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P.L. Mitchell



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    MO06 - NSCLC - Chemotherapy I (ID 108)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO06.05 - DISCUSSANT (ID 3937)

      16:35 - 16:45  |  Author(s): P.L. Mitchell

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    O02 - NSCLC - Combined Modality Therapy I (ID 111)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Combined Modality
    • Presentations: 1
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      O02.02 - Tecemotide (L-BLP25) in unresectable stage III non-small cell lung cancer in the phase III START study: Further endpoint and exploratory biomarker results (ID 2779)

      10:40 - 10:50  |  Author(s): P.L. Mitchell

      • Abstract
      • Presentation
      • Slides

      Background
      The phase III START study evaluated the mucin 1 (MUC1) antigen-specific cancer immunotherapy tecemotide (L-BLP25) vs. placebo in patients with stage III unresectable non-small cell lung cancer (NSCLC) who did not progress following initial chemo-radiotherapy (chemo/RT). The primary objective of overall survival (OS) prolongation was not met, however, pre-defined subgroup analyses revealed a clinically meaningful prolongation of survival with tecemotide in patients previously treated with concurrent chemo/RT (p=0.016). Sensitivity analyses suggested the observed treatment effect may have been under-estimated due to a clinical hold, which resulted in a median suspension of recruitment and investigational treatment of about 4.4 months. Tecemotide was well tolerated and no safety concerns were identified.

      Methods
      From January 2007 to November 2011, 1513 patients with unresectable stage III NSCLC and stable disease or objective response following initial chemo/RT were randomized (2:1, double-blind) to subcutaneous tecemotide (806 µg lipopeptide) or placebo, weekly for 8 weeks and then 6-weekly until disease progression or withdrawal. A single dose of cyclophosphamide (300 mg/m2) or saline was given 3 days prior to first tecemotide/placebo dose. Primary endpoint, OS, and secondary endpoints progression-free-survival (PFS) and time-to-treatment-failure (TTF) used a Cox proportional hazards regression model adjusting for randomization strata. While RECIST 1.0 had to be observed for determination of disease progression, there was no formal imaging schedule to determine disease progression; this was done according to institutional practice. Exploratory analyses were done for treatment interaction for HLA-A02, -DRB4 and -B08. Baseline peripheral blood anti-nuclear antibodies (ANA), serum MUC1 (sMUC1), lymphocyte count and neutrophil:lymphocyte ratio (NLR) currently are being explored.

      Results
      The primary analysis population (N=1239) was defined prospectively to account for the clinical hold and prospectively excluded 274 patients randomized within 6 months prior to onset of the hold. Median PFS was 9.6 months with tecemotide vs. 7.7 months with placebo (HR 0.865, 95%CI 0.755–0.990, p=0.036). In keeping with OS data, tecemotide treatment effects on PFS were more pronounced in patients treated with concurrent chemo/RT (N=806; HR 0.826, 95%CI 0.696–0.980, p=0.029) vs. sequential chemo/RT (N=433; HR 0.947, 95%CI 0.756–1.187, p=0.638). Median TTF was 8.9 months with tecemotide vs. 7.2 months with placebo (HR 0.887, 95%CI 0.777–1.012, p=0.075). A prolongation of TTF with tecemotide was seen in patients with prior concurrent chemo/RT (HR 0.844, 95%CI 0.715–0.996, p=0.045), which was absent in the subgroup with prior sequential chemo/RT (HR 0.977, 95%CI 0.784–1.217, p=0.835). Detailed biomarker results will be presented.

      Conclusion
      While the primary endpoint of prolongation of OS was not met, secondary endpoints PFS and TTF support the previously-reported finding of a more favorable effect of tecemotide in patients treated with concurrent but not sequential chemo/RT. Any potential further clinical investigation of tecemotide in locally advanced NSCLC should focus on patients following concurrent chemo/RT therapy.

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    O27 - Clinical Trials and Practice (ID 142)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Other Topics
    • Presentations: 1
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      O27.03 - Meta-analysis of progression-free survival and objective response rate as predictors of overall survival in locally advanced or metastatic non-small-cell lung cancer (ID 3170)

      16:35 - 16:45  |  Author(s): P.L. Mitchell

      • Abstract
      • Presentation
      • Slides

      Background
      Improving overall survival (OS) in locally advanced or metastatic non-small-cell lung cancer (NSCLC) remains a goal for clinicians. OS is often the primary endpoint in Phase III clinical trials, however with the increased use of multiple lines of treatment and crossover/rescue therapy in NSCLC trials, overall survival differences are frequently confounded. Other clinically meaningful endpoints such as progression-free survival (PFS) are becoming increasingly important. A systematic review and meta-analysis was undertaken to investigate whether the treatment effect on PFS, or objective response rate (ORR), was predictive of the treatment effect on OS in locally advanced or metastatic NSCLC.

