Virtual Library

 x 
My Library Virtual Library FAQ

Start Your Search

A. Lisberg



Author of

  • +

    P1.05 - Poster Session with Presenters Present (ID 457)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Early Stage NSCLC
    • Presentations: 1
    • +

      P1.05-003 - Coexpression of CD8a and PD-L1 Frequently Observed in Resected NSCLC Tumors from Smokers (ID 4764)

      14:30 - 14:30  |  Author(s): A. Lisberg

      • Abstract

      Background:
      With the approval of anti-programmed cell death-1 (PD-1) therapy in advanced non-small cell lung cancer (NSCLC), identifying patients with early stage disease most likely to benefit from therapy has become a priority. It has been hypothesized that patients whose tumors show evidence of PD-1 mediated T cell exhaustion, via the presence of both tumor infiltrating lymphocytes (TILs) and PD-L1 expression, are more likely to respond to anti-PD-1 therapy (Teng et al, 2015). The current study utilized microarray analysis to evaluate the relationship between both clinicopathologic features and overall survival (OS) with tumor microenvironment (TME) composition.

      Methods:
      Gene expression microarray analysis was performed using the Agilent Whole Human Genome 4x44K 2-color platform for 319 NSCLC and 15 normal resection specimens. The reference sample was an equal mixture of 258 of the NSCLC samples. Rosetta Resolver and Statistica 13.0 were used for analysis. Samples with PD-L1 expression levels greater or unchanged from reference level were classified as positive, while those significantly lower [log (ratio)<0 and p<0.01] than the reference were classified as negative. CD8a expression was used as a surrogate for TILs as previously described by Ock et al. (2016), and categorized in the same manner as PD-L1. Relationships between TME composition and clinicopathologic features were evaluated with the chi-square test. Survival analysis was performed using the Kaplan-Meier method and compared using the log-rank test.

      Results:
      In the 319 NSCLC samples the incidence of a Type I TME (+CD8a/+PD-L1) was 45%, Type II TME (-CD8a/-PD-L1) 12%, Type III (-CD8a/+PD-L1) 25%, and Type IV (+CD8a/-PD-L1) 18%. When assessing for survival, patients with a PD-L1 negative/CD8a positive (Type IV) TME had improved OS compared to patients with PD-L1 negative/CD8a negative (Type II) TME (p=0.02). When assessed for smoking, ever smokers were more likely to evidence a PD-L1 positive/CD8a positive (type I) TME compared to never smokers, 49% vs 32%, while never smokers more frequently evidenced a PD-L1 positive/CD8a negative (Type III ) TME compared to ever smokers, 37% vs 22% (P=0.05). Interestingly, 75% of normal lung samples evidenced a PD-L1 positive/CD8a positive microenvironment.

      Conclusion:
      Evidence of both TILs and PD-L1 expression was observed in the majority of normal lung specimens and also more frequently in tumors from smokers compared to non-smokers. Patients whose tumors showed evidence of CD8a, but not PD-L1, had improved OS compared to patients without evidence of either. Future studies will utilize immunohistochemistry to corroborate these findings and investigate other components of the TME.

  • +

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

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
    • +

      P2.01-078 - Frequent High TIM-3 (HAVCR2) Expression in Resected NSCLC Specimens, Most Notably in Adenocarcinoma Histology (ID 5400)

      14:30 - 14:30  |  Author(s): A. Lisberg

      • Abstract

      Background:
      Approved anti-programmed cell death-1 (PD-1) therapies have produced durable responses in advanced non-small cell lung cancer (NSCLC), but objective response rates in unselected populations remain modest at approximately 20%. As a result, therapies targeting other immune checkpoints are currently being investigated as monotherapy or in combination with anti-PD-1 therapy. One such immune checkpoint is T-cell immunoglobulin and mucin-domain containing 3 (TIM-3), which is involved in T-cell exhaustion and has also been found on NSCLC tumor cells, more frequently in adenocarcinoma. The present study sought to further characterize the expression of TIM-3 in resected NSCLC specimens via microarray analysis.

      Methods:
      Gene expression microarray analysis was performed using the Agilent Whole Human Genome 4x44K 2-color platform for 319 NSCLC and 15 normal lung resection specimens. The reference sample was an equal mixture of 258 of the NSCLC samples included in the study. Microarray data was imported into Rosetta Resolver for analysis. Samples with expression significantly greater than the reference level were classified as high, samples with expression unchanged from the reference were classified as moderate, and samples with significantly lower levels were classified as low (P<0.01). Relationships between TIM-3 expression and smoking status, histology, T stage, and gender were evaluated with the chi-square test. The three survival curves based on TIM-3 expression were compared and a single p-value based on chi-square test was determined using Statistica 13.0.

