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A. Rajan



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    P1.02 - Biology/Pathology (ID 614)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P1.02-063 - Tumor Heterogeneity Analyses by Integrated Proteo-Genomics of Thoracic Tumors from Sequential Biopsies and Warm Autopsies (ID 10355)

      09:30 - 16:00  |  Author(s): A. Rajan

      • Abstract

      Background:
      Tumor heterogeneity modulates treatment response to targeted therapy. Both intra-tumor and inter-tumor heterogeneity is well characterized in various cancers, including lung cancer, the commonest cause of cancer death in both men and women. Tumor heterogeneity studies have been conducted mostly for early stage lung cancer. Furthermore, these studies have focused primarily on next-generation sequencing (NGS).

      Method:
      We applied whole exome sequencing (WES), RNA-seq, OncoScan CNV and mass spectrometry-based proteomic analyses on 46 tumor regions from metastatic sites including lung, liver and kidney, obtained by rapid/warm autopsy from 4 patients with stage IV lung adenocarcinoma, 1 patient each with pleural mesothelioma and thymic carcinoma. 3/6 patients were admitted to NIH Clinical Center to receive in-patient hospice care before death under this study and the autopsy procedure was initiated between 2-4 hours of death in all patients. We have also performed similar integrated proteogenomics analyses on 11 different biopsies, including at autopsy of an “exceptional responder” lung adenocarcinoma patient who survived with metastatic lung adenocarcinoma for 7 years. We used the “super-SILAC” and TMT labeling strategies for quantitative proteomics using a Thermo Orbitrap Elite mass spectrometer. Patient-specific databases were built incorporating all somatic variants identified by NGS to interrogate the mass spectrometry data and an extensive validation pipeline was built for confirmation of variant peptides.

      Result:
      Here, we report an integrated analysis at the level of somatic variants, copy number, transcript, protein expression, and the phosphoproteome to demonstrate the extent of tumor heterogeneity and its potential impact on tumor biology. All tumors displayed organ-specific, branched evolution that was consistent across exome, transcriptome and proteomic analyses. RNA-seq, CNV-seq and proteomics analyses complemented the clonal evolution analyses performed using WES. The degree of heterogeneity at the genomic and proteomic level was patient-specific. There was extreme heterogeneity within the tumors of one of four patients with lung adenocarcinoma and in the thymic carcinoma patient (both non-smokers). Further examination of the heterogenous thymic and lung adenocarcinoma tumors showed strong enrichment of APOBEC-mutagenesis signature and high APOBEC3B mRNA levels. We identified a high risk APOBEC3AB germline allele in the thymic carcinoma patient that results in increased APOBEC expression and mutagenesis.

      Conclusion:
      Our integrated proteo-genomics analyses reveal significant differences in the genomic and proteomic intra-tumor and inter-tumor heterogeneity. APOBEC-mutagenesis is a significant driver of extreme cases of heterogeneity. High risk APOBEC germline alleles and increased APOBEC expression drive APOBEC mutagenesis in select patients.

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    P2.03 - Chemotherapy/Targeted Therapy (ID 704)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Chemotherapy/Targeted Therapy
    • Presentations: 1
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      P2.03-052 - Local Ablative Therapy for Oligoprogressive, EGFR-Mutant, Non-Small Cell Lung Cancer (NSCLC) After Treatment with Osimertinib (ID 10360)

      09:30 - 16:00  |  Author(s): A. Rajan

      • Abstract

      Background:
      EGFR tyrosine kinase inhibitors (EGFR-TKIs) improve progression-free survival (PFS) in patients with EGFR-mutant NSCLC, but disease progression limits efficacy. Retrospective studies show a survival benefit to local ablative therapy (LAT) in patients with oligoprogressive disease (progression at a limited number of anatomic sites).

      Method:
      This is a prospective study of LAT in patients with oligoprogressive EGFR-mutant NSCLC. Patients with no prior EGFR-TKI therapy (cohort 1) or progression after 1[st]/2[nd] generation EGFR-TKIs with acquired T790M mutation (cohort 2) receive osimertinib. Upon progression, eligible patients with <= 5 progressing sites undergo LAT and resume osimertinib until disease progression. Patients previously treated with osimertinib qualifying for LAT upon disease progression are also eligible for treatment (cohort 3). Primary endpoint: evaluation of safety and efficacy of reinitiation of osimertinib after LAT (assessed by PFS2). Additional goals are assessment of mechanisms of resistance to osimertinib by multi-omics analyses of tumor, blood, and saliva.