      Methods
      Embase, MEDLINE and the Cochrane Library databases were searched to identify relevant published randomised controlled trials (RCTs). Included RCTs compared pharmacological treatments in two or more groups in patients with locally advanced or metastatic (Stage IIIb or IV) NSCLC. The reported outcomes had to include median PFS and median OS. Data were analyzed with locally weighted least squares regression (LOWESS) to validate the linear relationship. Unweighted linear regression and weighted linear regression were used to estimate the relationship between OS treatment difference and PFS treatment difference. A similar analysis was also done to compare ORR difference and OS difference. The analysis also considered whether potential baseline prognostic factors could also change OS difference. Univariate weighted linear regression was used to assess the relationship of each prognostic factor with OS difference, followed by multivariate weighted linear regression.

      Results
      A total of 124 RCTs (N=40,568 patients) were included in the analysis. Of the 124 trials, 98 (79%) were published since 2005. The age of patients ranged from middle aged cohorts to the elderly. There were 87 studies (70%) with first-line therapy and therapy type was predominantly chemotherapy (71 studies, 57%). The LOWESS of OS difference versus PFS difference was a relatively straight line, therefore a linear relationship appeared to be justified. Weighted linear regression showed a highly significant relationship between OS treatment difference and PFS treatment difference [slope 1.317 months (95%CI 1.000, 1.634) p<0.001 R[2] = 36.6%]. Diagnostic plots revealed several statistical outliers. A weighted linear regression of OS difference versus PFS difference with six outlier studies removed also showed a highly significant linear relationship [slope 0.994 months (95%CI 0.749, 1.240) p<0.001 R[2] = 36.7%]. The relationship between ORR difference and OS difference was also significant [slope 12.503 (95%CI 7.042, 17.963) p<0.001 R[2] = 16.0%]. Univariate weighted linear regressions showed that the only baseline prognostic factor with a significant linear relationship with OS difference was the proportion of patients with non-squamous histology. Multivariate weighted linear regression showed none of the baseline prognostic factors was significant when PFS difference or ORR difference was included in the model.

      Conclusion
      The treatment effect on PFS was predictive of the treatment effect on OS. For a 1 month increase in PFS treatment difference, OS treatment difference increases by approximately 1.3 months. A 10% increase in ORR treatment difference was also associated with an increase in OS of 1.25 months. PFS is an important outcome for healthcare decision-making.

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    O28 - Endoscopy (ID 124)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Pulmonology + Endoscopy/Pulmonary
    • Presentations: 1
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      O28.07 - Intra-operative scanning confocal endomicroscopy of pleural disease: in vivo diagnosis of malignancy (ID 2977)

      11:35 - 11:45  |  Author(s): P.L. Mitchell

      • Abstract
      • Presentation
      • Slides

      Background
      The intra-operative diagnosis of pleural malignancy may facilitate surgical decision-making including the need for pleurodesis. A scanning laser confocal endomicroscopy device has been developed which allows histological-detail optical imaging of subsurface tissues in vivo. Confocal laser microscopy illuminates and detects light from a fixed point of a specimen which is scanned across a tissue plane and adjustable depths, providing a 3D structural view in a living body. Applied to screening of mucosal lesions in patients undergoing GI endoscopy, endomicroscopy obviates the need for many tissue biopsies and operators can rapidly learn to identify malignant tissues.

      Methods
      We performed the first intra-operative examination of pleural tissues using this equipment which is a thoracoscope-mounted endomicroscope device in patients administered iv fluorescein prior to imaging. Intra-operative endomicroscopic images were correlated with biopsies of pleural tissues.

      Results
      Sixteen patients were imaged: including mesothelioma 5 (2 biphasic) and pleural metastases from malignancies of lung 2, ovary 2 and one case each of breast, adenoidcystic (see figure), thyroid, colorectal, carcinoid and non-Hodgkin’s lymphoma, and also one benign case. We were able to image and identify normal mesothelium, sub-mesothelium, connective tissues and blood vessels (including RBC). Malignant cells and clusters of cells had a characteristic appearance including poor uptake of fluorescein and cellular pleomorphism. Appearances of mesothelioma correlated closely with histology. Glandular and papillary structures were identified in metastatic pleural tumour. In ovarian cancer calcification was readily identified as were psammoma bodies, while the typical cystic spaces surrounded by small dark cells mirrored closely the histological appearances of adenoidcystic carcinoma.

