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N. Pavlakis



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    MO09 - Mesothelioma I (ID 120)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track:
    • Presentations: 1
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      MO09.07 - Disease and Patient Characteristics related to Survival in a large population-based cohort of patients with Malignant Pleural Mesothelioma (MPM) (ID 3184)

      16:15 - 17:45  |  Author(s): N. Pavlakis

      • Abstract
      • Presentation
      • Slides

      Background
      Despite advances in therapy, the prognosis of MPM remains poor (median overall survival (OS) of 9-12 months). Nevertheless, as described in surgical series, a small proportion of patients survive far longer. Previously identified prognostic factors in patients undergoing extra-pleural pneumonectomy (EPP) include histological subtype, gender and neutrophil-lymphocyte ratio (NLR). Similar factors including stage and performance status have also been shown to be prognostic in chemotherapy studies. We aim to assess in the general MPM patient population, what factors predict for better prognosis independent of the treatment path chosen.

      Methods
      We reviewed records of patients registered (2002 -2009) with the NSW Dust Diseases Board; a government compensation body for NSW workers with occupational asbestos exposure. We evaluated a priori prognostic factors including age, gender, histological subtype, staging on CT imaging and NLR using Kaplan Meier and Cox regression analysis, and by treatment interventions, smoking and asbestos exposure history. Exploratory subgroup analyses compared these factors in long-term (>20 months) survivors versus the remainder of the study population.

      Results
      We identified 913 patients: 90% male; median age 71.9 years; histological subtype (epithelioid 54%; biphasic 11%; sarcomatoid 16.3%; unknown 19%); stage on CT imaging (Tx-I-II 49%; III-IV 51%). 51% of patients received chemotherapy and 6% underwent EPP (of which 67% received chemotherapy. Median age of first occupational asbestos exposure was 18 years, cumulative duration of exposure, 24 years and latency from exposure to diagnosis, 50 years. Median OS was 10.0 months, 15.0 months (range(1-120) in patients receiving chemotherapy and/or EPP and 5.8 months (range 0-125) in patients receiving neither. On univariate analysis, younger age (<70 vs. >70yrs at diagnosis; 13.1 vs. 8.5 months; p<0.001); female gender (12.0 vs. 9.8months; p<0.001); epithelioid subtype (11.8 vs. 7.2 months ;p>0.001); and NLR <5 (12.9 vs. 7.5months; p<0.001) were associated with prolonged OS. Patients who underwent chemotherapy (13.6 vs. 7.2 months; p<0.001) and EPP (17.9 vs. 9.6 months; p<0.001) also had an improved survival. Smoking history (current/ex vs. never) and cumulative asbestos exposure did not affect survival. A trend to improved survival was noted with early stage disease (11.2 vs. 9.1 months; p=0.284) and younger age at first exposure (<18 vs. >18 years of age; 10.9 vs. 9.4 months; p=0.091). On multivariate analysis, age, gender, histological subtype, NLR, EPP and chemotherapy administration remained significant. 24% of patients demonstrated survival over 20 months. Of those, 14% underwent EPP, and 63% received chemotherapy. On multivariate analysis, epithelioid histology (p<0.001), chemotherapy use(p=0.002), undergoing EPP(p=0.01) and NLR<5(p=0.007) were independently associated with survival over 20 months.

      Conclusion
      In this large, population based cohort of MPM patients, we have validated age, gender, histological subtype and NLR as significant prognostic factors. Patients undergoing interventions such as EPP or chemotherapy demonstrated more favourable survival, however it is important to note that 86% of long survivors did not receive radical surgery, and 37% did not receive chemotherapy. As such, we hypothesise that apart from active treatment and inherent selection criteria, there are additional factors, such as favourable tumour biology, that seem to positively influence survival of MPM patients.

