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G.A. Otterson



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    MA08 - Treatment Monitoring in Advanced NSCLC (ID 386)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
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      MA08.01 - A Highly Sensitive Next-Generation Sequencing Platform for Detection of NSCLC EGFR T790M Mutation in Urine and Plasma (ID 4637)

      11:00 - 11:06  |  Author(s): G.A. Otterson

      • Abstract
      • Presentation
      • Slides

      Background:
      Non-invasive genotyping of NSCLC patients by circulating tumor (ct)DNA is a promising alternative to tissue biopsies. However, ctDNA EGFR analysis remains challenging in patients with intrathoracic disease, with a reported 26-57% T790M mutation detection rate in plasma (Karlovich et al., Clin Cancer Res 2016; Wakelee et al., ASCO 2016). We investigated whether a mutation enrichment NGS could improve mutation detection in plasma and urine from TIGER-X, a phase 1/2 study of rociletinib in patients with EGFR mutation-positive advanced NSCLC.

      Methods:
      The therascreen (Qiagen) or cobas (Roche) EGFR test was used for EGFR T790M analysis in tumor biopsies. Urine and plasma were analyzed by trovera mutation enrichment NGS assay (Trovagene).

      Results:
      Of 174 matched tissue, plasma and urine specimens, 145 (83.3%) were T790M+ by central tissue testing, 142 (81.6%) were T790M+ by plasma, and 139 (79.9%) were T790M+ by urine. Urine and plasma combined identified 165 cases (94.8%) as T790M+. Of 25 cases positive by ctDNA but negative/inadequate by tissue, 16 were double-positive in plasma and urine, unlikely to be false positive (Figure 1). T790M detection rate was higher for extrathoracic (n=119) vs intrathoracic (n=55) disease in plasma (87.4% vs 69.1%, p=0.006) but not urine (81.5% vs 76.4%, p=0.42). Combination of urine and plasma identified T790M in 92.7% of intrathoracic and 95.8% of extrathoracic cases (p=0.47). In T790M+ patients, objective response rate was similar whether T790M mutation was identified by tissue, plasma or urine: 37.4%, 33.1% and 36.6%, respectively. 4 of 9 patients T790M+ by urine but negative by tissue responded, and 2 of 8 patients T790M+ by plasma but negative by tissue responded.

      Conclusion:
      Mutation enrichment NGS testing by urine and plasma combined identified 94.8% of T790M+ cases. Combination of urine and plasma may be considered before tissue testing in EGFR TKI resistant NSCLC, including patients without extrathoracic metastases. Figure 1



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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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      P2.01-092 - PRMT5 is a Poor Prognostic Marker for NSCLC and Inhibition of PRMT5 Results in Increased Lung Cancer Sensitivity to Cisplatin and Radiotherapy (ID 6137)

      14:30 - 14:30  |  Author(s): G.A. Otterson

      • Abstract

      Background:
      Protein arginine methyltransferase 5 (PRMT5), a member of the protein arginine methyltransferase family, has important regulatory function in many cellular processes through epigenetic control of target gene expression. Because of its overexpression in a number of human cancers and its essential role in cell proliferation, transformation and cell cycle progression, PRMT5 has been recently proposed to function as an oncoprotein in cancer cells. In this study, we explore prognostic and predictive value of PRMT5 expression in lung cancer. Impact of PRMT5 inhibition in the setting of radiation therapy and platin-based chemotherapy was investigated.

      Methods:
      PRMT5 expression levels in lung tumors as well as their paired normal tissue obtained from TCGA public databases were compared. The impact of PRMT5 expression on lung cancer patient survival was investigated by using “Director’s challenge Consortium for the Molecular Classification of Lung Adenocarcoma” and JBR10 datasets. SiRNA designed to target PRMT5 was used to transiently knockdown (KD) PRMT5 expression in several lung cancer cell lines. Clonogenic survival assays of lung cancer cell lines with increasing doses of cisplatin or radiation were performed in cells with normal endogenous PRMT5 expression or in cells after siRNA knockdown. Impact of PRMT5 knockdown in cell cycle, apoptosis, DNA damage response was investigated through cell cycle analysis, Annexin/PI flow cytometry, ɣH2A foci measurements in lung cancer cells with normal or reduced PRMT5 expression.

