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F. Blackhall



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    MO10 - Molecular Pathology II (ID 127)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      MO10.07 - ALK immunohistochemistry and fluorescence in-situ hybridization in Lung adenocarcinomas from the ETOP Lungscape tumour cohort (ID 2267)

      16:15 - 17:45  |  Author(s): F. Blackhall

      • Abstract
      • Presentation
      • Slides

      Background
      The European Thoracic Oncology Platform LungScape database contains 2614 cases of primary resected lung carcinoma from 16 centres with patient demographics, pathological tumour data and detailed clinical follow-up. A total of 1281 cases of adenocarcinoma with >2 years clinical follow-up were selected for analysis of ALK status by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Test positive cases were matched, in order of importance at ratio 1:2, by stage, gender, smoking status, study centre, year of surgery and age with test negative cases -both for IHC and for FISH testing.

      Methods
      Testing was performed in all centres using the same protocol (IHC: Novocastra 5A4 clone antibody at 1:10 dilution, Novolink detection system. FISH: Abbott Vysis ALK break-apart probe). Each centre passed an external QA test using unknown cases in a tissue microarray before conducting the LungScape tumour testing. IHC was scored according to three intensity scores (1+, 2+, 3+) using ‘objective’ methodology previously described [1]. Maximum staining intensity was recorded. Any IHC staining was defined as IHC positive result. FISH preparations were assessed according to the Vysis protocol on all 82 IHCpositive cases plus their 164 IHCnegative matches.

      Results

      IHC cases, n=1281 FISH positive(264 tested)
      IHC negative 1199 (93.6%) 0 (0.0% of 164 controls) FISH specificity: 100%
      IHC 1+ 43 (3.35%) 2 (4.6% of IHC 1+)
      IHC 2+ 16 (1.25%) 6 (37.5% of IHC 2+)
      IHC 3+ 23 (1.8%) 20 (87% of IHC 3+)
      IHC any positive 82 (6.4%) 28 (34.1% of IHC+) FISH sensitivity: 34.1%
      FISH sensitivity was 87% for IHC 3+. IHCpositive/FISHnegative cases (n=54) were mostly IHC 1+ (75.9%), sometimes IHC 2+ (18.5%) and rarely IHC 3+ (5.5%). The frequency of never smokers was higher in the ALK IHCpositive group (29.3%) versus IHCnegative group (18.3%) {p=0.011}. Age, gender and tumour stage did not differ between IHC groups. The hazard of an event for IHCpositive cases decreases by 32% in relapse-free survival {RFS; p=0.03} and by 38% in either time-to-relapse {TTR; p=0.02} or overall survival {OS; p=0.016}. Multivariate models -adjusted for patient and tumour characteristics- indicated that IHC-ALK was a significant predictor for all three time-to-event outcomes (RFS, TTR, OS). In stratified Cox analysis, significantly higher OS was retained in the IHCpositive (HR=0.59, p=0.04) and FISHpositive (HR=0.34, p=0.03) cases in the matched cohorts, while conditional logistic regression yielded non-significant associations with 3-year survival status.

      Conclusion
      In this large cohort of surgically resected primary lung adenocarcinoma: ALK IHC positivity was 6.4%. IHC 3+ staining (prevalence 1.8%) showed 87% probability of ALK FISH positivity ALK IHC positivity was higher in never smokers and related to better clinical outcome ALK testing can be reliably implemented across multiple laboratories {1} Ruschoff et al. Virchows Arch. 2010;457(299-307).

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    MO13 - SCLC I (ID 118)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO13.02 - Age as a prognostic factor in small cell lung cancer. A pooled analysis of randomized clinical trials from the Manchester lung cancer group (MLCG) and the UK Medical Research Council Clinical Trials Unit (MRC CTU). (ID 2270)

      10:30 - 12:00  |  Author(s): F. Blackhall

      • Abstract
      • Presentation
      • Slides

      Background
      About 40% of all cases of small cell lung cancer (SCLC) occur in the over 70 year age group (70+), and 10% in patients aged over 80 years. A SEER database reports decreasing SCLC 5-year survival with age (7.1%, 3.9% and 2.2% in the <70, 70-79 and 80+ age groups, respectively). However age has been inconsistently reported as a prognostic factor in SCLC trials. Recently a series of randomized trials of chemotherapy (CT) in SCLC were pooled to analyze the prognostic impact of patient sex (Wheatley-Price et al, Annals of Oncology 2009). We used the same dataset to investigate the impact of age.