      Result:
      Between 04/2016 and 06/2017, 18 patients were enrolled (cohort 1: 11, cohort 2: 4, cohort 3: 3). Median age was 57 (range 36-71). The most common adverse events (AEs) on osimertinib treatment were rash, diarrhea, thrombocytopenia, and alanine transaminase elevation with most of the AEs being grade 1 or 2. Among evaluable patients, confirmed objective response rates prior to LAT in cohorts 1 and 2 were 66.7% (6/9) and 75% (3/4), respectively, with 11.3 months median PFS (95% CI: 3.4-11.3 months) in cohort 1 and 8.9 months in cohort 2 (95% CI not defined due to the small number of patients). To date, 7 patients had progressive disease, 6 of which had oligoprogression and subsequently underwent LAT (cohort 1: 2; cohort 2: 1; cohort 3: 3). Three patients were treated with combination of surgery and radiotherapy (RT), 2 patients with surgery, and 1 patient with RT. Whole exome sequencing (WES) and RNA-seq were performed on tumor tissues obtained pre-treatment and upon progression on osimertinib. MET amplification, transformation to small cell lung cancer, and EGFR C797S mutation were identified as mechanisms of resistance to osimertinib. One patient with MET amplification was referred for a clinical trial of osimertinib and savolitinib, a MET inhibitor, upon second progression on osimertinib re-challenge, and had a response to treatment.

      Conclusion:
      Patients with EGFR-mutant NSCLC and oligoprogression after EGFR-TKI therapy can be safely treated with LAT. In select patients, this approach could potentially maximize duration of EGFR-TKI treatment and prevent premature switching to other systemic therapies.

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    P2.07 - Immunology and Immunotherapy (ID 708)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      P2.07-058 - First-In-Human Study of JNJ-64041757, a Live Attenuated Listeria Monocytogenes Immunotherapy, for Non-Small Cell Lung Cancer (ID 9480)

      09:30 - 16:00  |  Author(s): A. Rajan

      • Abstract
      • Slides

      Background:
      JNJ-64041757 (JNJ-757) is a live attenuated, double-deleted (LADD) Listeria monocytogenes (Lm)-based immunotherapy engineered to induce adaptive immune responses against the tumor-associated antigen mesothelin. The goals of Part 1 of this first-in-human (FIH) study were to establish the recommended phase 2 dose (RP2D), characterize the safety profile, and evaluate the immunological activity of JNJ-757 in patients with adenocarcinoma of the lung.

      Method:
      This is an ongoing FIH trial in patients with advanced adenocarcinoma non-small cell lung cancer (Stage IIIb or IV) who have progressed after standard therapy (ClinicalTrials.gov: NCT02592967). Patients were treated at 1 of 2 dose levels (10[8] CFU or 10[9] CFU), infused over 1 hour every 3 weeks until disease progression or unacceptable toxicity. Dose limiting toxicities (DLTs) were evaluated during the first cycle. Disease response was assessed every 3 cycles according to RECIST 1.1. Post-infusion blood, urine, fecal, and saliva samples were evaluated for the presence of JNJ-757. Immunological activity of JNJ-757 was assessed by evaluation of peripheral cytokines and immune cells as well as ELISPOT analysis to defined antigens.

      Result:
      Nine subjects were enrolled; 6 at 10[8] CFU and 3 at 10[9] CFU. There were no DLTs in either dosing cohort, and 10[9] CFU was identified as the RP2D. Most adverse events (AEs) were of grade 1/2 severity, with fatigue, headache, nausea, and vomiting as the most reported events. One drug-related AE of grade ≥3 severity (hypokalemia, grade 3) was reported in the 10[8] CFU cohort. Best response was stable disease. Four patients had received at least 7 cycles (range, 1 to 14 cycles). JNJ-757 was quickly cleared after infusion, with 7/9 patients showing negative blood cultures at 2 hours; all were negative after 24 hours. Correlative studies demonstrated activation of both innate and adaptive immune responses. Natural killer cell and T cell activation were observed 24 hours after infusion, coinciding with elevated cytokine production (i.e., IFN-γ, TNF-α). Specific T cell responses against Listeria listeriolysin O and mesothelin antigens were documented in a subset of patients, consistent with the mechanism of LADD to prime new immune responses.

      Conclusion:
      The RP2D of JNJ-757 is 10[9] CFU, with a safety profile consistent with other LADD Lm-based agents such as CRS-207. Both innate and mesothelin-specific adaptive immune responses were demonstrated in multiple patients. Recruitment in the trial continues to further characterize the safety profile and immune response, and a phase 1b/2 trial with JNJ-757 and nivolumab is planned.

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