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G. Ostoros
Moderator of
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SC18 - Precision Screening for Lung Cancer (ID 342)
- Event: WCLC 2016
- Type: Science Session
- Track: Radiology/Staging/Screening
- Presentations: 5
- Moderators:A. Nicholson, G. Ostoros
- Coordinates: 12/06/2016, 16:00 - 17:30, Lehar 1-2
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SC18.01 - Field Cancerization in the Airways and its Application to Lung Cancer Early Detection (ID 6671)
16:00 - 17:30 | Author(s): I. Wistuba
- Abstract
- Presentation
Abstract:
Molecular alterations that are characteristic of lung tumors have been shown to be present in normal-appearing airway epithelium adjacent to lung tumors suggestive of an airway field cancerization phenomenon (1, 2). These field effects include altered gene expression, loss of heterozygosity (LOH), gene mutation and methylation and microsatellite instability (3-7). Microarray studies have pointed to expression profiles that are dissimilar between airways in smokers with and without lung cancer (8, 9). It has been recently demonstrated gene expression profiles that are shared between normal-appearing airway cells and nearby NSCLCs and that can distinguish airways of smokers with lung cancer from those without the malignancy (8). Studies from several groups suggest that the field cancerization provides biological insights into non-small cell lung carcinoma (NSCLC) ad small cell lung carcinoma (SCLC) pathogenesis and clinical opportunities for lung cancer detection (6, 8). It is important to note that smoking perpetuates inflammation throughout the exposed airway epithelium (10). This effect is pronounced in patients with Chronic Obstructive Pulmonary Disease (COPD) (10). Notably, among smokers, even after smoking cessation, airway inflammation persists while the risk of lung cancer continues to increase (10). It is not known which tumor promoting profiles in the airway field cancerization may drive lung cancer development in COPD patients. Using microarray profiling, studies have pointed to expression profiles that are dissimilar between airways in smokers with lung cancer and airways in smokers without cancer (11-13). Importantly, these gene-expression changes within the “field of injury” have been leveraged for development and validation of a clinically-relevant biomarker that can improve the diagnostic performance of bronchoscopy for detection of lung cancer (predominantly NSCLC) among smokers with suspect disease (8, 12). In addition, gene expression array analysis pointed to airway field expression profiles that are spatially and temporally modulated in early stage patients following surgery and that may be associated with disease relapse (13). Further, we have recently demonstrated that there is significant enrichment in gene expression profiles measured in both small (adjacent to tumor) and large (mainstem bronchus) airway compartments of the airway field of injury, suggesting that gene-expression changes in the large airway can serve as a surrogate for the molecular changes occurring in the airway epithelium adjacent to the tumor (9). Taken together, studies from our group and others suggest that, by sampling “normal” and relatively accessible tissue (e.g., bronchial airway), the airway field of injury provides biological insights into the earliest phases in the development of lung malignancy and potential valuable clinical opportunities such as early detection (1, 2). Identifying molecular aberrations that precede cellular morphological changes will provide biological insights into why some smokers develop lung cancer and, thus, clinical opportunities for improved lung cancer detection. References: 1. Kadara H, Wistuba, II. Field cancerization in non-small cell lung cancer: implications in disease pathogenesis. Proceedings of the American Thoracic Society. 2012;9(2):38-42. 2. Steiling K, Ryan J, Brody JS, Spira A. The field of tissue injury in the lung and airway. Cancer Prev Res. 2008;1(6):396-403. 3. Belinsky SA, Nikula KJ, Palmisano WA, Michels R, Saccomanno G, Gabrielson E, Baylin SB, Herman JG. Aberrant methylation of p16(INK4a) is an early event in lung cancer and a potential biomarker for early diagnosis. Proc Natl Acad Sci U S A. 1998;95(20):11891-6. 