      Methods
      Five randomized phase II and III CT trials, performed by the MLCG and MRC CTU between 1993 and 2005, were pooled for analysis (one study from the previous analysis was excluded as it did not contain elderly patients). One trial investigated a dose-dense approach and 4 trials compared CT regimens. The primary endpoints were overall survival (OS) in limited stage (LS) and extensive stage (ES) and the rates of haematological and non-haematological toxicity.

      Results
      In total 1439 patients were included, of whom 45% were female and 36% had ES disease. The median age was 63 years (range 30-88), and 343 (24%) were 70+, and only 33 (2%) were 80+. Anthracycline-based CT was given in 61%, versus platinum-based CT in 38% of patients. More patients in the younger group had a good performance status (ECOG 0-1, Karnofsky 80-100); 65% versus 39% (p=0.0007). Baseline hyponatremia was present in 35% and did not differ by age group. Overall, median OS was significantly longer in younger patients in univariate analysis (9.3 months versus 7.4 months; HR 0.79, 95% CI 0.66-0.95, p=0.01). By disease stage, median OS in LS patients was significantly longer in younger patients (HR 0.88, 95% CI 0.79-0.99, p=0.04), and a similar effect was observed in ES (HR 0.75, 95% CI 0.55-1.01, p=0.06). However in multivariate analysis (age, stage, sex, hyponatremia, anemia), factors significantly associated with longer survival were LS, female sex, good PS and absence of hyponatremia, but younger age was no longer prognostic (HR 0.96, 95% CI 0.86-1.08, p=0.52). The elderly were more likely to experience grade 3 or 4 leucopenia (52% versus 40%, p=0.0035), neutropenia (36% versus 31%, p=0.045) and thrombocytopenia (34% versus 22%, p=0.0003), but less likely to experience grade 3 or 4 emesis (8% versus 14%, p=0.022) or mucositis (5% versus 11%, p=0.021). There were no differences in infection rates or blood transfusion rates, although the elderly required more platelet transfusions (p<0.0001). The dose intensity (total number of CT cycles delivered divided by the planned number of cycles) was higher in the younger group (p<0.0001).

      Conclusion
      In a large pooled analysis of CT trials in SCLC, age was not a prognostic factor for survival. However the elderly experienced higher rates of grade 3 and 4 hematological toxicity. Further analysis is ongoing.

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    O11 - Symptom Management (ID 137)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Supportive Care
    • Presentations: 2
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      O11.02 - The "CLiC" Cough in Lung Cancer Study: The Characterisation of Cough in Lung Cancer (ID 2986)

      16:15 - 17:45  |  Author(s): F. Blackhall

      • Abstract
      • Presentation
      • Slides

      Background
      The “CLiC” Study seeks to characterise cough and identify its predictors using subjective and objective cough assessment tools, including the recently validated Manchester Cough in Lung Cancer Scale (MCLCS). Results will enable the identification of robust endpoints and therapeutic targets for novel antitussive interventional trials.

      Methods
      Patients with lung cancer (LC) and complaining of cough were recruited irrespective of stage and treatment, from two cancer centres. Demographic and clinical data were collected. Patients completed the MCLCS, Cough Severity Diary (CSD), cough severity Visual Analogue Scale (VAS) and the Brief Reflux Inventory (BRI, a validated 5-item questionnaire assessing gastro-oesophageal reflux disease (GORD)). The oncology specific European Organization for Research and Treatment of Cancer Quality of Life (QoL) Questionnaire (EORTC QLQ) C30 with the module (LC13), (including item 31: "In the past week, how often did you cough?") was also completed. Cough was graded according to Common Toxicity Criteria for Adverse Events (CTCAEv4.0). A sample size of 178 patients was required for analysis of 160 (based on Peduzzi J Clin Epidem 1996) for 10 participants per correlate per outcome in binary logistic regression, assuming a 10% attrition rate, the prevalence of severe cough to be 50% and 8 cough predictors.

      Results
      We recruited 179 patients (Oct'11-Nov'12). The median age was 65 yrs (range 25-83 years), with 53% patients male. The majority (79%) had non small cell lung cancer (NSCLC) and advanced stage disease (>IIIA 60%). In total, 36% were receiving cancer therapy at entry. Overall, 60% felt their cough warranted treatment. Having ensured validity of the cough assessment tools, the mean cough severity score (VAS) (n=171) was 43.4mm (SD 29.6). The mean cough-specific QoL score (MCLCS) was 25.3 (SD 8.8, with a range 1-50, high scores representing worse QoL).