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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 2
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      P1.11-003 - Exon 19 deletions, smoking history and gender as additional predictive factors for treatment benefit with EGFR Tyrosine Kinase Inhibitors in patients harbouring activating EGFR mutations: A Meta-analysis of 1432 patients in six randomised trials. (ID 1789)

      09:30 - 16:30  |  Author(s): N. Pavlakis

      • Abstract

      Background
      Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are now recognised as the standard first-line therapy for patients with advanced non-small cell lung cancer (NSCLC) harbouring activating EGFR mutations. Many studies consistently demonstrated superior tumour response and progression-free survival (PFS) over chemotherapy. However, there are still ongoing questions whether there are any significant differences in treatment outcomes between patients of different ethnicity, gender, age, performance status, smoking history, tumour histology and different subtypes of EGFR mutation. We performed a meta-analysis to assess the impact of these factors on the PFS benefit of EGFR-TKIs in advanced NSCLC patients harbouring activating EGFR mutations.

      Methods
      An electronic search of all randomised controlled trials comparing efficacy of first-line therapy of EGFR-TKI vs chemotherapy in advanced NSCLC patients harbouring EGFR mutation was performed. We extracted the published hazard ratio (HR) and the 95% confidence interval (CI) for PFS, if available, or obtained unpublished data, for subgroups defined by each factor. For each subgroup, pooled estimates of treatment efficacy of EGFR-TKI vs chemotherapy were calculated with the fixed-effects inverse variance weighted method. The predictive effect of each factor was analysed by a test for interaction between the factor and treatment effect; P<0.05 was considered statistically significant. All statistical tests were two-sided.

      Results
      We included 6 eligible studies, with two trials for each of these different EGFR-TKIs - Gefitinib, Erlotinib, and Afatinib – with a total of 1432 patients. As expected, overall the use of EGFR-TKIs in this mutated population significantly prolonged PFS as compared with chemotherapy (HR 0.37, 95% CI 0.32 to 0.43, P<0.001). While mutations at both Exon 19 (deletions) and at Exon 21 (L858R point mutations) were associated with significantly prolonged PFS, the benefit with Exon 19 mutations was greater: HR 0.26, 95% CI 0.21 to 0.31, P<0.001; as contrasted to Exon 21: HR 0.42, 95% CI 0.34 to 0.52, P<0.001 (treatment-EGFR mutation interaction P=0.001). Smoking status also showed differential benefit in this mutated population: never smokers: HR 0.30, 95% CI 0.26 to 0.36, P<0.001; contrasted to current or ex-smokers: HR 0.48, 95% CI 0.37 to 0.61, P<0.001; treatment-smoking history interaction P=0.003). There was also a trend for greater benefit for females with EGFR-TKI therapy as contrasted to males (HR [females] 0.32, 95% CI 0.27 to 0.38, P<0.001; HR [males] 0.42, 95% CI 0.33 to 0.53, P<0.001; treatment-gender interaction P=0.06). Interestingly, several parameters were not significant predictors of PFS benefit with EGFR-TKI treatment in this mutated population: performance status (ECOG 0 and 1 vs 2; interaction P=0.86); age (<65 vs ≥65 years; interaction P=0.58); ethnicity (Asian vs others; interaction P=0.18); and tumour histology (adenocarcinoma vs others; interaction P=0.52).

      Conclusion
      While EGFR-TKIs significantly prolong PFS in all advanced NSCLC patients harbouring classic activating EGFR mutations when compared with chemotherapy, other molecular and demographic factors have a further influence on benefit. Exon 19 deletions, never-smoking history, and possibly female gender were all associated with longer PFS in these patients when treated with EGFR-TKIs as compared with chemotherapy. These findings should enhance better trial design in future clinical trials.

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      P1.11-029 - The addition of anti-angiogenic tyrosine kinase inhibitors to chemotherapy for advanced non-small cell lung cancer: a systematic review and meta-analysis of randomised controlled trials (ID 2140)

      09:30 - 16:30  |  Author(s): N. Pavlakis

      • Abstract

      Background
      Non-small cell lung cancer (NSCLC) remains a major cause of death worldwide. Targeting tumour angiogenesis has held great promise in NSCLC based on the ubiquitous role of angiogenesis in NSCLC biology. The monoclonal antibody bevacizumab has shown greatest efficacy when added to first line chemotherapy in the adenocarcinoma subgroup. Small molecule, anti-angiogenic tyrosine kinase inhibitors (AATKIs) have been evaluated in several settings. This review was undertaken to evaluate the benefits and harms of AATKIs when added to chemotherapy for advanced NSCLC.

