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D. Owen



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    MA16 - Novel Strategies in Targeted Therapy (ID 407)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 1
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      MA16.03 - Global RET Registry (GLORY): Activity of RET-Directed Targeted Therapies in RET-Rearranged Lung Cancers (ID 4325)

      14:20 - 15:50  |  Author(s): D. Owen

      • Abstract
      • Presentation
      • Slides

      Background:
      GLORY is a global registry of patients with RET-rearranged non-small cell lung cancer (NSCLC). In order to complement ongoing prospective studies, the registry’s goal is to provide data on the efficacy of RET-directed targeted therapies administered outside the context of a clinical trial. We previously reported results from our first interim analysis (Gautschi, ASCO 2016). Following additional accrual into the registry, updated results are presented here, with a focus on an expanded efficacy analysis of various RET inhibitors.

      Methods:
      A global, multicenter network of thoracic oncologists identified patients with pathologically-confirmed NSCLC harboring a RET rearrangement. Molecular profiling was performed locally via RT-PCR, FISH, or next-generation sequencing. Anonymized data including clinical, pathologic, and molecular features were collected centrally and analyzed by an independent statistician. Response to RET tyrosine kinase inhibition (TKI) administered off-protocol was determined by RECIST1.1 (data cutoff date: April 15, 2016). In the subgroup of patients who received RET TKI therapy, the objectives were to determine overall response rate (ORR, primary objective), progression-free survival (PFS), and overall survival (OS).

      Results:
      165 patients with RET-rearranged NSCLC from 29 centers in Europe, Asia, and the USA were accrued. The median age was 61 years (range 28-89 years). The majority of patients were female (52%), never smokers (63%), with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent metastasic sites were lymph nodes (82%), bone (51%) and lung (32%). KIF5B-RET was the most commonly identified fusion (70%). 53 patients received at least one RET-TKI outside of a clinical protocol, including cabozantinib (21), vandetanib (11), sunitinib (10), sorafenib (2), alectinib (2), lenvatinib (2), nintedanib (2), ponatinib (2) and regorafenib (1). In patients who were evaluable for response (n=50), the ORR was 37% for cabozantinib, 18% for vandetanib, and 22% for sunitinib. Median PFS was 3.6, 2.9, and 2.2 months and median OS was 4.9, 10.2, and 6.8 months for cabozantinib, vandetanib, and sunitinib, respectively. Responses were also observed with nintedanib and lenvatinib. Among patients who received more than one TKI (n=10), 3 partial responses were achieved after prior treatment with a different TKI.

      Conclusion:
      RET inhibitors are active in individual patients with RET-rearranged NSCLC, however, novel therapeutic approaches are warranted with the hope of improving current clinical outcomes. GLORY remains the largest dataset of patients with RET-rearranged NSCLC, and continues to accrue patients.

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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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      P2.04-020 - Expression Patterns and Prognostic Value of PD-L1 and PD-1 in Thymoma and Thymic Carcinoma (ID 5520)

      14:30 - 15:45  |  Author(s): D. Owen

      • Abstract

      Background:
      Thymic epithelial tumors (TETs) including thymoma (TA) and thymic carcinoma (TC) are rare, and little data are available to guide treatment. As the thymus plays a critical role in immune homeostasis, immunotherapy with checkpoint blockade is an attractive treatment strategy for patients with TET. Published data regarding the expression patterns and prognostic implications of PD-L1 expression in TET have yielded conflicting results, and have included limited data regarding PD-1 expression.

      Methods:
      A retrospective review was carried out at Ohio State University of 35 pts with TET, with tumor specimens available at our institution from 2000 – 2010. PD-1 and PD-L1 expression was assessed by immunohistochemistry on tumor samples (utilizing PD-1 clone: NAT105 and PD-L1 clone:22C3 antibodies), and graded 0-5 according to expression (0 – no expression, 5 – high expression). Clinicopathologic characteristics assessed included age, grade, stage, overall survival, smoking status, and diagnosis of myasthenia gravis.