      Table showing association between cough predictors and cough severity (VAS) and cough specific QoL (MCLCS) scores on univariate analysis[*]
      Cough Severity (VAS) Cough Specific QoL (MCLCS) Comment
      Age (≤70yrs vs >70yrs) p=0.365# p=0.834#
      Gender p=0.048# p=0.171# women worse cough severity
      Smoking Status (current, ex, never) p=0.191## p=0.356##
      Performance Status (WHO PS 0-3) p<0.0001## p<0.0001## poorer PS worse cough severity poorer PS worse cough related QoL
      Histology (NSCLC vs SCLC) p=0.348# p=0.274#
      Stage (early vs advanced) p=0.358# p=0.301#
      Tumour Location (central vs peripheral) p=0.486# p=0.040# central tumours poorer cough related QoL
      COPD (Chronic Obstructive Pulmonary Disease) (self-reported) p=0.578# p=0.128#
      LRTI (Lower Respiratory Tract Infection) (self-reported) p=0.022# p=0.044# LRTI worse cough severity LRTI worse cough related QoL
      Asthma (self-reported) p=0.021# p=0.054# asthma worse cough severity
      GORD (BRI questionnaire) p<0.0001# p<0.0001# GORD worse cough severity GORD worse cough related QoL
      Nausea (EORTC QLQ C30) p=0.004## p=0.017## Increased nausea worse cough severity. Increased nausea worse cough related QoL
      Oral Steroids p=0.434# p=0.017# On steroids worse cough related QoL
      Over the Counter Antitussives p=0.011# p=0.067# On antitussives worse cough severity
      Opiates p=0.497# p=0.018# On opiates worse cough related QoL
      *Not all analysed cough predictors shown # Mann-Whitney-U Test ## Kruskal-Wallis Test

      Conclusion
      This is the largest single study to use validated cough-specific assessment tools in LC to characterise and assess potential influences on cough. LC patients have a severe cough, with comparable VAS scores to those of patients presenting to specialist chronic cough clinics. New antitussive therapies are needed. Key predictors of cough severity and reduced cough-specific QoL are performance status (PS), nausea and GORD. Preclinical research suggests that the neurokinin-1 pathway may mediate the vagal cough reflex pathway. Our results further support this hypothesis and imply that the neurokinin-1 pathway may be a relevant therapeutic target. The association with GORD may be explained by the shared vagal innervation of the airway and upper gastrointestinal tract.

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      O11.03 - The "CLiC" Cough in Lung Cancer Study: The Validation of Objective and Subjective Cough Assessment Tools in Lung Cancer Patients (ID 3006)

      16:15 - 17:45  |  Author(s): F. Blackhall

      • Abstract

      Background
      Cough is a common lung cancer (LC) symptom, yet effective therapies are lacking. The development and testing of novel therapies relies upon appropriate tools for the assessment of cough. CLiC is the first study to evaluate two new tools 1) objective ambulatory cough monitoring (ACM) from acoustic recordings (VitaloJAK™) and 2) the Manchester Cough in Lung Cancer Scale (MCLCS) quality of life (QoL) questionnaire. These provide complementary assessments of cough frequency and its impact upon the patient.

      Methods
      Patients with LC and complaining of cough were recruited, irrespective of stage or treatment, from two cancer centres. Demographic and clinical data were collected. All patients completed the MCLCS, Cough Severity Diary (CSD) and cough severity Visual Analogue Scale (VAS). The European Organization for Research and Treatment of Cancer QoL Questionnaire (EORTC QLQ) C30 with the module (LC13), (including item 31: "In the past week, how often did you cough?") was also completed. The Common Toxicity Criteria for Adverse Events (CTCAEv4.0) was used to grade cough. A subgroup underwent ACM and MCLCS on Days 0&60.

      Results
      We recruited 179 patients (Oct'11-Nov'12): median age 65yrs (range 25-83 years), 53% male. Majority (79%) had non small cell lung cancer, 60% advanced stage (>IIIA), 36% were on cancer therapy.

