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    P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.06-053 - Clinical utility of circulating serum and plasma biomarkers for personalised radiotherapy treatment of non-small cell lung cancer (NSCLC) (ID 3098)

      09:30 - 16:30  |  Author(s): C. Dive

      • Abstract

      Background
      Personalised strategies that tailor radiotherapy (RT) dose and schedule according to clinical and molecular factors, novel drug-RT combinations and/or advanced RT techniques are needed to optimise outcomes from RT for NSCLC. Development of such approaches would benefit from objective measures to inform on survival, chance of response and/or toxicity. We evaluated 26 circulating proteins and cytokines implicated in angiogenesis, metastasis, apoptosis, hypoxia and inflammation for prognostic (survival), predictive (RT response/toxicity) and/or pharmacodynamic significance in the context of RT for stage I-III NSCLC.

      Methods
      NSCLC patients donated blood prior to, serially and on completion of RT treatment. Samples were analysed for cell death (M30, M65, CYFRA), hypoxia (osteopontin, CA-IX), angiogenesis (Ang2, FGFb, HGF, VEGFA, VEGFC, PDGF, IL8, PlGF, KGF, VEGFR1, VEGFR2, Ang1, Tie2), metastatic (EGF, E-Selectin, VCAM1) and inflammatory (IL1b, IL10, IL12, TNFa, IL6) cytokines using single- or multi-plex ELISAs (SearchLight multiplex Aushon BioSystems, Peviva, R&D Systems). Clinical data were collected for age, gender, performance and smoking status, ace27 co-morbidity score, weight loss, TNM stage, haemoglobin, treatment received, various lung function and RT treatment parameters, histology, treatment received, toxicity, response and survival. Standard statistical methods were used to explore for associations and prognostic significance (Stata version 10).

      Results
      Seventy-eight patients were enrolled from March 2010 to August 2011: 61% male; majority (44%) squamous histology; 82% PS 0 or 1; 72% ex-smoker; 9% stage I/II, 44% stage IIIA, 47% IIIB; median age 66 years (range 31-86), 42% age > 70; 20% weight loss of 5-10%, 11% weight loss >10%; 62% prior chemotherapy/sequential RT, 20% concurrent chemoradiotherapy, 18% radiotherapy alone. RT treatment doses administered ranged from 50-55Gy in 20 fractions to 60-66 Gy in 33 fractions. Significant associations (p<0.05) were observed for EGF levels with gender and age, for FGFb with co-morbidity score and for IL8, IL1B and KGF with smoking status. Positive correlations of biomarkers at baseline (p<0.001) were observed for TNFa with FGFb, IL1b, IL8, IL12; FGFb with IL1b, IL8, IL12 KGF; IL1b with IL8, IL12; IL8 with KGF, IL12; KGF with IL12. In the overall population, at day 8 during RT significant decreases were observed for Ang2, EGF, E Selectin, FGFb, HGF, VCAM1, VEGFC & VEGFR2. Post completion of RT Ang2, EGF, E Selectin, FGFb, HGF & VEGFC levels remained significantly lower than at baseline prior to RT, and in addition significant global decreases in Ang1 and VEGFA were observed. The median survival overall was 16.8 months at a median follow up of 12 months. In univariate analysis there were non-significant trends to worse survival for older patients, weight loss >5%, higher TNM stage, higher co-morbidity scores and current smokers. Better survival was observed for patients with higher baseline levels of IL1b (p = 0.005) and TNFa (p = 0.022).

      Conclusion
      Preliminary analysis demonstrates appreciable changes of various circulating biomarkers during RT and identifies interleukin-1 beta and tumor necrosis factor alpha as potential prognostic factors. Multivariate analyses and correlation of biomarkers with response and toxicity are ongoing and will be presented.

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    P1.09 - Poster Session 1 - Combined Modality (ID 212)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P1.09-011 - Phase I clinical trial assessing the MEK inhibitor selumetinib (AZD6244; ARRY-142886) with concomitant thoracic radiotherapy (RT) in patients with Stage III-IV non small cell lung cancer (NSCLC) (ID 1415)

      09:30 - 16:30  |  Author(s): C. Dive

      • Abstract

      Background
      The RAS/RAF/MEK/ERK signalling cascade has a central role in cancer proliferation and in modulating response to treatment. RAS mutations can confer a radiation-refractory phenotype and MAPK signaling can be stimulated by treatment with ionizing radiation in non-small cell lung cancer (NSCLC). Selumetinib (AZD6244; ARRY-142886) is an orally available inhibitor of MEK1/2 which was shown to enhance the effect of radiotherapy in preclinical studies. This effect was due to the ability of selumetinib to directly sensitize tumor cells to the cytotoxic effect of radiation and to modulate tumor vessel functionality by reducing VEGF-A expression. In a Phase II study, selumetinib given in combination with docetaxel showed promising activity in NSCLC patients with KRAS activating mutations. Aim To determine the recommended Phase II dose (RP2D) of selumetinib in combination with standard dose thoracic radiotherapy (RT) in NSCLC.

