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E.S. Kim



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    O15 - NSCLC - Chemotherapy II (ID 109)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O15.06 - Randomized Phase III Trial of Gemcitabine (G)/Carboplatin (C) with or without Iniparib (I) in Patients (Pts) with Previously Untreated Stage IV Squamous Lung Cancer (ID 3322)

      10:30 - 12:00  |  Author(s): E.S. Kim

      • Abstract
      • Presentation
      • Slides

      Background
      Iniparib is an agent originally thought to function as an inhibitor of the DNA repair enzyme PARP-1, which is overexpressed in squamous lung cancers. Promising phase II activity and safety were reported with iniparib in combination with GC in pts with metastatic triple-negative breast cancer (O’Shaughnessy, NEJM 2011); however, subsequent phase III data were negative. Further study of iniparib’s mechanism of action suggests that this agent induces DNA damage, cell cycle arrest in the G2/M phase, and potentiates DNA-damaging chemotherapies not through PARP inhibition. Herein we report the final results from an international Phase III trial (NCT01082549) of first-line chemotherapy and iniparib in pts with advanced squamous lung cancer.

      Methods
      Pts were randomized 1:1 to GC or GCI. All pts received G 1000 mg/m[2] IV days (D) 1 and 8, and C AUC=5 IV D1 of each 21-D cycle. Iniparib was dosed 5.6 mg/kg IV D 1, 4, 8, and 11. All pts were assessed for response per RECIST 1.1 every 6 weeks. Pts without evidence of progressive disease (PD) or other reason for discontinuation could remain on treatment beyond 6 cycles. Accrual of 780 pts provides 89% power to detect an improvement in survival from 8 months (mos) anticipated with GC to 10.7 mos with GCI (HR of 0.75). Eligibility: Pts with newly diagnosed stage IV (M1a and M1b) squamous lung cancer, ECOG PS 0-1. Exclusion criteria included: history of recent cardiac disease, untreated brain metastases, and treatment for early-stage lung cancer within 12 months of study entry. The primary endpoint was overall survival (OS). Interim analyses for safety and futility were performed by an independent data safety monitoring board.

      Results
      780 pts were enrolled and randomized (GC, 390), (GCI, 390) from March 2010 to May 2012. Baseline characteristics were well balanced between groups (GC/GCI): median age 66 years (21-86); 74%/73% male; 30%/33% ECOG 0; 28%/33% current smokers; 66%/62% past smokers. The median number of cycles for GC/GCI were 4 (1-26)/5 (1-32). Dose reductions, dose intensity, and discontinuations due to tumor progression or adverse events were similar in both arms. The median OS for GC/GCI was 8.9 v. 8.9 months, HR 1.08 (0.92-1.28), p=.348. 1-year OS was 41 v. 40%. The median progression-free survival (PFS) for GC vs GCI was 4.9 v. 4.8 months, HR 0.99 (0.83-1.19), p=.92. The objective response rate (ORR) for GC v GCI was 34 v. 32%, p=.648. The safety profile was similar in both arms; anemia (28/26%), neutropenia (31/35%), thrombocytopenia (27/28%), and fatigue (6/9%).

      Conclusion
      The addition of iniparib did not improve the efficacy of GC in the treatment of pts with advanced squamous lung cancer. Further development of iniparib in squamous lung cancer is not recommended.

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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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      P1.03-001 - Multiplexing technology for in situ biomarker profiling of Non-Small Cell Lung Cancer (NSCLC) (ID 1467)

      09:30 - 16:30  |  Author(s): E.S. Kim

      • Abstract

      Background
      NSCLC is a heterogeneous neoplasm comprising several histologic types, etiology, genetics, survival and response to therapy. Accurate analysis of these subtypes has increased sample requirements, which is challenging in the era of minimally invasive procedures. A recent survey of 90 US pathologists presented at ASCO 2013 meeting, concluded insufficient sample availability in 6% of all NSCLC samples recently handled by these pathologists. Moreover, subcellular localization of marker expression linked to tumor pathobiology necessitates methodological advancement. With the development of a new platform that allows in situ, multiplexed sub-cellular analysis of over 60 proteins, this project aims to demonstrate the feasibility of detailed in situ molecular profiling and perform comparative analysis of known cancer pathways and prognostic markers on the same serial section.

      Methods
      Multiplex immunofluorescence staining and imaging of over 30 biomarkers, including several RTKs, cell adhesion molecules, select members of PI3K, MAPK/ERK, JAK/STAT pathways, angiogenesis, hypoxia, proliferation and chemotherapy resistance markers were performed on replicate FFPE tissue microarrays (TMA) from 382 samples. Cell-level and subcellular-level marker expressions were quantified using image analysis algorithms and compared between serial sections. Associations between marker expressions and histological subtypes and survival were investigated in European male smokers. Multivariate analysis was performed using logistic regression and Cox proportional hazard models on over 300 quantitated features of marker expression. All models controlled for age. Serial sections were modeled separately and combined to improve confidence in associations. EGFR and cMET positivity was evaluated using whole cohort median expression values to define positive cells and the summary statistics are reported using 10% positive cells as cutoff for characterizing positive samples.

      Results
      In concordance with previous reports, differential expression of RRM1, CK5 and CK7 was observed in SCC vs AD in the high grade, early stage male smokers (N=86). With a 10% cell positivity threshold, 72.7% (76.3%, serial section (SS)) of all male smokers (N=183 (190, SS)) were positive for EGFR. EGFR positivity was higher in SCC, 83.9% (86.0%, SS) compared to AD 54.9% (61.8%, SS). Opposite was observed for cMET with 81.7% (78.9%, SS) of AD characterized as positive compared to only 58.0% (57.0%, SS) SCC. Among the several previously reported prognostic markers evaluated in this study, only CA9 expression was associated with overall patient survival with a hazard ratio of 1.47, p-value 0.0005 (N=278). Again, analysis of serial section produced a similar result confirming the robustness of the platform.

      Conclusion
      The study demonstrates the capabilities of multiplexing technology (MultiOmyx[TM]) for assessment of limited lung samples, encompassing topographic expression features and the ability to observe relationships between markers through in situ pathway profiling. Additionally, by evaluating markers on exactly the same sample set (same section), a direct comparison of their relative significance in predicting course of disease is now feasible.