      Table showing correlations between subjective cough assessment tools
      EORTC QLQ C30 cough item 31 CTCAE Cough Grading MCLCS Manchester Cough LC Scale CSD Cough Severity Diary
      VAS Cough Severity 0.54**§ n=171 0.50**§ n=170 0.67**§ n=163 0.70**¥ n=84
      EORTC QLQC-30 cough item Q31 0.45**§ n=173 0.57**§ n=165 0.52**§ n=85)
      CTCAE Cough Grading 0.56**§ n=164 0.59**§ n=85
      MCLCS Manchester Cough LC Scale 0.76**¥ n=82
      ** p<0.0001 ¥high correlation §moderate correlation
      Table showing correlations between objective ACM and subjective cough tools
      VAS Cough Severity MCLCS Manchester Cough LC Scale Log Cough/hr Asleep Log Cough/hr Awake Log Cough/hr 24-hour
      VAS Cough Severity 0.73** n=37 0.33* n=37 0.61** n=37 0.57** n=37
      MCLCS Manchester Cough LC Scale 0.24 n=35 0.51* n=35 0.44* n=35
      Log Cough/hr Asleep 0.52** n=35 0.62** n=35
      Log Cough/hr Awake 0.97** n=37
      ** p<0.0001 * p<0.05
      Intra-class correlations demonstrated good repeatability over time between Days 0&60 for cough frequency (24hour: r=0.77, p<0.0001, awake: r=0.79, p<0.0001, sleep: r=0.66, p=0.004) and MCLCS: r=067,p<0.001 .The median cough scores/hour were 14.1(24hour: range 0.7-156), 18.5 (awake: range 1-233) and 6.0 (asleep: range 0-110).

      Conclusion
      We have demonstrated moderate to strong correlations between established measures of cough and two novel assessment tools, suggesting the validity of MCLCS and ACM. Their good repeatability suggests they have excellent potential for the assessment of novel treatments in future intervention studies for LC-related cough. In contrast, standard oncology tools are blunt and poorly discriminate cough.

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    O16 - NSCLC - Targeted Therapies III (ID 115)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O16.05 - Efficacy, safety, and patient-reported outcomes (PROs) with crizotinib versus chemotherapy in Asian patients in a phase III study of previously treated advanced <em>ALK</em>-positive non-small cell lung cancer (NSCLC) (ID 2818)

      10:30 - 12:00  |  Author(s): F. Blackhall

      • Abstract
      • Presentation
      • Slides

      Background
      Crizotinib is a potent selective ATP-competitive ALK inhibitor demonstrating a high ORR in patients with advanced ALK-positive NSCLC. The main objective of the present post hoc analyses was to compare the impact of crizotinib on efficacy, safety, and PROs with that of standard second-line chemotherapy in a subgroup of patients of Asian ethnicity from the ongoing phase III study PROFILE 1007.

      Methods
      Patients with stage IIIB/IV ALK-positive NSCLC who had received one prior platinum-based regimen were randomized to open-label crizotinib (250 mg PO BID) or chemotherapy (pemetrexed 500 mg/m[2] or docetaxel 75 mg/m[2], IV q3w). In these subgroup analyses, PFS and ORR based on independent radiologic review, OS, safety, and PROs were evaluated. PROs were assessed at baseline, on day 1 of each cycle, and at end of treatment using the validated cancer-specific questionnaire EORTC QLQ-C30 and its LC module QLQ-LC13. Time to deterioration (TTD) was defined as the time from randomization to the earliest time with a ≥10-point increase from baseline (worsening) in pain in chest, dyspnea, or cough. Repeated measures mixed-effects analyses were performed to compare change from baseline scores between the treatment arms.

      Results
      Of 347 patients randomized, 45% were of Asian ethnicity (crizotinib, n=79; chemotherapy, n=78 [pemetrexed, 50; docetaxel, 27; no treatment, 1]). At data cutoff (March 2012), 52 Asian patients (crizotinib, 41; chemotherapy, 11) were continuing on treatment. PFS was significantly longer with crizotinib than with chemotherapy (median 8.1 vs. 2.8 months; HR, 0.53; P=0003). The ORR on crizotinib (75%) was significantly higher than on chemotherapy (22%; P<0.0001). In an interim analysis, median OS had not yet been reached in the crizotinib arm and was 22.8 months in the chemotherapy arm (HR, 0.89; P=0.347, noting that in the overall study population, only 40% of planned events had occurred and 64% of patients in the chemotherapy arm subsequently received crizotinib in another study). The most common all-causality AEs with crizotinib were diarrhea (70%), vision disorder (68%), and nausea (66%) and with chemotherapy were decreased appetite (40%), nausea (39%), and fatigue (35%). Crizotinib treatment was associated with a significantly longer TTD in LC symptoms compared with chemotherapy (median 4.2 vs. 1.6 months; HR, 0.66; 95% CI, 0.44−0.98; P=0.037). A significantly greater improvement from baseline was observed with crizotinib for global QOL (P<0.05), cough (P<0.001), dyspnea (P<0.001), pain in arm or shoulder (P<0.001), pain in chest (P<0.001), pain in other parts (P<0.05), fatigue (P<0.05), insomnia (P<0.05), and pain (P<0.001). A significantly greater improvement was observed with crizotinib compared with chemotherapy for emotional functioning (P<0.05), physical functioning (P<0.05), hair loss (P<0.001), and sore mouth (P<0.05). A significantly greater deterioration was observed in the crizotinib arm for constipation (P<0.05) and diarrhea (P<0.001) compared with chemotherapy.

