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A. Rajan



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    OA18 - New Insights in the Treatment of Thymic Malignancies (ID 408)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 2
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      OA18.02 - Evaluation of a Modified Dosing Regimen (2-Weeks on/1-Week off) of Sunitinib as Part of a Phase II Trial in Thymic Carcinoma (ID 6289)

      11:00 - 12:30  |  Author(s): A. Rajan

      • Abstract
      • Presentation
      • Slides

      Background:
      Sunitinib is active in patients with recurrent thymic carcinoma (TC). We have previously reported an objective response rate of 26% and disease control rate (partial response and stable disease) of 91% in patients with TC when sunitinib is administered at a dose of 50 mg once daily for 4 weeks followed by 2 weeks off (4/2 dosing schedule). Grade 3 or 4 treatment-related adverse events (TEAEs) occurring in more than 10% of patients included fatigue, oral mucositis and lymphocytopenia (20% each), and hypertension (13%). Grade 3 decrease in left ventricular ejection fraction (LVEF) was observed in 8% of patients. Alternative dosing schedules have been evaluated in solid tumors to improve tolerability. As part of an ongoing phase II study (NCT01621568), we evaluated the clinical activity and tolerability of sunitinib in patients with TC using a 2-weeks-on/1-week-off (2/1) dosing regimen.

      Methods:
      Patients with progressive TC after at least one prior platinum-containing chemotherapy regimen, measurable disease, and adequate end organ function were enrolled and received sunitinib at a dose of 50 mg orally once daily using a 2/1 schedule until disease progression or development of intolerable adverse events. The primary objective was evaluation of response rate. Tumor assessments were performed every 6 weeks using RECIST version 1.1 and toxicity was assessed every 3 weeks using CTCAE version 4.0. Exploratory correlative studies including evaluation of immune cell subsets will be reported separately.

      Results:
      Between July 8, 2014 and January 14, 2016, 15 patients were enrolled. Median age was 62 years (range, 41-76), and 33% were male. A median of 4 (range, 1 – 33+) cycles of sunitinib was administered. Among 13 evaluable patients, there was 1 (8%) partial response, 11 (85%) stable disease and 1 (8%) progressive disease. After a median follow-up of 16 months, the median progression-free survival was 5 months and median overall survival was 16 months. Grade 3 or 4 TEAEs occurring in more than 10% of patients included lymphocytopenia (40%), neutropenia and leucopenia (20% each), thrombocytopenia and oral mucositis (13% each). Grade 3 decrease in LVEF was observed in 1 (7%) patient.

      Conclusion:
      Sunitinib, administered using a 2/1 dosing schedule, has clinical activity in patients with TC, and the frequency of clinically significant TEAEs (fatigue, mucositis, hypertension) is acceptable. Studies are ongoing to identify novel immunological biomarkers of activity.

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      OA18.03 - Safety and Clinical Activity of Avelumab (MSB0010718C; Anti-PD-L1) in Patients with Advanced Thymic Epithelial Tumors (TETs) (ID 6141)

      11:00 - 12:30  |  Author(s): A. Rajan

      • Abstract
      • Slides

      Background:
      Avelumab (MSB0010718C) is a fully human, IgG1 anti-PD-L1 antibody under clinical development. We report safety and clinical activity in patients with relapsed TETs enrolled in a phase I trial (NCT01772004).

      Methods:
      Patients previously treated with one or more standard therapies, no prior immune checkpoint inhibitors, and with no history of autoimmune disease were eligible. Treatment consisted of avelumab at doses of 10-20 mg/kg iv q2 weeks until disease progression or toxicity. Responses were assessed q6 weeks by RECIST 1.1. Correlative studies included evaluation of tumor cell PD-L1 expression and peripheral blood immune subset analysis.

      Results:
      7 patients with thymoma and 1 with thymic carcinoma (TC) were treated with avelumab; 3 patients with thymoma (2 B3, 1 B2/B3) received avelumab 20 mg/kg; 4 patients with thymoma (1 B1, 3 B2) and 1 TC received 10 mg/kg. Two (29%) patients with thymoma had a confirmed partial response (PR;1 at 20 mg/kg, and 1 at 10 mg/kg), 2 (29%) had unconfirmed PRs, 2 (29%) stable disease (SD) and 1 (14%) progressive disease; the TC patient had SD. Most adverse events (AEs) were mild (grade 1 or 2). Grade 3 and 4 AEs were observed in 3 (38%) patients each, and included potential immune-related AEs (irAEs) in 5 cases. irAEs resolved completely with oral steroids in 3 patients, and incompletely in 1 patient. One patient required cyclosporine A for treatment of irAEs. All 4 responders experienced irAEs (myositis in 3 patients, all after 1 dose of avelumab, and enteritis in 1 patient). Pre- and post-treatment tumor biopsies were available for analysis of PD-L1 expression and intratumoral immune infiltrates from three patients treated at 20 mg/kg. In one case the post-treatment biopsy showed necrotic tissue with no viable tumor. In the other two cases diffuse, membranous PD-L1 staining of epithelial cells was seen in both pre- and post-treatment biopsies. The immune infiltrate consisted of immature T cells in pre-treatment tumor samples in both cases. The post-treatment biopsy showed continued presence of immature T cells in one case and a mature CD8+ T cell phenotype in the other case. Decreased CTLA4+ regulatory T cells and decreased ratio of granulocytic vs. monocytic myeloid-derived suppressor cells was seen post-treatment at the 20mg/kg dose.

      Conclusion:
      Avelumab is active in patients with recurrent thymoma. Strategies need to be developed to reduce the risk of development of irAEs in response to immune checkpoint inhibitor therapy in patients with thymoma.

      Information from this presentation has been removed upon request of the author.

