and blinded pre-treatment VS classification, were randomized 1:1 to receive E or CT at standard doses. Primary endpoint was overall survival (OS) and the primary hypothesis was a significant interaction between VS status and treatment. Sample size was calculated based on an estimated 65%/35% VSG:VSP ratio and hazard ratio (HR) for interaction of 2.35, with a 2-sided α=0.05 and 90% power.

      Results
      263 pts (129 CT, 134 E) were included in the per protocol primary analysis. 68% of pts in CT arm and 72% in E arm were classified as VSG, and analysis was performed at 226 survival events.VSP classification was significantly correlated with worse PFS as compared to VSG, in overall comparison (HR=1.75, 95%CI: 1.34-2.95, P <0.001) , in the CT (HR = 1.69, 95%CI: 1.15-2.48, P <0.007) and the E (HR = 1.91, 95%CI: 1.340-2.80, P<0.001) arms, demonstrating its prognostic value also in PFS. In VSG median PFS was 4.8 months (m) on CT, and 2.5 m on E (HR = 1.26, 95% CI: 0.94-1.69, P =0.129); in VSP median PFS was 2.8 m on CT and 1.7 m on E (HR=1.51, 95% CI: 0.96-2.38, P =0.078). No statistical significant interaction was detected (p=0.44)

      Conclusion
      The analysis of PFS and OS indicates that the differential treatment benefit in OS related to VS classification is determined by the combination of prognostic and predictive properties of the test.

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    P1.10 - Poster Session 1 - Chemotherapy (ID 204)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.10-056 - The Elderly Patient Individualized Chemotherapy Trial (EPIC): A Randomized Phase III Multicenter Trial of Customized Chemotherapy versus Standard of Care for 1st Line Treatment of Elderly Patients with Advanced Non-Small-Cell Lung Cancer (ID 1117)

      09:30 - 16:30  |  Author(s): A. Bearz

      • Abstract

      Background
      This is an ongoing phase III multicenter randomized trial comparing first line pharmacogenomic-driven chemotherapy based on Excision-Repair-Cross-Complementing-1 (ERCC1), Ribonucleotide Reductase subunit M1 (RRM1) and Thymidylate Synthase (TS) gene expression, versus standard first line treatment in elderly patients (pts) with advanced non-small-cell lung cancer (NSCLC). Chemotherapy selection based on an individual patient’s molecular profile is a potentially promising approach to optimize efficacy with the already available cytotoxic drugs. In older pts this is particularly relevant owing to their rapid deterioration of symptoms and their increased propensity to suffer therapy-induced toxicity.

      Methods
      Pts aged >70 years, with ECOG Performance Status (PS) 0 or 1, previously untreated for stage IV NSCLC will be evaluated. In a 2:1 fashion, pts will be randomized to experimental arm (A) or standard arm (B). They must have measurable disease and EGFR negative mutational status. In arm A, treatment with single or dual-agent chemotherapy will be based on histology, ERCC1 (E), RRM1 (R) and TS (T) expression at the mRNA level. Expression of E, R and T is assessed by qRT-PCR on paraffin-embedded tumor specimens in a central laboratory. The cut off for high or low expression have been previously defined. Pts with squamous NSCLC who are: E low/R high will be treated with single agent carboplatin, E high/R low with single agent gemcitabine, E low/R low with carboplatin and gemcitabine and E high/R high with docetaxel or vinorelbine. In non-squamous NSCLC pts: E low/T high will be treated with carboplatin, E high/T low with pemetrexed, E low/T low with carboplatin and pemetrexed, E high/T high/R low with gemcitabine and E high/T high/R high with docetaxel or vinorelbine. In arm B treatment will be standard of care at the discretion of the care provider. The primary endpoint is overall survival (OS). The secondary endpoints are progression-free survival (PFS), disease response according to RECIST 1.1 and tolerability (using CTCAE version 4.0). Feasibility of treatment selection based on pharmacogenomic parameters will also be assessed. Treatment will continue to a maximum of 6 cycles if tolerated or until disease progression. Switch maintenance treatment is not allowed in either arm. Continuation maintenance (one or more of the agents used in the initial regimen) is allowed at the discretion of the investigator. Treatment upon progression is at the discretion of the care provider. Assuming an exponential survival distribution for both treatment arms and a median survival time of 8 months in the control arm we anticipate to detect an improvement of 3 months in the median survival time in the experimental arm. To have 90% power to detect a three-month improvement in median survival at a significance level of 5% (2-sided) and assuming a 10% failure rate in gene analyses or loss to follow up rate, a sample size of 567 patients is planned to be enrolled.

      Results
      Not Applicable

      Conclusion
      We hypothesize that such tailored approach will improve survival decreasing the exposure to ineffective toxic agents in advanced NSCLC elderly pts. To our knowledge this is the first pharmacogenomic-driven randomized trial in this population.