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J.C. Horobin



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    P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.06-048 - Malignant mesothelioma lacking merlin shows enhanced sensitivity to the FAK Inhibitor VS-6063: Evaluation of merlin/NF2 status in clinical samples (ID 3377)

      09:30 - 09:30  |  Author(s): J.C. Horobin

      • Abstract

      Background
      Malignant pleural mesothelioma (MPM) is an aggressive tumor in the pleural lining of the lung often resulting from prior exposure to asbestos. Median overall survival following frontline chemotherapy with pemetrexed/cisplatin is approximately 12 months. There is no established second line treatment. New therapeutic modalities are urgently needed to improve the prognosis of MPM patients. Approximately 50% of MPM patients exhibit homozygous disruption of the NF2 tumor suppressor gene by mutation and/or deletion resulting in lack of expression of functional merlin protein. VS-6063 is a potent, orally active, inhibitor of focal adhesion kinase (FAK).

      Methods
      Proliferation of drug-treated mesothelioma cell lines in 3-dimensional (3D) Matrigel culture was assessed by MTS, and orthotopic MPM xenograft growth in the lungs was measured in vehicle- vs. VS-6063-treated SCID mice. Since absence of merlin expression can theoretically result from several mechanisms including NF2 mutation and chromosome 22 abnormalities, we assessed NF2 gene deletion by FISH and merlin protein levels by IHC in the same human mesothelioma tumor samples.

      Results
      Among a panel of mesothelioma cell lines in 3D culture, MPM lines lacking expression of merlin protein were found to be especially sensitive to the selective FAK inhibitor VS-6063. In contrast, MPM cell lines with wild-type merlin were less sensitive with EC~50~ values greater than 1 μM. Accordingly, oral dosing of VS-6063 induced significant tumor growth inhibition in a merlin-negative mesothelioma model pre-implanted in the lungs of mice. To enable the planned stratification of MPM patients by merlin status, an immunohistochemistry (IHC) assay has been optimized to quantify merlin protein levels. A merlin IHC H-score below the defined cutoff was associated with loss of at least one copy of chromosome 22, indicating that chromosomal deletion is an important mechanism of merlin loss in mesothelioma patients.

      Conclusion
      These data support the clinical development of VS-6063 for treatment of malignant pleural mesothelioma patients stratified by merlin/NF2 status. VS-6063 is being studied in a registration-directed mesothelioma trial.

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    P2.14 - Poster Session 2 - Mesothelioma (ID 196)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 1
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      P2.14-014 - A Phase 2 Randomized, Double-blind, Placebo-Controlled, Multicenter Study of VS-6063 as Maintenance Therapy in Subjects with Malignant Pleural Mesothelioma which has Not Progressed on at least 4 Cycles of Pemetrexed/Platinum therapy (ID 3375)

      09:30 - 09:30  |  Author(s): J.C. Horobin

      • Abstract

      Background
      Malignant pleural mesothelioma (MPM) is an aggressive tumor in the pleural lining of the lung usually caused by asbestos exposure. Median OS following frontline chemotherapy with pemetrexed/cisplatin is ~12 months. There is no established second line therapy. Approximately 50% of MPM patients exhibit homozygous disruption of the NF2 tumor suppressor gene by mutation and/or deletion resulting in lack of expression of functional merlin protein. Preclinical data have indicated that mesothelioma cell lines that lack NF2/Merlin are especially sensitive to focal adhesion kinase (FAK) inhibition in both cellular and animal models. Interestingly, pemetrexed and cisplatin increase cancer stem cells (CSCs), while FAK inhibitors have been found to decrease CSCs in mesothelioma models. Given the sensitivity of mesothelioma cells lacking NF2/Merlin and the effect on CSCs, the use of a FAK inhibitor in a maintenance setting after first line chemotherapy may be an attractive strategy to extend survival of MPM patients. VS-6063 is an orally bioavailable selective inhibitor of FAK. In a phase 1 trial VS-6063 was generally well tolerated, with grade 1/2 nausea, vomiting and fatigue as the most frequent adverse events (Jones SF J Clin Oncol 2011 29:1 suppl; abstr 3002).

      Methods
      A multinational, randomized, double-blind, placebo controlled, phase 2 clinical trial was designed to determine if VS-6063 provides superior clinical benefit compared with placebo as a maintenance treatment in patients with MPM following frontline therapy with pemetrexed/platinum therapy. The study aims to assess whether VS-6063 improves median OS and median PFS over placebo. Randomization will be stratified by Merlin status (high versus low) and patients will receive either VS-6063 400mg BID continuously or matched placebo (1:1). The study follows an adaptive enrichment design where, pending results from an interim analysis, sampling may be restricted to patients with low Merlin protein expression if promising results are observed among the subpopulation. Approximately 370 eligible patients with pathologically confirmed MPM, who have PR or SD following at least 4 cycles of pemetrexed with either cisplatin or carboplatin, Karnofsky PS ≥70%, will be enrolled. Patients will continue treatment until disease progression. Archival tumor tissue will be used for the analysis of Merlin status and is therefore required for participation. Secondary endpoints include patient-reported outcomes of health-related quality of life and disease- or treatment-related symptoms utilizing the LCSS-meso scale, objective response and safety and tolerability. Clinical trial information: NCT01870609.

      Results
      not applicable

      Conclusion
      not applicable