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B. Dougherty



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    MO18 - NSCLC - Targeted Therapies IV (ID 116)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO18.12 - Impact of <em>KRAS</em> codon sub-types in a Phase II second-line trial in <em>KRAS</em>-mutant advanced non-small cell lung cancer (NSCLC) of selumetinib plus docetaxel versus docetaxel alone (ID 3331)

      17:20 - 17:25  |  Author(s): B. Dougherty

      • Abstract
      • Presentation
      • Slides

      Background
      Phase II data from patients with KRAS mutation-positive NSCLC, selumetinib (AZD6244, ARRY-142886) plus docetaxel showed promising efficacy versus placebo plus docetaxel alone (Jänne et al. Lancet Oncol 2013;14:38–47). Median OS was 9.4 months (95% CI 6.8–13.6) in the selumetinib group and 5.2 months (95% CI 3.8–non-calculable) in the placebo group (HR for death 0∙80, 80% CI 0.56–1.14; one-sided p=0.21). Median PFS was 5.3 months (95% CI 4.6–6.4) and 2.1 months (95% CI 1.4–3.7), respectively (HR for progression 0∙58, 80% CI 0.42–0.79; one-sided p=0.014). 37% of patients in the selumetinib group and 0% in the placebo group had an objective response (two-sided p<0.0001). The KRAS mutation codon subtype might impact on prognosis and/or response to therapy. The BATTLE trial suggested that G12V or C KRAS mutations confer relatively poorer outcome within the KRAS mutant NSCLC sub-type (Ihle et al. J Natl Cancer Inst 2012;104:228–39). In cell lines carrying these codons, Akt phosphorylation but not ERK phosphorylation was low compared with other codons, suggesting these codons might confer greater dependence upon MEK/ERK signaling. We sought to understand if any codons or combinations of codons selected for striking treatment effects either between or within treatment groups in the Phase II study.

      Methods
      Post-hoc analysis explored the hypotheses that patients whose tumours carried G12C or G12V KRAS mutations would have a worse prognosis and that these patients would have a better outcome with the addition of selumetinib. Clinical benefit was measured by PFS, OS and ORR.

      Results
      G12V or G12C mutations were present in 57% of patients and whilst not reaching statistical significance, trends for PFS, OS and ORR support the hypothesis (see table, PFS). Patients with G12V mutations responded better to selumetinib plus docetaxel than other patients as measured by change in tumour size at week 6 (G12V=-62%, G12C=-8%, G12D=+3%, reduction across all codons=-18%; two sided p=0.007). It is therefore possible that trends supporting the primary hypothesis were driven by effects in the small number of G12V codons (n=9). Table. Summary of analysis of progression-free survival (PFS): MITT by mutation subgroup

      Subgroup Selumetinib + docetaxel, n (number of PFS events) Docetaxel, n (number of PFS events) Selumetinib + docetaxel vs docetaxel, PFS HR (80% CI)
      G12C or G12V 24 (18) 23 (21) 0.48 (0.31–0.74)
      Other 19 (17) 17 (15) 0.72 (0.44–1.16)
      Overall 43 (35) 40 (36) 0.58 (0.42–0.79)

      Conclusion
      Any impacts of codon sub-type on the treatment effect in this trial were not sufficiently significant to be detected in this small Phase II trial of 87 patients, but the trends observed in this retrospective subgroup analysis warrant monitoring of the impact of specific codons or groups of codons in future clinical trials.

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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): B. Dougherty

      • 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.

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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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      P3.06-048 - Progress with candidate predictive gene expression signatures for MEK inhibitors in non-small cell lung cancer (NSCLC) (ID 3243)

      09:30 - 09:30  |  Author(s): B. Dougherty

      • Abstract

      Background
      Several MEK inhibitors are in late-stage clinical trials in mutant BRAF melanoma, where novel patient selection biomarkers are not major impediments to clinical development. In non-mutant BRAF disease, there is a presumption that the optimum patient population may also be selected according to gain of function mutations in key genes, resulting in pathway activation. In the present work we have taken a different approach, based on two publications (Dry et al. Cancer Res 2010;70:2264–2273; Loboda et al. BMC Med Genomics 2010;3:26), attempting to define NSCLC patient populations for MEK inhibitors based on gene expression signature measurements of pathway output.

      Methods
      In silico analyses were performed to test the sensitivity of candidate transcriptome signatures for detecting KRAS mutations in NSCLC. NanoString assays were subsequently developed for the signatures and used in: i) cell line based cross-platform comparisons with Affymetrix technology ii) formalin-fixed paraffin-embedded (FFPE) NSCLC samples to determine measurable genes, variation in gene expression and the limit of quantification for the signatures iii) matched tumour samples from the same patients iv) a blinded cohort of 50 NSCLC samples with known KRAS mutation status.

      Results
      In silico data confirmed the published correlations of transcriptome signatures with KRAS status in NSCLC samples. NanoString data appear to be robust, demonstrating a strong correlation with the Affymetrix platform and reproducible signature scores across separate samples from the same tumour. Reproducibility is maintained across dilutions of the same isolated RNA sample and supports previous observations regarding the sensitivity of these signatures for detecting KRAS mutations in clinical samples. In addition, we showed that high expression of these signatures is not restricted to samples with KRAS mutation, confirming previous observations that RAS or MEK activation is not exclusively linked to KRAS mutation.

      Conclusion
      We have developed a clinically relevant, robust assay platform, determined biological variation within tumours and confirmed the link to KRAS mutation status in a cohort of blinded NSCLC samples. The NanoString assays provide a means to test the prognostic and predictive capabilities of the gene signatures in the samples routinely provided in clinical practice. We intend to test the concordance of the gene signature indices between primary and metastatic tumours from the same patients, the prognostic relevance of the signatures in first- and second-line NSCLC patients treated with standards of care and wherever possible in future clinical trials of MEK inhibitors.