      Methods
      Selumetinib (Hyd-Sulfate capsule) was administered orally twice daily as a single agent for one week and then in combination with thoracic RT for 6 to 6.5 weeks (60 to 66 Gy in 30 to 33 fractions) in a single institution, open label Phase I trial using a modified Fibonacci sequence. Prior standard chemotherapy was permitted with a minimum interval between day8 of the last cycle of chemotherapy and day1 of administration of selumetinib of ≥ 2weeks. Other eligibility included: histologic or cytologic diagnosis of NSCLC, stage III not suitable for concurrent chemo-radiotherapy or stage IV with dominant thoracic symptoms, disease encompassable within a radical RT treatment volume, ECOG PS 0-1., no prior RT or investigational agents.

      Results
      A total of six consecutive patients with inoperable stage III (n=3) or stage IV (n=3) NSCLC were given selumetinib 50 mg twice daily (dose level 1) with concomitant thoracic RT (59.8-66 Gy in 30-33 fractions). All patients completed the combined treatment. Selumetinib delivery was > 80%. Four out of the six patients had dose interruptions of 2-3 days due to expected adverse events (AEs). Skin rash (6/6), diarrhoea (5/6) and fatigue (4/6) were the most common toxicities. Grade 3/4 AEs included hypertension (2/6), diarrhoea (2/6), skin rash (1/6), pulmonary embolism (1/6), fatigue (1/6) and pericardial effusion (1/6). Pulmonary embolism (grade 3) was considered not related to the study treatment. One patient experienced dose limiting toxicity (DLT) consisting of a combination of diarrhoea (grade 3) and fatigue (grade 3). Response to treatment was assessed 4 weeks post RT. Distant recurrence was seen in 1 patient; 3 patients had SD, 1 patient experienced a PR and 1 a CR. Median duration of response was 2 months (range 1-4 months).

      Conclusion
      Selumetinib given at 50 mg twice daily with concomitant radical thoracic RT was tolerated with no unexpected toxicities or enhancement of expected RT toxicities. Although the protocol-defined criteria to further escalate the selumetinib dose were met, because of the heterogeneous and small patient cohort and AEs encountered further evaluation of the 50 mg twice daily was preferred in order to obtained additional safety data. An expanded cohort of 15 patients having additional FLT-PET scans.

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    P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.06-016 - Expression and clinical significance of the monocarboxylate transporter MCT1 as a novel therapeutic target in Small-Cell-Lung-Cancer (SCLC) (ID 1473)

      09:30 - 16:30  |  Author(s): C. Dive

      • Abstract

      Background
      Small cell lung is a rapidly proliferating disease. Because of its high proliferation index, cancer cells rely on glycolysis, rather than oxidative phosphorylation, for ATP generation. Furthermore SCLC tumours often contain regions of hypoxia which switches tumour cells to a glycolytic phenotype. Increased glycolysis leads to increased lactate production which is effluxed from the cell in order to prevent reduced intracellular pH or inhibition of metabolic pathways via the monocarboxylate transporter (MCT) proteins MCT1 and MCT4. Inhibition of these transporters has been proposed as a method of selectively targeting highly glycolytic cancer cells. AZD3965 is an orally bioavailable MCT1 specific inhibitor currently under evaluation in phase I clinical trials. In an in vitro model of SCLC we have recently shown that in hypoxic conditions resistance to AZD3965 is associated with increased MCT4 levels (Polanski et al. submitted). Aim: To examined the expression and clinical significance of MCT1 and MCT4 in SCLC.

      Methods
      Archival SCLC biopsy specimens and clinical data from 78 patients presenting to the University Hospital of South Manchester and the Christie Hospital between 1994 and 2005 were analyzed. Nine representative cores from the tumour specimens were used to generate three TMAs. Sections were then stained for the markers MCT1, MCT4 and for the hypoxic marker CAIX. Staining was evaluated by two independent scorers and extent and intensity of the staining were estimated. A combined score for each case was calculated as the mean product of extent and intensity for all the cores in a case. The association between MCT1, MCT4 or CAIX and known prognostic factors was evaluated by Fisher’s exact test. Kaplan-Meier analysis was used to assess overall survival rates and Log Rank test was used for the comparison of the survival distributions.

      Results
      The proportion of tumours with any expression of MCT1, MCT4 or CAIX was 99%, 99%, 90% respectively. Higher levels of expression (intensity x extent) were observed for MCT1 (median=8.17) compared to MCT4 (median=2.21; p<0.001). A positive correlation was observed for CAIX expression and MCT4 expression. Tumours with CAIX expression, high MCT1 expression (>median) and low MCT4 expression ( 10 x 109/L, platelets < 150 x 109/L, Na < 135 mmol/L; LDH > 550 IU/L). However, high MCT1 expression score was associated with worse survival (14 vs. 32 months; p=0.019). Neither MCT4 nor CAIX expression was prognostic. Of the known prognostic factors assessed, extensive stage was significantly associated with shorter overall survival (6 vs. 27 months; p<0.001).

      Conclusion
      MCT1 and MCT4 are often expressed in SCLC and 21% cases in this series express a pattern associated with potential sensitivity to MCT1 inhibition. Higher expression of MCT1 is an adverse prognostic factor in univariate analysis reinforcing further evaluation of MCT1 inhibition in this disease.