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M.G. Zauderer



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    MINI 06 - Quality/Prognosis/Survival (ID 111)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Localized Disease - NSCLC
    • Presentations: 1
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      MINI06.13 - Multiple Lung Cancers: Is Their Survival Better or Worse Then Other Lung Cancers? (ID 3058)

      16:45 - 18:15  |  Author(s): M.G. Zauderer

      • Abstract
      • Presentation
      • Slides

      Background:
      Multiple lung cancers (MLCs) are determined using the Martini-Melamed clinical criteria, and comprehensive pathologic assessment. The prognosis of MLCs is not known. Herein, we evaluate the prognosis of patients with MLCs, one resected LC, and recurrent LC, to ascertain whether patients with MLCs have a distinct natural history compared to the other two groups.

      Methods:
      After IRB approval, we conducted a retrospective review of all patients who underwent an R0 resection for stage IA-IIIA LC from 2008-2013 in our institution. Patients with carcinoid tumors, adenocarcinoma-in-situ, multiple ground-glass opacities, intrapulmonary metastases and cancers not originating from the lung, were excluded. MLCs were defined using Martini-Melamed criteria and comprehensive pathologic assessment. Clinicopathologic data was collected. We used the Kaplan-Meier method and log-rank test to assess overall survival (OS) of patients with MLCs, one LC, or recurrent LC, from the time of surgery/pathologic confirmation of their MLC, one LC, or recurrent LC, respectively.

      Results:
      2352 patients were identified: one LC (n=2238), recurrent LC (n=348), MLC (n=113).Median OS and 2-year OS for patients in these subgroups stratified by stage, is depicted in Table 1. In patients with one LC, never smokers (p<0.001), adenocarcinoma histology (p<0.001), and surgery type (p<0.001) were associated with improved OS. In patients with recurrent LC, never smokers (p=0.015), and adenocarcinoma histology (p=0.009) were associated with favorable OS, compared to smokers and squamous histology respectively. In patients with MLCs, adenocarcinoma histology was associated with improved OS when compared to squamous histology (p=0.049).

      Pathologic Stage (n) Median Overall Survival (months, 95% CI) Two-Year Overall Survival p value
      One Lung Cancer (n=2238) All Not Reached (75.2-NA) 0<0.001
      IA 0.914
      IB 0.841
      IIA 0.789
      IIB 0.755
      IIIA 0.691
      Multiple Lung Cancers(n=113) All 55.5 (49.4-NA) 0.32
      IA 0.810
      IB 0.806
      II/III 0.830
      Recurrent Lung Cancer (n=348) All 10.4 (9.1-12.3) 0.077
      IA 0.263
      IB 0.180
      IIA 0.273
      IIB 0.351
      IIA 0.083


      Conclusion:
      Martini-Melamed criteria and comprehensive pathologic assessments successfully identify patients with MLCs. Prognostic data for patients with MLCs, one LC and recurrent LC, highlight that these patients have a long natural history. MLCs have a long survival stage for stage, which underscores a definitive therapeutic approach where possible, based on favorable prognosis of these patients.

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    MINI 24 - Epidemiology, Early Detection, Biology (ID 140)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      MINI24.05 - Discussant for MINI24.01, MINI24.02, MINI24.03, MINI24.04 (ID 3427)

      16:45 - 18:15  |  Author(s): M.G. Zauderer

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MINI 38 - Biology and Prognosis (ID 167)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 2
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      MINI38.02 - BAP1 Inactivation in Mesothelioma Is Highly Prevalent (ID 657)

      18:30 - 20:00  |  Author(s): M.G. Zauderer

      • Abstract
      • Presentation
      • Slides

      Background:
      Efforts to elucidate tumorigenic mutations in mesothelioma are essential to advance therapy. Prior efforts to characterize the molecular heterogeneity of this disease have been limited by sample condition and testing platforms. Herein, we describe efforts to prospectively test patients using next-generation sequencing with matched patient germline controls.