      Conclusion
      Consistent with previously reported results in the overall study population, crizotinib treatment showed significantly greater improvement in PFS, ORR, patient-reported LC symptoms, and global QOL compared with chemotherapy in a subgroup of patients of Asian ethnicity with previously treated advanced ALK-positive NSCLC, confirming the utility of crizotinib in this patient population.

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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): F. Blackhall

      • 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): F. Blackhall

      • 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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    P1.18 - Poster Session 1 - Pathology (ID 175)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P1.18-015 - Screening for ALK-rearranged NSCLC in selected cases using immunohistochemistry followed by FISH and RT-PCR testing of tumours with increased ALK protein expression in a routine clinical diagnostic setting (ID 2838)

      09:30 - 16:30  |  Author(s): F. Blackhall

      • Abstract

      Background
      The diagnosis of anaplastic lymphoma kinase (ALK) gene rearrangement in non small cell lung cancer (NSCLC) has acquired therapeutic significance, subsequent to the established response of ALK-rearranged tumours to crizotinib therapy. General recommendations on NSCLC ALK testing will be published later this year by the National Institute for Health and Care Excellence. In advance of this, patients were prospectively screened for ALK-rearranged NSCLC at the Christie Hospital, Manchester, U.K. from May 2012 to May 2013.

      Methods
      Pulmonary adenocarcinomas were selected for testing by ALK immunohistochemistry (IHC) based the presence of any of the following clinicopathologic features associated with ALK rearrangement; never smoker, light ex-smoker, age less than 50 years, signet ring/goblet cell morphology. IHC was performed with the 5A4 clone (Novocastra) according to the European Thoracic Oncology Platform protocol. All IHC-positive cases (intensity score 1+, 2+ or 3+) were tested for ALK rearrangement by both fluorescent in situ hybridisation (FISH) and reverse transcriptase polymerase chain reaction (RT-PCR). FISH analysis using the Abbott Molecular LSI ALK Dual Colour Break Apart Probe required a minimum of 15% of (at least 100) tumour cells with gene rearrangement for a positive diagnosis. RT-PCR testing was employed to detect EML4-ALK fusion transcripts using a series of primers located in EML4 exons 1 to 22, a reverse primer located in ALK exon 20 (Sanders et al., 2011;204:45-52) and sample RNA extracted from a single 40 µM section. Amplified products were Sanger sequenced to establish the fusion variant present.

      Results
      Ninety-one specimens were screened by ALK IHC and of these, 13 demonstrated positive staining. FISH and RT-PCR results were concordant (with the exception of one RT-PCR negative case which failed FISH testing) and 9 cases were diagnosed with ALK-rearrangement (9.9%). The majority of the EML4-ALK fusion transcripts were of variant 1 type (77.8%), with just two subtypes diagnosed as variant 3 (22.2%). The median time from referral for FISH/RT-PCR to the issue of reports was 5 working days.

      Table 1. Summary of clinicopathological features, IHC, FISH and RT-PCR results of cases positive for ALK protein staining on IHC. (ACA =adenocarcinoma)
      Case Age Sex Sample type Histology IHC H-score FISH % + RT-PCR Final ALK diagnosis EGFR mutation
      1 84 F Node excision ACA, signet ring cells 170 55 E13;A20 variant 1 + -
      2 59 M Lung resection ACA, solid with hepatoid cells 190 77 E13;A20 variant 1 + -
      3 56 M Pleural effusion ACA, hepatoid cells 240 64 E13;A20 variant 1 + -
      4 46 M Node biopsy Adenosquamous 300 64 E6;A20 variant 3 + -
      5 64 M Pleural biopsy ACA, solid with hepatoid cells 300 48 E13;A20 variant 1 + -
      6 60 F Node aspirate ACA, signet ring and hepatoid cells 300 66 E13;A20 variant 1 + -
      7 41 F Node biopsy ACA, hepatoid cells 300 71 E13;A20 variant 1 + -
      8 40 M Pleural biopsy ACA, solid with hepatoid cells 300 58 E6;A20 variant 3 + -
      9 65 F Node aspirate ACA, signet ring and hepatoid cells 300 45 E13;A20 variant 1 + -
      10 54 M Pleural effusion ACA 20 5 Negative - -
      11 52 F Pericardial effusion ACA 10 Failed Negative - -
      12 49 F Pleural fluid ACA 35 0 Negative - +
      13 70 F Lung resection ACA, solid with hepatoid cells 54 9 Negative - Unknown

      Conclusion
      In keeping with reported findings ALK-rearranged NSCLC was found in 9.9% of selected adenocarcinomas. Although FISH/RT-PCR was not carried out on IHC-negative cases in this group, the application of IHC as a screening method appears to be a cost-effective means of highlighting ALK-rearranged tumours. RT-PCR testing of formalin-fixed, paraffin-embedded tissue is feasible in the clinical diagnostic setting, and may have an important role in the determination of specific variants detected by IHC.