      Information from this presentation has been removed upon request of the author.

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    P2.01 - Poster Session with Presenters Present (ID 461)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P2.01-041 - Integrated Proteo-Genomics Analyses Reveal Extensive Tumor Heterogeneity and Novel Somatic Variants in Lung Adenocarcinoma (ID 6082)

      14:30 - 15:45  |  Author(s): A. Rajan

      • Abstract

      Background:
      Tumor heterogeneity is a major impediment to targeted treatment response in a variety of cancers, including lung cancer, the commonest cause of cancer death. However, the extent of heterogeneity at the genomic and proteomic level along with its effects on treatment response may be patient-specific.

      Methods:
      We undertook comprehensive whole genome, exome or targeted sequencing, together with mass spectrometry-based proteomics analyses on twelve sequentially procured lung and lymph node metastatic sites and normal blood from an African American never-smoker lung adenocarcinoma patient who had survived with metastatic disease for over seven years while being treated with single or combination ERBB2-directed therapies.

      Results:
      Surprisingly, only 1% of somatic variants were common between the two sites, as revealed by WGS. Interestingly, one novel somatic translocation, PLAG1-ACTA2 was identified in both sites resulting in overexpression of ACTA2 that may have been the driver of early metastasis in this patient. The likely predominant driver of proliferation, ERBB2, was focally amplified along with CDK12, greater in the lung compared to the lymph nodes. However, an ERBB2 L869R mutation was specific to the lymph node. We also discovered a novel CDK12 G879V mutation that was specific to the lung. Isogenic MCF10A cells expressing ERBB2 L869R were more proliferative than those expressing wild type ERBB2. Cells expressing ERBB2 L869R that developed lapatinib resistance showed a mesenchymal phenotype, increased migration, and produced significantly more lung metastases than lapatinib-sensitive ERBB2 wild-type cells in a tail-vein injection assay, implicating this mutation in repeated progression of lymph node metastases. The CDK12 mutation is expected to have resulted in a non-functional kinase, lower expression of DNA damage response genes, greater instability of the lung tumor genome, and increased sensitivity to chemotherapy. Accordingly, there was no metastatic sites evident at autopsy in the lung, suggesting the lung metastatic sites were essentially cured. We further sought to correlate the genomic heterogeneity with alterations in the proteome and phosphoproteome using high-resolution mass spectrometry. For this purpose, we first assembled patient-specific database including all somatic variants, as revealed by WGS, from the lung and lymph node to interrogate the mass spectrometry data. Several aspects of the genomic heterogeneity were evident at the protein-level. These include the identification of the mutant CDK12 G879V peptide and higher expression of ERBB2 in the lung.

      Conclusion:
      The integrated proteo-genomics analyses reveal unprecedented tumor heterogeneity in a patient with lung adenocarcinoma. However, similarities in key tumor driver pathways remain.

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    P2.04 - Poster Session with Presenters Present (ID 466)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 1
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      P2.04-019 - A Peripheral Immune Signature Associated with Clinical Activity of Sunitinib in Thymic Carcinoma (ID 6184)

      14:30 - 15:45  |  Author(s): A. Rajan

      • Abstract

      Background:
      We have previously reported an objective response rate of 26% and disease stabilization in 65% of patients with advanced thymic carcinoma (TC) treated with the multikinase inhibitor sunitinib after failure of platinum-based chemotherapy. The current study investigates the impact of sunitinib on systemic immunity in patients with thymic epithelial tumors with an aim to discover blood-based, predictive immune biomarkers.

      Methods:
      Patients with thymoma and TC received sunitinib at a dose of 50 mg once daily in 6-week cycles consisting of 4 weeks of treatment followed by 2 weeks without treatment. Results from 15 patients with TC are reported here. Blood samples were collected before initiation of sunitinib therapy (Cycle 1 day 1; C1D1), and prior to treatment on day 1 of cycles 2 and 3 (C2D1; C3D1). Multiparameter flow cytometry was used to study T-cell subsets with immune checkpoint expression, four phenotypes of myeloid-derived suppressor cells (MDSCs) with CD40, and CD14+ monocytes with HLA-DR expression. Expression of 730 immune-related genes in peripheral blood was analyzed by NanoString technology. Differences in paired markers or changes in markers between two time points was evaluated by the Wilcoxon signed rank test. The Kaplan-Meier method was used to obtain estimates of progression-free survival (PFS) and overall survival (OS).

      Results:
      Immunosuppressive Tim-3-positive Tregs declined after 2 cycles of sunitinib (p=0.024). A decrease in granulocytic MDSCs (p=0.012), lineage negative (CD3-CD19-CD56-) MDSCs (p=0.013), and immature MDSCs (p=0.01) but not monocytic MDSCs was observed after 1 cycle of sunitinib. TC patients with no objective response to sunitinib had a higher baseline immature MDSC level than responders (p=0.0044). Greater than median declines in granulocytic MDSC CD40 (C2D1 p=0.027, C3D1 p=0.0046) and lineage-MDSC CD40 (C3D1, p=0.0046) after sunitinib therapy was associated with improved PFS. Similarly, a greater than median decline in CD14[+]HLA-DR[lo/neg ]monocyte levels on C2D1 was associated with longer PFS (p=0.020). Among the immune genes examined, higher baseline FEZ1 expression was associated with improved PFS and OS.

      Conclusion:
      Our findings suggest significant interplay between sunitinib and systemic immunity impacts therapeutic outcome in TC. Monitoring CD40 expression on specific MDSC phenotypes and FEZ1 gene expression may predict a survival benefit after treatment with sunitinib. These results, if validated in larger studies, can serve as potential blood-based predictive biomarkers in TC patients treated with sunitinib.