4. Mao L, Lee JS, Kurie JM, Fan YH, Lippman SM, Lee JJ, Ro JY, Broxson A, Yu R, Morice RC, Kemp BL, Khuri FR, Walsh GL, Hittelman WN, Hong WK. Clonal genetic alterations in the lungs of current and former smokers. J Natl Cancer Inst. 1997;89(12):857-62. 5. Tang X, Shigematsu H, Bekele BN, Roth JA, Minna JD, Hong WK, Gazdar AF, Wistuba, II. EGFR tyrosine kinase domain mutations are detected in histologically normal respiratory epithelium in lung cancer patients. Cancer research. 2005;65(17):7568-72. 6. Wistuba, II, Behrens C, Milchgrub S, Bryant D, Hung J, Minna JD, Gazdar AF. Sequential molecular abnormalities are involved in the multistage development of squamous cell lung carcinoma. Oncogene. 1999;18(3):643-50. 7. Wistuba, II, Lam S, Behrens C, Virmani AK, Fong KM, LeRiche J, Samet JM, Srivastava S, Minna JD, Gazdar AF. Molecular damage in the bronchial epithelium of current and former smokers. J Natl Cancer Inst. 1997;89(18):1366-73. 8. Spira A, Beane JE, Shah V, Steiling K, Liu G, Schembri F, Gilman S, Dumas YM, Calner P, Sebastiani P, Sridhar S, Beamis J, Lamb C, Anderson T, Gerry N, Keane J, Lenburg ME, Brody JS. Airway epithelial gene expression in the diagnostic evaluation of smokers with suspect lung cancer. Nat Med. 2007;13(3):361-6. 9. Kadara H, Fujimoto J, Yoo SY, Maki Y, Gower AC, Kabbout M, Garcia MM, Chow CW, Chu Z, Mendoza G, Shen L, Kalhor N, Hong WK, Moran C, Wang J, Spira A, Coombes KR, Wistuba, II. Transcriptomic architecture of the adjacent airway field cancerization in non-small cell lung cancer. J Natl Cancer Inst. 2014;106(3):dju004. 10. Punturieri A, Szabo E, Croxton TL, Shapiro SD, Dubinett SM. Lung cancer and chronic obstructive pulmonary disease: needs and opportunities for integrated research. J Natl Cancer Inst. 2009;101(8):554-9. 11. Gustafson AM, Soldi R, Anderlind C, Scholand MB, Qian J, Zhang X, Cooper K, Walker D, McWilliams A, Liu G, Szabo E, Brody J, Massion PP, Lenburg ME, Lam S, Bild AH, Spira A. Airway PI3K pathway activation is an early and reversible event in lung cancer development. Sci Transl Med.2(26):26ra5. 12. Silvestri GA, Vachani A, Whitney D, Elashoff M, Porta Smith K, Ferguson JS, Parsons E, Mitra N, Brody J, Lenburg ME, Spira A, Team AS. A Bronchial Genomic Classifier for the Diagnostic Evaluation of Lung Cancer. N Engl J Med. 2015;373(3):243-51. 13. Kadara H, Shen L, Fujimoto J, Saintigny P, Chow CW, Lang W, Chu Z, Garcia M, Kabbout M, Fan YH, Behrens C, Liu DA, Mao L, Lee JJ, Gold KA, Wang J, Coombes KR, Kim ES, Hong WK, Wistuba, II. Characterizing the molecular spatial and temporal field of injury in early-stage smoker non-small cell lung cancer patients after definitive surgery by expression profiling. Cancer prevention research. 2013;6(1):8-17.
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SC18.02 - Integrating Lung Cancer Biomarkers into Future Screening Programs (ID 6672)
16:00 - 17:30 | Author(s): P.P. Massion
- Abstract
- Presentation
Abstract:
Low-dose computed tomography for high-risk individuals has for the first time demonstrated unequivocally that early detection save lives. The currently accepted screening strategy comes at the cost of a high rate of false positive findings while still missing a large percentage of the cases. Therefore, there is increasing interest in developing strategies to better estimate the risk of an individual to develop lung cancer, to increase the sensitivity of the screening process, to reduce screening costs and to reduce the numbers of individuals harmed by screening and follow-up interventions. New molecular biomarkers candidates show promise to improve lung cancer outcomes. This review discusses the current state of biomarker research in lung cancer screening with the primary focus on risk assessment. The rationale for developing biomarkers for the early detection of lung cancer is very strong and well established. It stems from the fact that, at the population level, the earlier we detect the disease, the better the outcome and the lower the health care cost. The impetus for biomarker development has grown stronger since the NLST trial demonstrated that early detection via chest CT screening reduced the relative risk for lung cancer death in the high risk individuals. Low dose chest CT in this group alone may save up to 12,000 lives a year, but it represents only about 8 % of individuals dying of this disease every year. Thus, much is to be done to capture these lung cancers