      Methods
      We undertook a systematic review of randomised controlled trials (RCTs) of AATKIs added to chemotherapy for advanced or metastatic NSCLC. We searched the electronic databases (MEDLINE/PubMed, EMBASE, The Cochrane Library) in addition to conference proceedings from ASCO, ESMO, IASLC WCLC and Clinical Trials Registries. Data was independently extracted by two reviewers. The primary endpoint was overall survival (OS), with secondary endpoints progression-free survival (PFS), objective response rate (ORR) and ≥ grade 3 common toxicity criteria adverse events (G≥3CTCAE). Meta-analysis of the data was performed to obtain pooled hazard ratios (HR) for OS and PFS, and pooled odds ratios (OR) for ORR and G≥3CTCAE. Statistical analysis was performed using Review Manager v5.2 software (Cochrane). Pre-specified subgroup analyses were performed according to line of chemotherapy, second-line chemotherapy partner and histology.

      Results
      Fifteen RCTs involving 7904 patients with advanced NSCLC were included in this meta-analysis. In the overall population (N = 7904), the addition of AATKI to chemotherapy significantly prolonged OS (HR 0.93; 95% confidence interval [CI] 0.88, 0.99; P=0.02) and PFS (HR 0.83; 95% CI 0.79, 0.88; P<0.00001). There was no significant heterogeneity between the RCTs. (Chi² = 12.31, df = 14, P = 0.58; I² = 0% for OS. Chi² = 10.64, df = 13, P = 0.64; I² = 0% for PFS). The addition of AATKI to chemotherapy significantly increased ORR (OR 1.64, 95% CI 1.34, 2.02; P<0.00001) and G≥3CTCAEs (OR 1.78, 95% CI 1.41, 2.25; P<0.00001). Used first line (N = 3867), AATKI significantly prolonged PFS (HR 0.86; 95% CI 0.79, 0.93; P<0.0001) but not OS (HR 0.96; 95% CI 0.89, 1.05; P=0.38). Used second line (N=4037), AATKIs significantly prolonged both OS (HR 0.91; 95% CI 0.84, 0.98; P=0.02) and PFS (HR 0.80; 95% CI 0.74, 0.87; P<0.00001). Here, the greatest OS benefit was seen in patients with adenocarcinoma (HR 0.85; 95% CI 0.75, 0.96, P=0.01) and patients receiving docetaxel (HR 0.89; 95% CI 0.81, 0.98; P=0.02). The addition of AATKIs to second line pemetrexed did not improve OS (HR 0.95; 95% CI 0.79, 1.13; P=0.54) nor in patients with squamous histology (HR 1.01; 95% CI 0.87, 1.16; P=0.92).

      Conclusion
      The addition of AATKIs to chemotherapy in patients with advanced NSCLC prolongs OS, PFS and increases ORR, at the expense of increased toxicity. Greatest benefit is in second line, in adenocarcinomas and in patients receiving docetaxel. Whilst the search for predictive biomarkers of the angiogenic phenotype continues, an individual patient data meta-analysis may clarify subgroups with the most benefit from AATKIs to guide future studies in enriched populations.

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    P2.10 - Poster Session 2 - Chemotherapy (ID 207)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.10-040 - Prognostic significance, accuracy and usefulness of oncologists' estimates of survival time for patients starting first-line chemotherapy for advanced non-small-cell lung cancer (ANSCLC) (ID 2560)

      09:30 - 16:30  |  Author(s): N. Pavlakis

      • Abstract

      Background
      Oncologists are frequently required to provide estimates of survival time for their patients with advanced cancer. The aims of this study were to determine the accuracy and prognostic significance of oncologists’ estimates of survival time above and beyond conventional prognostic factors.