      Results:
      Within the 319 NSCLC tissue samples, 90 samples (28%) had high TIM-3 expression, 150 samples (47%) had moderate expression, and 79 samples (25%) had low expression. Interestingly, 47% (7/15) of normal lung samples evidenced high TIM-3 expression, while none had low TIM-3 expression. Tumors with adenocarcinoma histology had a greater percentage of samples with high TIM-3 expression, 34%, compared to those with squamous cell histology, 17% (p=0.03). Gender and T stage were not significantly related to TIM-3 expression level, while a trend towards high TIM-3 levels was observed in smokers compared to non-smokers (p=0.10). In this surgical cohort, TIM-3 expression did not appear to be prognostic for survival.

      Conclusion:
      Our findings suggest that high TIM-3 expression occurs frequently in resected NSCLC, supporting the ongoing evaluation of anti-TIM-3 therapy in NSCLC. Additionally, TIM-3 expression was more frequently high in adenocarcinoma, normal lung, and a trend towards high expression was noted in smokers. Future efforts will focus on identifying cell type specific TIM-3 expression via immunohistochemistry analysis and selecting patients for anti-TIM-3 clinical trials.

  • +

    P3.02b - Poster Session with Presenters Present (ID 494)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
    • +

      P3.02b-042 - Reduction in Peripheral Blood Cytokine Levels Observed in EGFR Mutant (EGFRm) Patients Treated with Erlotinib (ID 5403)

      14:30 - 14:30  |  Author(s): A. Lisberg

      • Abstract

      Background:
      A retrospective analysis of EGFRm non-small cell lung cancer (NSCLC) patients enrolled on ­­the KEYNOTE-001 trial at UCLA showed a significantly lower objective response rate for those treated with a tyrosine kinase inhibitor (TKI) prior to pembrolizumab than those who were TKI naïve (Garon et al, WCLC 2015). Since nivolumab treated squamous NSCLC patients that had high baseline cytokine levels had a median overall survival almost three times longer than those with low baseline levels (Lena et al, ELCC 2016), we used multiplex cytokine analysis to assess effects of an EGFR TKI on peripheral blood cytokine concentrations.

      Methods:
      Paired baseline and cycle 2 day 1 samples were evaluated in 60 stage IIIb or IV NSCLC patients [EGFRm=12, EGFR wild type (wt)=33, unknown EGFR=15] enrolled on a clinical trial of erlotinib +/- fulvestrant for 30 cytokines [Bio-Rad Bio-Plex Human Cytokine 27-plex and Bio-Plex Pro TGF 3-plex (M500KCAF0Y, 171W4001M)]. Cytokine concentration values were compared between EGFR groups with GEE models. In these models, cytokine values were log-transformed and terms for treatment, EFGR status, and their interaction were included. Age (continuous), sex (binary), smoking status (ever/never), and tumor stage (binary) were also included in the model. R software was used for analyses. A p-value <0.05 was considered statistically significant with no adjustment for multiple comparisons.

      Results:
      For the 12 EGFRm patients treated with erlotinib +/- fulvestrant, 83% (25/30) of the cytokines evaluated showed a quantitative decrease, 17% (5/30) showed a significant decrease, and none showed a significant increase. Similar patterns were not observed in the 33 EGFRwt patients, in whom only 23% (7/30) of the cytokines evaluated showed a decrease, significant in 7% (2/30) with 40% (12/30) showing a significant increase. No clear directional change based on inclusion of fulvestrant in the treatment regimen was seen.

      Conclusion:
      A decrease in peripheral blood cytokine concentrations was observed in EGFRm patients treated with erlotinib +/- fulvestrant but not EGFRwt patients. Although unknown whether these changes persist after erlotinib discontinuation, the decrease in EGFRm patient peripheral blood cytokine levels in response to TKI therapy could contribute to the lower efficacy of anti-PD-1 therapy observed in this population. Future studies will evaluate cytokine levels for EGFRm patients treated with 3[rd] generation TKIs, as well as patients enrolled on a single center investigator-initiated trial evaluating front-line pembrolizumab in EGFRm PD-L1+ patients.

  • +

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

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
    • +

      P3.02c-083 - Treatment Related Adverse Events Predict Improved Clinical Outcome in NSCLC Patients on KEYNOTE-001 at a Single Center (ID 5509)

      14:30 - 14:30  |  Author(s): A. Lisberg

      • Abstract

      Background:
      It has been suggested that certain patients could be primed to respond to anti-programmed cell death-1 (PD-1) therapy due to heightened baseline “immunocompetence,” but data supporting this is limited as is our ability to measure it. The experience with ipilumumab suggests that immune related adverse events (irAEs) experienced by melanoma patients may predict improved clinical outcomes (Weber et al, J Clin Oncol 2012). We retrospectively analyzed NSCLC patients from a single center on the KEYNOTE-001 trial and evaluated the association between treatment related adverse events (trAE) and clinical outcomes.