that escape chest CT screening as currently recommended despite its high sensitivity and specificity. The reason for limited detection relates to how many at-risk individuals are studied with CT and to how we best define this risk. Detection and careful management of indeterminate pulmonary nodules are integral parts of this effort. Lung cancer screening using chest CT also raises many questions, some of which could be addressed with well poised biomarkers. For example, who is at utmost risk for lung cancer? How do we expand the screening criteria from the NLST without causing more harm than good? Once the CT screening studies are done, how do we approach a non-invasive diagnosis of lung cancer? How do we prevent the overdiagnosis bias? Here we focus on biomarkers that could be used in a risk assessment evaluation for screening programs. We will discuss current molecular biomarkers of risk assessment in those without measurable disease and before a chest CT has been done. Consideration of the use of such biomarkers should trigger a discussion with the patient before ordering it to address the intent of the test and the implications of the possible results. Many biomarkers have been developed over the years to predict tumor development. Let us consider the characteristics of such a biomarker to assess the risk of lung cancer. For screening purposes, given the low prevalence of disease, a strong negative predictive value (NPV) of a test is a very attractive feature. High specificity on the other hand is always desirable so we do not overcall cancers (false positive). Should such a test be positive, it would push individuals into a higher risk group to consider appropriate surveillance. The biomarker could measure a genetic risk (e.g. altered metabolism of carcinogens, DNA repair machinery abnormalities, predisposition to inflammation, or germline mutations) or the influence of the environment on tumor development (exposure to carcinogens or surrogates of risk such as epigenetic changes in the airway epithelium or the prevalence of preinvasive lesions). There has been recent interest in the potential for genetic variants to give insight into the pathogenesis of lung cancer. These variants indicate that there is great heterogeneity in mechanisms of disease development that is modulated by inherited genetic variation. With these come the opportunity to improve models predicting lung cancer risk. A larger question of timeliness of biomarker use in clinical practice will be discussed during the presentation. What are the risk and benefits of precision screening? Are current risk prediction models safe to use or robust to guarantee an advantage over current standard of care? There is a clear need to evaluate the benefit of risk assessment biomarkers with repeated measures over time. The assumption is that as risk increases, molecular moieties should be more readily available (e.g. in the circulation) over time. This may be true for tumor specific antigens and ctDNA, but would not apply to genetic risk. Statistical models could test the ability of different biomarkers to complement each other in a single population, in order to eventually determine those that could be tested prospectively. Given biomarkers' non-specificity and commonality in predicting diseases, modeling multiple markers of the same clinical diagnostic criteria can be used to develop more accurate individual and cumulative risk estimates for specific diseases. We should therefore consider a joint effects approach to determine individual biomarker associations as well as to ascertain the impact of simultaneous increases in multiple biomarker concentrations on the diagnosis of lung cancer. Biomarkers of risk would ideally be tested prospectively in a randomized clinical trial. However, given the relatively low prevalence of this disease, the number needed to screen may be prohibitive; therefore the development of registries is most appropriate. Registries are longitudinal cohort prospective studies where a biomarker is introduced but does not force providers to change their management. The lead time to diagnosis may be sufficient to cause a stage shift and therefore improve outcome. Finally, it is through better understanding of the biology of cancer development and of preinvasive lesions that we will shed further light into the field of biomarker research.
