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D. Ferry



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    MO12 - Prognostic and Predictive Biomarkers III (ID 96)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO12.02 - Association between Gene Expression Profiles and Clinical Outcome of Pemetrexed-Based Treatment in Patients with Advanced Non-Squamous Non-Small Cell Lung Cancer: Exploratory Results from a Phase II Study (ID 185)

      10:35 - 10:40  |  Author(s): D. Ferry

      • Abstract
      • Presentation
      • Slides

      Background
      We report exploratory gene expression profiling data from a prospective single-arm Phase-II-study in patients with non-squamous non-small cell lung cancer (nsNSCLC) treated with pemetrexed. Main results indicated a significant association of low thymidylate-synthase (TS) expression with longer PFS and OS [1].

      Methods
      Treatment-naive nsNSCLC patients (Stage IIIB/IV) received 4 cycles of first-line pemetrexed/cisplatin; non-progressing patients continued on pemetrexed maintenance [1]. Diagnostic tissue samples were used to assess TS expression (nucleus/cytoplasm) by immunohistochemistry (IHC, H scores), and to extract total mRNA for expression-array profiling (expression of 1,030 genes summarized from 60,000 transcripts). Cox proportional-hazard models were applied to explore the association between each gene and PFS/OS, mRNA gene expression was used both as continuous and binary (cutpoint: median) variable. Unadjusted p-values (significance level =0.01) and false discovery rates (FDR) were calculated. Genes significantly correlated with PFS/OS were further correlated with TS-protein expression (Spearman rank test). Finally, unsupervised clustering was applied to all samples with mRNA expression (n=51) for all 1,030 selected array genes and an overlapping 870-gene subset associated with adenocarcinoma (ADC, n=47) previously described [2].

      Results
      51/70 (72.9%) biopsies were evaluable; 9 of 1,030 genes were significantly associated with PFS/OS (unadjusted p<0.01). 8/9 genes were negatively correlated with nuclear TS expression; the test was statistically significant for 5/8 genes (unadjusted p<0.01, Table 1). None of these genes has a known relationship to folate metabolism. Cluster analysis of all 51 samples based on 1,030 genes revealed no clear trend regarding PFS/OS. Cluster-analysis of 47 ADC samples identified 3 groups (n=21, 11 and 15 patients, respectively) with median (95%CI) PFS and OS of 8.1 (6.9, not estimable [NE]) and 20.3 (17.5, N.E) months; 2.4 (1.2, NE) and 4.3 (1.4, NE) months; and 4.4 (1.2, NE) and 8.3 (3.9, NE) months, respectively. Figure 1

      Conclusion
      This exploratory analysis provides insights on key genes potentially linked to low TS expression. Nine genes were significantly associated with PFS/OS; however such association cannot be differentiated as prognostic or predictive since this study is single arm. Further research would be needed to understand the relationship of these markers with clinical outcomes. [1] Nicolson et al, J Thorac Oncol 2013, May 29 [Epub]. [2] Wilkerson et al, PLoS One 2012;7(5):e36530.

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    P2.05 - Poster Session 2 - Preclinical Models of Therapeutics/Imaging (ID 158)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.05-022 - Therapeutic potential of the FGFR Tyrosine Kinase Inhibitor, AZD4547 in Squamous non-small cell lung cancer (ID 3218)

      09:30 - 09:30  |  Author(s): D. Ferry

      • Abstract

      Background
      Background: As a result of the recent deep molecular profiling of NSCLC samples, FGF receptor inhibition has emerged as a promising strategy for targeting a sub-set of squamous NSCLC (Sq NSCLC) tumours that carry FGFR gene amplifications, mutations and fusions. AZD4547 is a potent, orally available and selective inhibitor of FGFR 1, 2 and 3 and is currently in phase II clinical development.

      Methods
      not applicable

      Results
      Results: In pre-clinical patient derived models of FGFR1 amplified Sq NSCLC, AZD4547 is able to induce dose dependent tumour growth inhibition and tumour regression and this is correlated to FGFR1 protein expression and inhibition of signalling pathways downstream of FGFR1. Since the FGFR2 mutations described in Sq NSCLC do not present as clear codon hot-spots we also investigated a sub-set of the FGFR2 mutations using inducible expression in non-transformed cells. We found these mutations to be constitutively active and capable of inducing 3D colony formation in non-transformed cells. Both FGFR signalling and 3D colony growth were inhibited potently by AZD4547 treatment. We have developed a number of biomarker assays that enable both patient selection and exploratory analysis of patient samples. We found that FGFR1 gene amplified samples are enriched for those expressing both FGFR1 mRNA and protein. AZD4547 is currently being tested as a monotherapy in Sq NSCLC patients whose tumours carry FGFR1 amplification and we will describe preliminary observations from this trial including a comprehensive molecular profile of the tumour from a patient who experienced a durable partial response following AZD4547 treatment.

      Conclusion
      Conclusion: In view of the strong and emerging platform of evidence that implicates dis-regulated FGFR signalling in Sq NSCLC and the early evidence of clinical activity, FGFR inhibition warrants continued clinical investigation in patients whose tumours carry FGFR genetic lesions including amplification, mutation and gene fusions.