      Methods:
      We performed a retrospective analysis of the 97 NSCLC patients treated on KEYNOTE-001 at UCLA with either 2 mg/kg Q3W or 10 mg/kg Q2/3W of pembrolizumab (data cut-off 3/2016). Investigators reported AEs and graded according to CTCAE v4.0, labeling them as unlikely, possibly, or probably treatment related. AEs labeled as possibly/probably related were considered trAEs. The initial scan was at 9 weeks and subsequent scans were every 9 weeks. Investigator assessed irRC was the radiographic assessment used for clinical decisions at individual sites. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method and compared using the log-rank test.

      Results:
      10% (85/826) of AEs reported on trial were considered trAEs. The most frequent trAEs were rash (29%), fatigue (9%), and pneumonitis (8%). The occurrence of a trAE was associated with higher objective response rate (ORR) (OR=0.1509, P=0.0009), PFS (HR=0.3004, P<0.0001) and OS (HR=0.4391, P<0.0001). To assess whether the shorter duration of follow-up in those progressing earlier biased this analysis, additional analyses were performed. The relationship remained, particularly for longitudinal outcomes, when assessed only in patients that continued on trial >9 weeks. This was true both when including trAEs over the entire trial duration (ORR: OR=0.1839, P=0.005; PFS: HR=0.3525, P<0.0001; OS: HR=0.4526, P=0.0008) or when including only trAEs occurring within the first 9 weeks (ORR: OR=0.4063, P=0.1047; PFS: HR=0.5568, P=0.0211; OS: HR=0.6404, P=0.0465). Neither number of prior lines of therapy nor age, gender, or smoking history predicted frequency of trAE occurrence.

      Conclusion:
      This single center, retrospective analysis, revealed that a trAE predicted for improved clinical outcome with pembrolizumab. When controlling for the inherent bias of asymmetric follow-up, these associations remained. Although this analysis has the weakness of being conducted at a single center representing less than 20% of patients on trial, the strength is that a limited number of investigators assessed if an event was an AE and was treatment related.

  • +

    P3.06 - Poster Session with Presenters Present (ID 492)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Trial Design/Statistics
    • Presentations: 1
    • +

      P3.06-009 - Multiple Oral Presentations at Major International Conferences from a Single Clinical Trial Are Common (ID 6043)

      14:30 - 14:30  |  Author(s): A. Lisberg

      • Abstract

      Background:
      Traditionally, study results have been presented as abstracts at major scientific meetings at the conclusion of the analysis. Recently, presentations of studies in progress and updates to previously presented data have been allowed at major meetings. The frequency and implications of a single study being presented multiple times, particularly in high profile oral presentations, have not been fully evaluated.

      Methods:
      To identify studies presented multiple times, abstracts from an approximately one year period from international conferences for three major societies devoted largely or in part to lung cancer research were assessed (ASCO 2015, World Lung 2015, ESMO 2015 and ASCO 2016). Abstracts were selected in a two-step process. The first step was for subject matter based on keywords: NSCLC, SCLC or immunotherapy. Searches differed slightly based on individual website functionality, with ASCO searched by track, World Lung by session and ESMO by individual abstract. In a second step, abstracts for which clinical outcome data was presented from a trial with an identifiable NCT number were selected. Immunotherapy abstracts that did not include the treatment of NSCLC or SCLC were excluded in the second step.

      Results:
      851 abstracts were identified that were related to NSCLC, SCLC or immunotherapy. Of these, 357 referred to a clinical trial. 110 of 357 (30%) described clinical trials that were presented multiple times (mean 2.75, range 2-7), and in 44 (12%), this occurred at the same conference. 113 of 357 abstracts (31%) were oral presentations. 75 (66%) of the oral presentations presented data from clinical trials that were presented multiple times, including 35 (31%) which were presented as oral presentations at least twice. Of the 16 unique clinical trials leading to multiple oral presentations, a variety of issues led to the duplicate presentations, including different cohorts of the same trial, biomarker analysis, analysis by one study variable, or simply updated data. In total, only 6 of 16 of these studies presented additional patients in a subsequent oral presentation, two presenting unique cohorts, and the other four presenting updated data that included additional patients, in one case, fewer than ten patients.

      Conclusion:
      There is a pattern of multiple presentations of clinical trials, particularly in oral presentations, at major meetings. Although a second oral presentation on the same concept may sound confirmatory to a conference participant, in most cases, data presented in subsequent oral presentations related entirely to patients whose data was presented in the previous oral presentation.