      Methods:
      Sequential mesothelioma patients were approached for consent to our IRB protocol NCT01775072 to perform MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets), a comprehensive molecular profiling platform based on solution-phase exon capture and next generation sequencing to detect somatic genetic alterations in FFPE tumor specimens. MSK-IMPACT involves hybridization capture and deep sequencing of all protein-coding exons of 341 key cancer-associated genes, including all genes that are druggable by approved therapies or are targets of experimental therapies being investigated in clinical trials at MSKCC.

      Results:
      51 patients with mesothelioma underwent MSK-IMPACT testing (see Table 1). 12 samples had low tumor content. Among 39 samples with reliable results, BAP1 was the most common alteration (46%). Another 3 samples had changes also thought to inactivate BAP1 (2 samples had gene copy number changes just below the cutoff for whole gene deletions and 1 had an inversion of LIMD-BAP1 thought to inactivate BAP1), making the incidence of BAP1 alterations possibly as high as 56%. In 4 samples with sufficient tumor content, no alterations were identified. Table 1

      N=39 (%)
      Gender M/F 26/13 (67/33)
      Primary site of disease * Pleural * Peritoneal * Testicular 32 (82) 6 (15) 1 (3)
      # identified alteration, average 3
      Alterations present in >6% * BAP1 * NF2 * CDKN2Ap16INK4A * SETD2 * CDKN2Ap14ARF * LATS1 * CREBBP * WT1 * CDKN2B * PI3KCA * PBRM1 * TP53 18 (46) 8 (21) 5 (13) 5 (13) 4 (10) 4 (10) 4 (10) 4 (10) 3 (8) 3 (8) 3 (8) 3 (8)


      Conclusion:
      Using MSK-IMPACT, BAP1 inactivation is the most common alteration. Other aberrations previously reported at high frequency were identified but albeit at lower frequencies (NF2 and p16, previously reported as 40% and 75% respectively). For multiple samples with deep coverage, no alterations were identified. The high incidence of BAP1 mutations in this systematic testing makes this pathway ideal for developing and testing targeted therapies.

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      MINI38.08 - Contemporary Analysis of Prognostic Factors in Patients with Unresectable Malignant Pleural Mesothelioma (MPM) (ID 1745)

      18:30 - 20:00  |  Author(s): M.G. Zauderer

      • Abstract
      • Presentation
      • Slides

      Background:
      The CALGB and EORTC have previously developed prognostic scoring systems for patients with MPM, but these included patients managed surgically and predated the use of pemetrexed. We sought to identify prognostic factors in a contemporary cohort of patients with unresectable MPM.

      Methods:
      We retrospectively reviewed the charts of patients with histologically proven MPM managed non-surgically at MSKCC from 2000-2012. Variables analyzed and correlated with overall survival (OS) included: sex, age at diagnosis, smoking history, asbestos exposure, tumor laterality, initial performance status (PS), tumor histology, clinical TNM, initial PET maximum Standardized Uptake Value (SUVmax), hemoglobin level, platelet, lymphocyte and neutrophil counts, treatment type (chemotherapy and/or radiotherapy), and response to treatment. OS was analyzed by Kaplan-Meier method, and significance (p<0.05) of prognostic factors was analyzed by log-rank test and Cox regression.

      Results:
      191 patients met study criteria: median age 71 years (range 46-90), 147 (77%) male, 128 (67%) epithelioid , 20 (10.5%) biphasic, and 28 (14.6%) sarcomatoid. 34 patients were stage I-II at presentation and 157 (82%) stage III-IV. First line chemotherapy included pemetrexed in 159 (90.3%) patients. Median time from diagnosis to treatment was 1.2 months. With a median follow-up of 13.2 months, median OS for all patients was 13.4 months. By univariate analysis, histology (p<0.001), platelet count (≤450 vs. >450, p<0.001), initial PS, maximum PET SUV (> or ≤8.1, p=0.037) were significant. Clinical staging (I/II vs III/IV) did not correlate with OS (p=0.35). By multivariable analyses, only histology, platelet count and PS were independent prognostic factors. 1-year OS was 69% (95%CI 62%-78%) for epithelioid versus 30% (95%CI 15%-59%) and 29% (95%CI 16%-51%) for biphasic and sarcomatoid tumors, respectively. Patients with PS 0-1 had a 1-year OS of 64% (95%CI 56%-73%) versus 42% (95%CI 31%-57%) for PS 2 or greater. Epithelioid histology, PS 0-1 and elevated neutrophil count at diagnosis were significantly associated with response to first line chemotherapy. Patients with response or stable disease after the first two cycles of chemotherapy had significantly better OS, median OS was 16.8 (95% CI 14.8 – 20.1) versus 6.5 (95% CI 5.4-8.5) months (p<0.001). Patients receiving more than one line of chemotherapy had better OS, median OS 14.2 (95% CI 12.1 – 16.8) versus 8.7 (95% CI 6.6 – 11.0 ) months (p=0.013). There was no significant association between use of radiotherapy and OS (p=0.058), but patients who received radiotherapy showed a 1-year OS of 60.5% vs 44.0% of patients who did not receive radiotherapy.