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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): F. Blackhall

      • 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.

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    P2.09 - Poster Session 2 - Combined Modality (ID 213)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P2.09-008 - Concurrent chemoradiotherapy (cCTRT) for locally advanced Non Small Cell Lung Cancer (NSCLC) followed by consolidation Pemetrexed: a phase II study (ID 1545)

      09:30 - 16:30  |  Author(s): F. Blackhall

      • Abstract

      Background
      cCTRT is the current standard treatment for good Performance Status (PS) unresectable locally advanced NSCLC. A phase III study demonstrated that Docetaxel consolidation does not improve overall survival (OS) after cCTRT (Hanna. JCO 2008). The role of consolidation chemotherapy after cCTRT is still investigational and our study was set up to evaluate the role of pemetrexed in this setting. A less toxic consolidation chemotherapy may enable a higher proportion of patients to comply to planned treatment which may improve outcome.

      Methods
      This was a single-institution prospective phase II study. Treatment comprised cisplatin (50 mg/m[2] days 1, 8, 29, 36), etoposide (50 mg/m[2] days 1-5 and 29-33) and concurrent thoracic radiotherapy starting on day 1 chemotherapy (66 Gy in 33 daily fractions; 3D conformal radiotherapy or IMRT) followed by consolidation pemetrexed (500 mg/m[2] on days 71, 92 and 133). The primary endpoint was 1 year OS. Secondary endpoints were progression-free survival (PFS), 2 yr OS, acute/late toxicity (CTCAE v3.0), compliance to treatment.

      Results
      35 patients were recruited between March 2008 and October 2010. Median age was 61 years (range 42-76). M:F ratio was 23(66%):12(34%). ECOG PS was 0:1 11(31%):24(69%). Histology: squamous 21(60%), adenocarcinoma 8(23%), undifferentiated 4(11%), other 2(6%). Stage: IIB 1(3%), IIIA 19(54%), IIIB 15(43%). All 35(100%) had PETCT staging. All 35 patients received concurrent chemotherapy (dose reduction in 3 patients) and 32 (91%) received the planned 66Gy (range 56-66 Gy). The number of patients who completed pemetrexed were: cycle 1=25 (71%), cycle 2=22 (63%), cycle 3=16 (46%). Radiation parameters: Gross Tumour Volume (GTV) was median 60.2 cm[3] (range 11.4-274.4 cm[3]), V~20Gy ~median 30.4% (range 10.5-35.3%), During the concurrent phase, grade 3/4 toxicity was noted for: neutropenia 17(49%) anaemia 1(3%), thrombocytopenia 1(3%), infection 8(23%), fatigue 6(17%), nausea±vomiting 4(11%), mucositis 3(9%), anorexia 3(9%). During the pemetrexed consolidation phase, the only grade 3/4 toxicities were: infection 5(20%), anaemia 3(12%), neutropenia 2(8%) and fatigue 2(8%). Acute radiotherapy toxicity (<3months): oesophagitis grade 3/4 10(29%) and late toxicity (>3months): pneumonitis grade 3/4 2(7%), oesophageal stricture 2 (7%), pulmonary fibrosis 1(3%). Median follow up was 25months. Median OS was 34months, with 1yr OS 77% (95% CI 60-88%), and 2yr OS 61% (95% CI 37-72%). Median PFS was 22months, with 1yr PFS 62% (95% CI 43-76%) and 2yr 49% (95% CI 31-65%). Of the 14 deaths, causes were, 1 suicide during radiotherapy, 2 treatment-related deaths (1 grade 5 pneumonitis and 1 grade 5 haemoptysis) and 13 due to lung cancer.

      Conclusion
      In an unselected locally advanced NSCLC population, staged with PETCT a median survival of 34 months can be achieved. The study reinforces the challenge of delivering consolidation chemotherapy and suggests that improved staging contributes to improved outcomes. Although there was failure to deliver all planned cycles of consolidation pemetrexed after cCTRT in 54% of patients, these are encouraging results that warrant further investigation.