      Results:
      PD-1 and PD-L1 expression were assessed in 35 pts, including 32 pts with thymoma and 3 pts with thymic carcinoma. PD-L1 expression was detected in 83% (29/35) tumor samples, including 100% (3/3) of thymic carcinoma pts and 81% (26/32) of thymoma pts. PD-1 expression was detected in 77% (27/35) of samples, including 33% (1/3) of thymic carcinoma pts and 81% (26/32) thymoma pts. High levels (IHC >/= 3) of PD-L1 were detected in 57% (20/35) of pts, and high levels of PD-1 expression (IHC >/= 3) were detected in 31% (11/35) pts. A nonsignificant trend towards poorer overall survival was seen in patients with PD-L1 expression (p=0.097, log-rank test). Unlike prior studies, PD-L1 expression was not associated with higher grade tumors (B2, B3, C) or higher stage at diagnosis. Interestingly, high PD-1 expression was significantly associated with lower grade tumors (p = 0.031), but not overall survival. Expression of PD-L1 and PD-1 was not significantly associated with stage at diagnosis, smoking, recurrence, or diagnosis of myasthenia gravis.

      Conclusion:
      This study confirms high expression of PD-L1 and PD-1 in TETs, including thymoma and thymic carcinoma. PD-L1 expression was associated with a trend towards shorter overall survival. The high proportion of patients with high PD-L1 and PD-1 expression supports the use of anti PD-1 therapies in this patient population, and prospective trials are needed to assess PD-L1 and PD-1 as predictive and prognostic biomarkers in TET.

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    P2.06 - Poster Session with Presenters Present (ID 467)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
    • Presentations: 1
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      P2.06-019 - A Phase II Study of Atezolizumab as Neoadjuvant and Adjuvant Therapy in Patients (pts) with Resectable Non-Small Cell Lung Cancer (NSCLC) (ID 4642)

      14:30 - 15:45  |  Author(s): D. Owen

      • Abstract

      Background:
      There is no curative treatment for patients with NSCLC who develop metastatic disease after resection. Trials of neoadjuvant and adjuvant chemotherapy have demonstrated an absolute survival benefit of 5% for patients with stages IB, II, and IIIA disease. Clearly, developing new treatment strategies to improve survival following resection is critical to improving outcomes for this patient population. Immunotherapy with checkpoint inhibitors such as antibodies to PD-1 and PD-L1 has demonstrated superior survival compared to chemotherapy in randomized clinical trials. PD-L1 expression is being investigated as a predictive biomarker for these therapies, but its ability to predict response has varied in published trials. Atezolizumab is a humanized IgG1 monoclonal PD-L1 antibody that was recently evaluated in the POPLAR trial (NCT01903993), a phase II randomized trial of patients with NSCLC who progressed on platinum based chemotherapy. Atezolizumab therapy improved overall survival compared with docetaxel (12.6 months vs. 9.7 months, HR 0.73 [95% CI 0.53 – 0.99]) with a manageable safety profile. Improvement in survival correlated with PD-L1 immunohistochemistry expression of tumor and tumor-infiltrating immune cells.

      Methods:
      Trial design: This phase II, open-label, single-arm study is designed to evaluate the efficacy and safety of atezolizumab as a neoadjuvant therapy in patients with Stage IB, II, or IIIA NSCLC prior to curative-intent resection. Approximately 180 patients with NSCLC will be enrolled in this study at 15 academic medical centers in the United States. There are two parts to this study: the first/primary part will evaluate the ability of neoadjuvant atezolizumab to produce objective pathologic responses in patients with early stage NSCLC. Atezolizumab 1200 mg IV will be given every 3 weeks for two doses. Surgical resection of tumors following treatment will allow determination of pathologic response rates and potential predictive biomarkers. Part 2 is exploratory and will evaluate atezolizumab adjuvant therapy for up to 12 months in patients who demonstrate clinical benefit (evidence of pathologic response or absence of radiographic progression) in Part 1. After surgical resection, patients may receive SOC adjuvant chemotherapy (with or without radiation) before starting atezolizumab adjuvant therapy in Part 2. The primary objectives are safety and major pathologic response based on surgical resection. Secondary objectives include overall response rate based on PD-L1 status, mutational load, antigen burden, and RNA-sequencing. This trial presents a unique opportunity to evaluate exploratory biomarkers, including pre- and post-treatment biopsy assessment of evolution of immune related markers associated with response.

      Results:
      Section not applicable

      Conclusion:
      Section not applicable