      Conclusion:
      This analysis in patients with unresectable MPM confirms that some elements of the CALGB and EORTC prognostic scoring systems (platelet count, PS, histology) correlate with OS, and identifies factors (PS, elevated neutrophil count, histology) associated with response to chemotherapy. Our analysis emphasizes the impact of histology and response to first-line chemotherapy on outcomes, but also the lack of predictability with the use of clinical staging.

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    P1.02 - Poster Session/ Treatment of Localized Disease – NSCLC (ID 209)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Localized Disease - NSCLC
    • Presentations: 1
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      P1.02-008 - Diagnostic Molecular Testing in Multiple Lung Cancers (ID 3149)

      09:30 - 17:00  |  Author(s): M.G. Zauderer

      • Abstract
      • Slides

      Background:
      Multiple lung cancers (MLCs) are determined using the Martini-Melamed clinical criteria, and comprehensive pathologic assessment. The underlying biology for why MLCs develop is not known. Herein, we evaluate clinicopathologic data for patients with MLCs, and report clonality between MLC lesions using diagnostic molecular testing.

      Methods:
      After IRB approval, we conducted a retrospective review of all patients who underwent an R0 resection for stage IA-IIIA LC from 2008-2013 in our institution. Patients with carcinoid tumors, adenocarcinoma-in-situ, multiple ground-glass opacities, intrapulmonary metastases, and cancers not originating from the lung, were excluded. MLCs were defined using Martini-Melamed criteria, and comprehensive pathologic assessment. Clinico-pathologic data was collected for patients with MLCs, including available diagnostic molecular data from sizing assays, Sanger sequencing and mass spectrometry genotyping (Sequenom).

      Results:
      2352 pts were identified: one LC (n=2238), recurrent LC (n=348), MLC (n=113). In patients with MLCs, adenocarcinoma histology (n=97) was associated with improved OS (p=0.049) compared to squamous histology (n=13, other n=3). Paired diagnostic molecular pathology was available in 51 patients with adequate tissue from MLCs. MLC pairs stratified by mutation type are depicted in Table 1. In 49 patients, both MLCs were adenocarcinomas (20= extended panel: sizing assays/Sanger sequencing/Sequenom, 29=limited panel: EGFR/KRAS sizing assay/Sanger sequencing): 51% (n=25/49) had concordant molecular results, suggesting a common tumor clone, and 49% (n=24/49) had discordant results. In 1 patient, one MLC was an adenocarcinoma and the other was a squamous carcinoma, and had discordant molecular results by limited panel testing. In 1 patient, both MLCs were squamous carcinomas, and had concordant molecular results by limited panel testing. In patients where MLCs both had a KRAS mutation (n=11), 3 pairs had the same mutation (KRAS G12C, KRAS G12D, KRAS G12F), and 8 had different mutations. Table 1: Multiple Lung Cancer: Molecular DataFigure 1



      Conclusion:
      Martini-Melamed criteria and comprehensive pathologic assessment, are currently used to diagnose MLCs. Assuming separate MLC lesions harbor distinct molecularly defined clones, paired molecular testing using limited panels is not sufficient to diagnose MLCs. Concordant molecular profiles do not necessarily define whether a lesion is an MLC or a metastatic lesion. Paired prospective testing of suspected MLC lesions including broader molecular tests such as DNA, RNA, protein expression and immune correlates, may advance our understanding of the biology of these tumors.