      Conclusion
      Images obtained on scanning confocal endomicroscopy of pleural malignancy generally correlated well with the histological appearance on biopsies. We plan now to extend our experience of malignancy and also the ability to discriminate between benign disease and malignancy of the pleura. Supported by a Tumour Stream Grant from the Victorian Cancer Agency. Figure: Endomicroscopy image of pleural metastases from adenoidcystic carcinoma of the parotid. Figure 1

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    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.06-039 - Expression of Mucin 1 in non-small cell lung cancer: Relationship between immunohistochemistry, tumour characteristics and survival (ID 2765)

      09:30 - 09:30  |  Author(s): P.L. Mitchell

      • Abstract

      Background
      Mucin 1 (MUC1), a glycoprotein highly expressed in many malignancies, is being explored as an antigen for immunotherapy. How best to measure MUC1 expression in non-small cell lung cancer (NSCLC) and its prognostic value in NSCLC are under discussion.

      Methods
      Tissue microarrays (TMAs) were constructed using triplicate 1mm cores of formalin-fixed paraffin-embedded tumour and stained with 214D4 (recognizes protein core) and MA695 (recognizes carbohydrate epitope) anti-MUC1 antibodies. TMAs were assessed for polarization, cytoplasmic and membranous staining intensity (scored 0–3) and proportion cells positive (0–100%; scored 0–5), averaged for multiple cores. A composite score (intensity x cells positive) was derived (range 0–15).

      Results
      TMAs from 518 patients were analyzed: 69% male, 95% Caucasian, 7% never-smoking; 49% adenocarcinoma, 35% squamous cell, 7% large cell; 43% stage I NSCLC, 33% stage II, 23% stage III. Immunohistochemistry staining intensity, proportion positive cells and depolarization were very similar between antibodies, with high concordance in composite score (R2=0.71, p<0.0001). Polarization was discordant in 8%. Similar scores were seen for N0, N1 and N2 when assessed by either antibody. For 77 cases with paired primary/N2 nodal tissue, mean 214D4 composite scores were 10.7 and 10.1 and MA695 scores 9.5 and 9.4, respectively. Discordant staining in primary but not node was seen in 5.2% and 10.4% with 214D4 and MA695, respectively. For 27 cases with neoadjuvant chemotherapy vs no chemotherapy, mean 214D4 scores were 10.2 vs 10.1 and MA695 9.3 vs 9.6, respectively. Higher scores with each antibody trended toward improved survival (non-significant). Polarization was associated with improved survival (whole cohort) with 214D4 (80.6 vs 47.8 months; HR 1.37 [95%CI 1.078–1.742], p=0.01 log rank test) and MA695 (95.8 vs 45.7 months; HR 1.48 [95%CI 1.159–1.878], p=0.002). Polarization with 214D4 was strongly associated with improved survival for adenocarcinoma (HR 1.92 [95%CI 1.385–2.668], p<0.0001) but not for non-adenocarcinoma. Similarly, polarization with MA695 conferred a survival advantage in adenocarcinoma (HR 1.68 [95%CI 1.225–2.311], p=0.001) but not non-adenocarcinoma cases. Data on MUC1 immunohistochemistry and circulating soluble MUC1 will be presented.

      214D4 MA695
      No staining 3.5% 6.2%
      Mean intensity
      - Cytoplasmic 1.8 1.7
      - Membranous 2.1 2.2
      Mean cells positive 3.9 3.6
      Mean composite score 10.1 9.6
      - Adenocarcinoma 13.1 12.0
      - Squamous cell 7.1 7.0
      - Large cell 7.2 7.7
      Depolarization 66.7% 62.4%

      Conclusion
      Over 93% were MUC1 immunohistochemistry positive, with higher scores in adenocarcinoma. Composite scores for the two antibodies were highly correlated and depolarization largely concordant. MUC1 expression was generally maintained in paired primary/nodal tumour and was similar across nodal stages and following neoadjuvant chemotherapy. Polarization was associated with improved survival in adenocarcinoma. Further investigation is needed to determine which antibodies best predict outcomes.