      Methods
      Medical oncologists from 26 sites in Australia and New Zealand recorded the “expected survival time in months” for individual patients with ANSCLC prior to randomisation in a trial of first-line chemotherapy with a platinum-based doublet. Blood samples, demographics, tumour and treatment characteristics were collected at baseline along with the oncologist’s rating of each patient using Spitzer’s Quality of Life Index (SQLI). Based on previous studies, we deemed estimates within 0.75-1.33 times observed survival as precise, and expected 50% of patients to live longer (or shorter) than their oncologist’s estimate, 50% to live from half to double their oncologist’s estimate (typical scenario); 5-10% to live ≤¼ of their estimate (worst-case scenario); and, 5-10% to live ≥3 times their estimate (best-case scenario). Associations between estimated and observed survival times in months were assessed with Cox proportional hazards regression before and after adjustment for baseline prognostic factors including age, gender, Eastern Cooperative Oncology Group performance status (ECOG PS), cancer extent, histology, co-morbidities, laboratory results and SQLI.

      Results
      Estimates of survival were available for 244 (98%) of the first 250 patients randomised. Patient characteristics were: median age 64 years; female 40%; adenocarcinoma 64%; ECOG PS 0-1 92%; and distant metastases 71%. After a median follow-up of 21 months there were 172 deaths (69%). The median (interquartile range, IQR) for observed survival was 10 months (5-20) and for estimated survival was 11 months (9-12). Oncologists’ estimates were imprecise (22% from 0.75-1.33 times observed) but well calibrated (47% of patients lived shorter than expected and 53% lived longer than expected). The proportions of patients with observed survival times falling within ranges bounded by simple multiples of their estimated survival times corresponded closely with our a-priori hypotheses: 10% lived ≤1/4 of their estimated survival time, 53% lived from half to double their estimated survival time, and 13% lived ≥3 times their estimated survival time. The oncologist’s estimate of survival time at baseline was the strongest predictor of observed survival in both univariable analysis (HR 0.90, 95% CI 0.86-0.95, p<0.001) and multivariable analysis (HR 0.90, 95% CI 0.86-0.95, p<0.001) accounting for all other independently significant predictors, namely: estimated neutrophil-lymphocyte ratio >5 (HR 3.15, 95% CI 1.76-5.64, p<0.001); haemoglobin <120g/L (HR 1.93, 95% CI 1.3-2.9, p=0.001) and total white cell count >11x10[9]/L (HR 1.55, 95% CI 1.05-2.27, p=0.03).

      Conclusion
      Oncologists' estimates of survival time were independently associated with observed survival time and provided a reasonable basis for estimating worst-case, typical and best-case scenarios for survival. Oncologists’ estimates provide useful additional prognostic information, above and beyond that provided by established prognostic factors.

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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.11-012 - Epidermal growth factor receptor tyrosine kinase inhibitors in advanced squamous cell carcinoma of the lung. (ID 1267)

      09:30 - 16:30  |  Author(s): N. Pavlakis

      • Abstract

      Background
      Tyrosine Kinase inhibitors (TKIs) with gefitinib or erlotinib targeting the epidermal-growth factor receptor (EGFR) are a well-established therapy in the treatment of metastatic pulmonary adenocarcinoma, particularly in patients with activating EGFR mutations. EGFR mutations are rarely found in squamous cell carcinomas (SCC) of the lung. There is conflicting data supporting the efficacy of EGFR inhibitors in advanced SCC of the lung. In this analysis we examined the impact of EGFR TKIs on progression-free survival (PFS) and overall survival (OS) in unselected patients with SCC of the lung.

      Methods
      We searched for Randomised controlled trials (RCTs) comparing EGFR-TKIs alone with placebo (PL) in patients with metastatic non-small cell lung cancer. RCTs in the front-line, maintenance and subsequent therapies were included. The primary outcome was PFS in the SCC population. We used published hazard ratios (HRs), and when not available unpublished data was sought. Non-adenocarcinoma was used as a surrogate for SCC when analysis was available by specific histology. Pooled estimates of treatment effect on OS and PFS were calculated using the random-effects inverse variance weighted method.