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    P2.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 225)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      P2.08-008 - A Phase 1 Dose Escalation Study of VS-5584, a PI3K/MTOR Inhibitor, Administered with VS-6063, a Focal Adhesion Kinase Inhibitor, in Mesothelioma (ID 2812)

      09:30 - 17:00  |  Author(s): M.G. Zauderer

      • Abstract

      Background:
      Malignant mesothelioma is a rare, but aggressive pleural or peritoneal tumor which is highly invasive and progresses rapidly. The median survival of patients with mesothelioma is between 9 and 13 months, and survival has not been significantly affected by most currently available therapeutic interventions. There are no approved therapies following first line treatment. VS-6063 is an oral inhibitor of focal adhesion kinase (FAK) currently being evaluated in a randomized phase 2 study in patients with malignant pleural mesothelioma who have stable disease or better after front line chemotherapy. VS-5584 is an oral dual inhibitor of PI3K/mTOR currently undergoing phase I testing in solid tumors. Previously reported literature has shown that dual PI3K/mTOR inhibitors have activity in patients with relapsed mesothelioma. In preclinical models, the combination of VS-6063 and VS-5584 have demonstrated synergy in tumor models of malignant mesothelioma supporting the potential exploration of this combination clinically.

      Methods:
      This is a multi-center, open-label, phase 1 trial in subjects with relapsed malignant mesothelioma. The study is comprised of two sequential parts: Part 1 (Dose Escalation of VS-5584 with a fixed dose of VS-6063) and Part 2 (Expansion). Patients receive VS-5584 orally on an intermittent dosing schedule and VS-6063 400 mg orally BID. Primary endpoints are to determine the maximum tolerated dose, recommended Phase 2 dose/schedule and to assess safety and tolerability of the combination in this patient population. Secondary endpoints include assessing the pharmacokinetics of VS-5584 and VS-6063 when co-administered. Exploratory endpoints include response rate and biomarker correlation with response and PD. The study is currently enrolling across 4 sites in the United States and United Kingdom. Clinical trial: NCT02372227.

      Results:
      Not applicable

      Conclusion:
      Not applicable

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    P3.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 226)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      P3.08-014 - COMMAND: A Phase 2 Randomized, Double-Blind, Study of Defactinib (VS-6063) as Maintenance Therapy in Malignant Pleural Mesothelioma (ID 2847)

      09:30 - 17:00  |  Author(s): M.G. Zauderer

      • Abstract

      Background:
      Malignant pleural mesothelioma (MPM) is an aggressive tumor in the pleural lining of the lung. Median OS with frontline chemotherapy of pemetrexed/cisplatin (pem/cis) is ~12 months. There is no established second line therapy. Pem/cis has been shown to enrich cancer stem cells (CSCs) in tumors. Focal adhesion kinase (FAK) inhibitors have been found to decrease CSCs in mesothelioma models. The use of a FAK inhibitor in a maintenance setting after frontline chemotherapy may therefore extend survival of MPM patients. Furthermore, approximately 40% of MPM tumors exhibit disruption of the NF2 tumor suppressor gene by mutation and/or deletion resulting in lack of expression of functional merlin protein. Mesothelioma cell lines that lack merlin are more sensitive to FAK inhibitors than those with wild type merlin. This Phase 2 study will determine if defactinib (VS-6063), an oral inhibitor of FAK, provides superior clinical benefit compared with placebo as maintenance treatment in patients with MPM following frontline pem/platinum therapy.

      Methods:
      COMMAND is a multinational, randomized, double-blind, placebo-controlled trial. Approximately 370 patients with PR or SD following ≥4 cycles of frontline pem/platinum therapy will be enrolled. Patients will receive defactinib 400 mg BID or matched placebo. Randomization will be stratified by merlin status, as determined by immunohistochemistry. Primary endpoints include OS and PFS. An adaptive enrichment design at the interim analysis (projected to occur in Q2 2015) may restrict patients to those with low merlin protein expression if greater benefit is observed among this subpopulation. Secondary endpoints include patient-reported outcomes, objective response and safety and tolerability. The study is currently enrolling across 15 countries. Clinical trial: NCT01870609.

      Results:
      Not applicable

      Conclusion:
      Not applicable