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    P2.18 - Poster Session 2 - Pathology (ID 176)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P2.18-017 - Multiplexed-based mutation profiling of non small cell lung cancer small biopsy samples using the Sequenom LungCarta™ Panel and MassARRAY® System (ID 2856)

      09:30 - 16:30  |  Author(s): F. Blackhall

      • Abstract

      Background
      The advent of specific therapies for non small cell lung cancer (NSCLC) based on individual tumour genotype has impacted the development of high throughput genomic profiling strategies. A single platform designed for the synchronous screening of multiple mutations across different genes can potentially enable molecular profiling in samples of limited tumour tissue such as small biopsy samples.

      Methods
      Haematoxylin and eosin-stained sections and accompanying reports were reviewed from patients diagnosed with NSCLC (2008 to 2012) in Greater Manchester, U.K. Samples with less than 20% tumour cell content (TCC) were macrodissected to increase the final TCC. In each case DNA was extracted manually from 1 5µM curl/section using the cobas® DNA Sample Preparation Kit. Mutation analysis was performed with the Sequenom LungCarta™ Panel which enables screening of 214 mutations in 26 genes, and utilises multiplexed polymerase chain reactions, single base extension reactions and mass spectrometry (Sequenom MassARRAY® platform).

      Results
      Results Sixty cases comprising 47 lung biopsies, 1 wedge resection, 6 lymph node biopsies, 4 pleural biopsies, 1 brain biopsy and 1 pericardial effusion were classified as 21 adenocarcinomas (ACA), 17 squamous cell carcinomas (SCC), 8 NSCLC favour ACA, 10 NSCLC favour SCC, 1 adenosquamous carcinoma and 3 NSCLC not otherwise specified (NOS). Mutations were successfully detected at a mutant allele frequency of 10% and definite mutations were reported in 28 cases (47%). Possible mutations of low allele frequency or uncertain significance were detected in an additional 15 cases (25%) and also in 10 cases with a definite mutation. In total 32 definite and 39 equivocal mutations have been detected and are currently being validated by a combination of pyrosequencing, next-generation sequencing and immunohistochemistry (IHC).

      Table 1. Unequivocal mutations detected according to histological subtype. ([a]Includes double mutant; TP53 and MAP2K1, [b]includes triple mutant; 2 TP53 and 1 KRAS, [c]includes double mutant; KRAS and MET)
      No. of definite mutations detected No. of mutated samples ACA NSCLC favour ACA SCC NSCLC favour SCC NSCLC NOS % of mutations detected in all ACA or SCC Comment
      13 TP53 12 3[a] 2[b] 5 1 1 17 % ACA 22% SCC 1 confirmed by next generation sequencing. 7 of 8 tested cases were strongly positive for P53 IHC
      12 KRAS 12 8[c] 1[b] 3 31% ACA 11% SCC 7 confirmed by pyrosequencing
      3 MET 3 2[c] 1 10% ACA 0% SCC 1 confirmed by next generation sequencing
      2 EGFR 2 2 7% ACA 0% SCC 2 previously detected by Sanger sequencing
      1 EPHA5 1 1 0% ACA 4% SCC Moderately differentiated SCC
      1 MAP2K1 1 1 3% ACA 0% SCC Poorly differentiated ACA TTF1+

      Conclusion
      The MassARRAY® system of testing for multiple mutations is a sensitive method that facilitates the optimal use of tumour DNA present in small specimens, and can detect concurrent mutations with the potential to influence responses to targeted therapies. Unequivocal mutations were reported in 59% and 37% of cases diagnosed/favoured as ACA and SCC respectively. This may reflect the LungCarta™ panel design, which was based on mutations detected in ACA.

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    P2.24 - Poster Session 2 - Supportive Care (ID 157)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Supportive Care
    • Presentations: 1
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      P2.24-034 - Treatment Beyond Progression in Patients with Non-Small Cell Lung Cancer Harbouring EGFR Mutations - The Manchester Lung Cancer Group Experience (ID 2431)

      09:30 - 16:30  |  Author(s): F. Blackhall

      • Abstract

      Background
      The presence of EGFR activating mutations in NSCLC and sensitivity of these tumours to EGFR tyrosine kinase inhibitors (TKI) was first described in 2005. For NSCLC patients harbouring an activating EGFR mutation the treatment of choice is an EGFR TKI which is better tolerated and easier to administer than chemotherapy. However, questions remain about duration of therapy and optimal management on radiological progression.