      Results
      Eight eligible RCTs were included: 2 first line, 6 second-line or beyond, evaluating 1781 patients (EGFR TKI v PL). Data was available for analysis of OS in 4 studies (second-line; N = 1420) and for PFS in 4 studies (three second-line, one first-line; N = 788). EGFR TKIs significantly prolonged PFS, with a hazard ratio of 0.77 [95% CI 0.65 – 0.92]. OS was prolonged with a hazard ratio of 0.88 [95% confidence interval (CI) 0.78 – 1.00]. Efforts to obtain further missing data from the other studies to complement the analysis are on-going.

      Conclusion
      EGFR mutations are rare in SCC of the lung, yet EGFR TKIs have a significant PFS benefit and (less certain) OS benefit compared to placebo in unselected patients with advanced pulmonary SCC, and should be considered as a therapeutic option in patients with advanced SCC of the lung. EGFR mutation independent mechanisms may explain efficacy of EGFR inhibitors in this setting. An individual patient data meta-analysis is warranted to further characterize the OS benefit.

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    P3.18 - Poster Session 3 - Pathology (ID 177)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P3.18-003 - ROS1 Gene Rearrangements in Non-Small Cell Lung Carcinoma - A New Genetic Target that can be Identified by Immunohistochemistry and FISH (ID 1482)

      09:30 - 16:30  |  Author(s): N. Pavlakis

      • Abstract

      Background
      Targeted therapies aimed at specific molecular genetic alterations are revolutionizing cancer treatment, particularly in non-small cell lung cancer (NSCLC). ROS1 is an oncogene that encodes a transmembrane tyrosine kinase receptor that has high homology with the intracellular kinase domain of ALK. Driver mutations involving translocation of the ROS1 gene have recently been identified in NSCLC and show promise as a target for tyrosine kinase inhibitors. In this study we aimed to: (1) Investigate the incidence and clinicopathological features of NSCLCs harbouring ROS1 rearrangements in an Australian population. (2) Investigate the accuracy of immunohistochemistry (IHC) compared to FISH at identifying tumours with ROS1 rearrangements.

      Methods
      We tested for ROS1 translocations using both a FISH breakapart probe (Zytovision and Abbott Molecular) (≥15% cells with split signals or single green 3' signal considered positive for rearrangement), and immunohistochemistry (D4D6 clone, Cell Signaling Technology). Testing was undertaken on both (1) A retrospective cohort of 316 early stage lung adenocarcinomas in tissue microarrays. (2) A prospective cohort of 42 NSCLC, selected on clinical grounds for mutation testing (eg EGFR/KRAS/ALK negative samples and young age or never/light smoker).

      Results
      In the retrospective cohort, only 1 case was positive for ROS1 gene rearrangement by FISH (0.3% incidence). ROS1 IHC identified positive staining in 7 (2.0%) cases, including the FISH+ case. ROS1 IHC had a sensitivity of 100% and specificity of 98% for identifying ROS1 gene rearrangements. In the prospective cohort of 42 cases, 4 cases with ROS1 gene rearrangement were identified by FISH and all 4 cases showed positive ROS1 immunohistochemical staining. Of the total 5 cases with ROS1 gene rearrangement, all occurred in adenocarcinomas from female patients with an age range of 33-81 years (mean 58). Four of the five patients were non-smokers and two were of Asian ethnicity. All 5 cases were negative for ALK rearrangements and in the 4 cases where EGFR status was known, they were all wild type.

      Conclusion
      ROS1 gene rearrangements occur in a very small percentage of lung adenocarcinomas with distinctive clinicopathological features and appear to be mutually exclusive with other driver mutations in the small number of positive cases available for evaluation. Screening with IHC may be a suitable method of reducing the number of cases requiring FISH testing.