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SC18.03 - Lung Cancer Screening, COPD and Cardiovascular Diseases (ID 6673)
16:00 - 17:30 | Author(s): R. Huber
- Abstract
- Presentation
Abstract not provided
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SC18.04 - Exhaled Biomarker Fingerprints for Early Detection (ID 6674)
16:00 - 17:30 | Author(s): I. Horvath
- Abstract
- Presentation
Abstract not provided
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SC18.05 - UK Lung Screening Trial Cost Effectiveness and Current Planning Status of International Lung Cancer Screening Programs (ID 6675)
16:00 - 17:30 | Author(s): J.K. Field
- Abstract
- Presentation
Abstract:
The UKLS Trial and cost effectiveness The pilot UKLS lung cancer RCT screening trial recruited 4,000 individuals [1], using the LLP~v2~ risk model (5% risk over 5 years) [2]. The lessons learnt from the UKLS CT pilot screening trial are: UKLS – A Population based trial – all IMD’s (socioeconomic groups) included [1]. Risk Stratification (LLP~v2~ 5 % risk over 5 years) [2] Volumetric assessment of CT detected nodules [3]. Care Pathway – Management pathway implemented [3]. Early Stage Disease (Stage 1 68%: Stage I&II 86%) [4] High Proportion suitable for Surgery (83%) [4] 1.7% lung cancers identified at baseline scan [1] Benign Resection rate – 10.3% (NLST 27%)[1] Psychological impact – transient not significant [5, 6] Cost effectiveness modelling within NICE parameters [1] The cost effectiveness of the UKLS trial has been modelled and compared with that of the US National Lung Screening Trial (NLST), which has published an estimate of $81,000 per quality-adjusted life-year (QALY) as its mean incremental cost-effectiveness ratio (ICER) [7]. All UKLS cost estimates were based on 2011-12 NHS tariffs (Costs provided in $: £1=$1.5 on 30-11-15). Owing to the brief duration of the trial, observations relevant to economic evaluation were limited to cost-incurring events associated with screening and the initial management of screen-detected cancers. Expected outcomes of the cancers detected were simulated on the basis of both life tables and published survival data from other studies. The costs incurred from UKLS are those of baseline and repeat screens ($424,072), diagnostic workup ($113,478), and treatment ($449,243), which totaled $1,036794 (95% CI, $719,332 to $1,350,766). Recruitment costs ($15) per person for invitation and selection) were modelled from the UK colorectal screening programme and we assumed a participation rate of 30% of those invited. The gross current costs of the programme amounted to $1,133,217 (CI $817,887 to $1,450,610). Summary of findings: The ICER of screen-detection compared with symptomatic detection was estimated at $9495 per life-year gained. Using data from previous studies, we associated quality of life weights with the estimated survival gains, enabling us to report outcomes as QALYs. On this basis, the ICER equaled $12,709 per QALY gained (CI $ 8280 to $18966). The difference in cost effectiveness between NLST and UKLS as suggested by the estimated ICERs is more apparent than real. Most of the discrepancy can be explained by differences between settings in (i) local unit costs, (ii) intensity of resource use, (iii) number of screening rounds and (iv) disease prevalence in the target population. Thus, UKLS selected high-risk subjects only whereas NLST screened a general population, yet the latter reported an ICER as low as $32,000 for its highest-risk quintile. Expected QALY gains from screen-detection were similar in both trials. Figure 1
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Author of
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OA05 - Treatment Advances in SCLC (ID 373)
- Event: WCLC 2016
- Type: Oral Session
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:A. Ardizzoni, J. Pujol
- Coordinates: 12/05/2016, 14:20 - 15:50, Strauss 2
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OA05.05 - Randomized Phase 2 Study: Alisertib (MLN8237) or Placebo + Paclitaxel as Second-Line Therapy for Small-Cell Lung Cancer (SCLC) (ID 4855)
14:20 - 15:50 | Author(s): G. Ostoros
- Abstract
- Presentation
Background:
Alisertib, an investigational selective Aurora A kinase inhibitor, showed single-agent antitumor activity in preclinical in vivo SCLC models and was synergistic with paclitaxel in this setting. We report the efficacy, quality of life (QoL), and safety from this study.
Methods:
Patients ≥18 years with SCLC relapsed <180 days after standard first-line platinum-based chemotherapy were randomized 1:1 to alisertib 40 mg orally twice-daily on days 1–3, 8–10, 15–17 + paclitaxel 60 mg/m[2] IV on days 1, 8, 15 (Arm A) or matched placebo + paclitaxel 80 mg/m[2] (Arm B) in 28-day cycles. Patients were stratified using an interactive voice response system (IVRS) by type of relapse post-frontline platinum (sensitive vs resistant/refractory) and presence/absence of brain metastases at baseline. Protocol Amendment 2 corrected the definition for relapse per standard guidance; stratification factors were corrected accordingly. Primary endpoint was progression-free survival (PFS) per stratified log-rank test. QoL outcomes were assessed per EORTC QLQ-C30 and -LC13.
Results:
178 patients were randomized, 89/89 to Arm A/B (median age 62/62 years). Survival, response, QoL, and safety results are presented in the Table. The analysis of PFS using IVRS stratification favored Arm A, as did the analysis per corrected stratification factors. Mean EORTC QLQ-C30 QoL scores were similar between arms, as were mean change-from-baseline values at end of treatment (-5.7 in Arm A vs -4 in Arm B). Figure 1
Conclusion:
Alisertib + paclitaxel shows favorable PFS over placebo + paclitaxel with both initial and updated IVRS stratification. A similar favorable trend was also observed for OS and ORR although not statistically significant. Comparable changes in QoL scores were observed from baseline in both arms. The alisertib + paclitaxel arm showed higher rates of AEs and discontinuation due to AEs. Updated survival analyses are pending.