      Methods
      A retrospective case note review was undertaken with the aim of establishing current practice in prescription and discontinuation of EGFR-TKIs, subsequent therapies and clinical outcomes. We identified consecutive patients from the database of the genetic testing laboratory (from Q4 2009 when routine testing commenced to a cut-off point of February 2013). 171 case- notes were reviewed for demographic and clinical data including survival.

      Results
      Of 171 cases 116 (69%) had received treatment with an EGFR TKI (Gefitinib 79%, Erlotinib 19%, both 2%). The reasons for not receiving treatment included: patient received radical therapy, patient died before oncology assessment and patient preference. 63% of patients were female, 26% never smokers, 44% ex-smokers, 6% current smokers and smoking history was not documented in 23%. 76% of patients had Stage IV disease and performance status was 0-1 in 47%, 2 in 22%, 3 in 7%, 4 in 2% and not documented in 23%. The average length of treatment on EGFR TKI was 10.5 months (range 0.5-40) and 36 (31%) patients were still on treatment at the time of analysis. Disease progression on the EGFR-TKI (PD) had occurred in 82 (71%) of patients and 28 (34%) of these continued EGFR TKI treatment beyond PD. The average length of time on treatment beyond PD was 5.6 months (range 1-16) and TKI treatment was ongoing in 9 of the 28 patients. 25 of the 73 patients (34%) with PD who had stopped EGFR TKI went onto receive a second line systemic treatment: pemetrexed and platinum 60%, gemcitabine and carboplatin 20%, single agent pemetrexed 8%, vinorelbine 8%, gemcitabine 4%. Third line therapy was received by 40% of those who had received 2[nd] line treatment.

      Conclusion
      Patients with EGFR activating mutations often derive a significant clinical benefit and marked reduction in tumour burden with oral EGFR TKI therapy, which results in a reluctance, from both patients and clinicians, to stop therapy at the time of radiological progression if the patient is still experiencing symptomatic improvement. Our results show that treatment beyond disease progression is common (34%) in ‘real –life’ clinical practice with some patients continuing to derive benefit for more than a year beyond the time of disease progression. .

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    P3.13 - Poster Session 3 - SCLC (ID 202)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.13-005 - CONVERT - the challenges of opening centres and recruiting patients to an international multi-centre chemo-radiotherapy trial in limited-stage small cell lung cancer (ID 1366)

      09:30 - 16:30  |  Author(s): F. Blackhall

      • Abstract

      Background
      CONVERT is a multicentre, randomised, phase III trial open in Europe and Canada in limited-stage small cell lung cancer. Patients are randomised to twice (45 Gy in 30 fractions) or once-daily radiotherapy (66 Gy in 33 fractions) given concurrently with 4-6 cycles of chemotherapy. This study is funded by Cancer Research UK and involves centres from the UK NCRI, the ‘Groupe Francais de Pneumo-Cancerologie’, the Spanish Lung Cancer Group, the EORTC and NCIC CTG.

      Methods
      To identify and review the challenges in site set-up. To review time taken from site initiation to first patient randomised, number of centres opened that included 0-2 patients and number of centres that recruited the majority of all patients.

      Results
      In June 2013, 519/532 patients had been recruited in 9 countries; 299 from 32 UK centres, 100 from 17 French centres, 39 from 9 Canadian centres, 27 from 6 Spanish centres, 26 from 3 Belgian centres, 13 patients from 1 centre in Slovenia, 9 from 2 centres in The Netherlands and 6 patients from 1 centre in Poland. Figure 1 shows the number of centres open and patients recruited. 96 sites are currently open to recruitment (5 sites opened in 2008, 34 in 2009, 31 in 2010, 17 in 2011, 8 in 2012 & 3 in 2013, 2 sites subsequently closed early) of which 74 (77%) have randomised at least 1 patient. 24 sites (25%) recruited only 1 or 2 patients. 10 sites have recruited 49% of the total number of patients with a single site recruiting 18.5% of all patients randomised. Time taken from site initiation to 1[st] patient randomised ranged from 0–1029 days with a median of 144 days. Time taken to complete the QA exercise from initial information sent to site ranged from 14-1181 days with a median of 290.5 days. Figure 1

      Conclusion
      Recruitment to an academic trial in LS-SCLC is a challenge but accrual has improved considerably since 2008. This can be directly related to the increasing number of sites opened to recruitment. Duration of site set-up and completion of the QA exercise are factors explaining slower than anticipated accrual rates particularly between 2008 and 2010. We anticipate that the study will close to recruitment in July 2013. International participation has been a key factor to the success of the trial and the experience gained will be of value to the design of future radiotherapy studies to ensure target accrual.