      Results:
      PRMT5 expression is significant higher in lung tumors compared to parired normal tissue in TCGA datasets (LUAD and LUSC) with p value ≤0.0001. Patients with high PRMT5 expression portend lower overall survival at 3 years (p=0.02) from director’s challenge lung cancer study. Patients with low PRMT5 expression had significantly better DFS at 5 years (p=0.3) if they received cisplatin while patients with high PRMT5 expression did not benefit from cisplatin treatment (p=0.7). In several lung cancer cell lines, we observed >90% PRMT5 KD in transiently transfected cells at 48 h and 72 h post transfection as verified by western blot analysis. This inhibition of PRMT5 activity achieved by transient KD lead to a significant decrease in colony survival after radiation and cisplatin. There is an increase of cell population in G1 arrest in PRMT5 transient KD cells.

      Conclusion:
      High PRMT5 expression is associated with worse survival in lung cancer patients. Inhibition of PRMT5 in lung cancer cells results in sensitization to cisplatin and radiotherapy,

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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 - 14:30  |  Author(s): G.A. Otterson

      • 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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    P3.02c - Poster Session with Presenters Present (ID 472)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P3.02c-056 - Interim Results From the Phase I Study of Nivolumab + nab-Paclitaxel + Carboplatin in Non-Small Cell Lung Cancer (NSCLC) (ID 4127)

      14:30 - 14:30  |  Author(s): G.A. Otterson

      • Abstract

      Background:
      Chemotherapy, including nab-paclitaxel, plus an immune checkpoint inhibitor has demonstrated antitumor activity in patients with metastatic breast cancer (mBC) and NSCLC. Here, results from the 2 lung cohorts of the phase I nivolumab + nab-paclitaxel in pancreatic cancer (± gemcitabine), NSCLC (+ carboplatin), and mBC safety trial are presented.

      Methods:
      Enrollment in the lung cohorts (C and D) was initiated in two sequential parts: Dose-limiting toxicity (DLT) evaluation was done in Part 1 prior to treatment arm expansion in Part 2. Chemotherapy-naive patients with stage IIIB/IV NSCLC received 4 cycles of nab-paclitaxel 100 mg/m[2] D 1, 8, 15 + carboplatin area under the curve (AUC) 6 D 1 + nivolumab 5 mg/kg D 15 (starting in cycle 1 [Arm C] or cycle 3 [Arm D]) of each 21-day cycle; nivolumab continued as monotherapy from cycle 5. Primary endpoints were DLTs (Part 1), and grade 3/4 treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation (Parts 1 and 2). Patients who received ≥ 2 nivolumab cycles and remained on study for 14 days after the last nivolumab dose or discontinued due to DLT prior to completing 2 nivolumab cycles were considered DLT-evaluable. Key secondary endpoints include safety, PFS, OS, and ORR.

      Results:
      As of May 25, 2016, 21 patients have enrolled in Arm C (18 nivolumab-treated); most were aged ≥ 65 years (57.1%) and female (71.4%), 33.3% had ECOG PS 0, 42.9% and 33.3% had adenocarcinoma and squamous cell carcinoma, respectively. No DLTs were reported (5 DLT-evaluable patients). The most common grade 3/4 AEs in Arm C (all patients) were neutropenia (28.6%), anemia (19.0%), and hypokalemia (14.3%); gastrointestinal disorders (11.1%) were the most frequent grade 3/4 immune-related AE in nivolumab-treated pts. Seven patients (5 nivolumab-treated) discontinued treatment (majority due to progressive disease [PD]). Of the 18 nivolumab-treated patients, 9 had a PR, 8 had stable disease, and data is pending in 1 patient; tumor shrinkage (baseline to nadir) ranged from 3% to 83%. The median PFS (n = 4 with PD or death; nivolumab-treated) was 7.3 months (treatment duration, 0.7 - 9.4 months). Eight patients have enrolled in Arm D (4 nivolumab-treated); 1 DLT (pneumonitis) was reported in 4 DLT-evaluable patients.

      Conclusion:
      These results demonstrate that the combination of nivolumab with nab-paclitaxel/carboplatin is tolerable and has promising antitumor activity in patients with NSCLC. Updated results will be presented at the meeting. (NCT02309177)