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OA23 - EGFR Targeted Therapies in Advanced NSCLC (ID 410)
- Event: WCLC 2016
- Type: Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:O.T. Brustugun, S. Lu
- Coordinates: 12/07/2016, 14:20 - 15:50, Stolz 2
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OA23.03 - Second-Line Afatinib for Advanced Squamous Cell Carcinoma of the Lung: Analysis of Afatinib Long-Term Responders in the Phase III LUX-Lung 8 Trial (ID 4711)
14:20 - 15:50 | Author(s): G. Ostoros
- Abstract
- Presentation
Background:
Squamous cell carcinoma (SCC) of the lung is a genetically complex and difficult-to-treat cancer. In LUX-Lung 8, afatinib (40mg/day) significantly improved OS (median 7.9 vs 6.8 months, HR=0.81 [95% CI, 0.69‒0.95], p=0.008), PFS (2.6 vs 1.9 months, HR=0.81 [0.69‒0.96], p=0.010) and DCR versus erlotinib (150mg/day) in patients with relapsed/refractory SCC of the lung (n=795). Notably, 12-month (36 vs 28%; p=0.016) and 18-month survival (22 vs 14%; p=0.016) was significantly higher with afatinib than erlotinib, indicating that some patients derive prolonged benefit from afatinib. Here, we present post-hoc analysis of baseline characteristics and efficacy/safety of afatinib in long-term responders (treatment for ≥12 months). Hypothesis-generating analysis of archived tumor samples and blood serum was undertaken to identify possible molecular/clinical biomarkers.
Methods:
Tumor samples were retrospectively analyzed using FoundationOne[TM] next-generation sequencing (NGS); EGFR expression was determined by immunohistochemistry. Pre-treatment serum samples were analyzed with VeriStrat[®], a MALDI-TOF mass spectrometry test, and classified as VeriStrat-Good or VeriStrat-Poor-risk.
Results:
15/398 patients treated with afatinib were long-term responders. Median duration of treatment was 16.6 months (range: 12.3‒25.8). Patient characteristics were similar to the overall dataset (median age: 65 years [range: 54‒81]; male: 80.0%; Asian: 13.3%; ECOG 0/1: 40.0%/60.0%; best response to chemotherapy CR or PR/SD: 53.3%/46.7%; current and ex-smokers: 80.0%). Median PFS was 16.2 months (range: 2.8‒24.0); median OS was 23.1 months (range: 12.9‒31.5). The most common treatment-related AEs (all grade/grade 3) were: diarrhea (73.3%/6.7%); rash/acne (66.7%/6.7%); stomatitis (13%/7%). AEs generally occurred soon after treatment onset (median onset, days [range]: diarrhea 11 [5‒48]; rash/acne 17 [9‒107]; stomatitis 15 [11‒19]). Four patients required a dose reduction to 30mg/day due to treatment-related AEs (diarrhea, rash, stomatitis, diarrhea/rash). NGS was undertaken in 9 patients and details will be presented at the meeting. Genomic aberrations in the ErbB/FGF gene families were identified in 44.4%/55.6% of long-term responders (overall dataset: 29.4%/58.0%). Of 14 patients assessed by VeriStrat, 85.7% were VeriStrat-Good (overall dataset: 61.6%). Immunohistochemistry data was available for two patients; one overexpressed EGFR (≥10% positive cells; H-score ≥200)
Conclusion:
Baseline characteristics of long-term responders to afatinib were similar to the overall dataset. In this sub-group, afatinib conferred a survival benefit of nearly 2 years. Afatinib was well tolerated with predictable and transient AEs that occurred soon after treatment onset. The dataset was too small to identify any clear NGS/VeriStrat predictive signals. Further studies are required to predict long-term response to afatinib.
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P1.07 - Poster Session with Presenters Present (ID 459)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.07-042 - Neutrophil-Lymphocyte and Platelet-Lymphocyte Ratios Predict Prognosis in Early-Stage Resected Small-Cell Lung Cancer Patients (ID 5657)
14:30 - 15:45 | Author(s): G. Ostoros
- Abstract
Background:
Surgical resection is rarely possible in small-cell lung cancer (SCLC), a highly aggressive malignancy with limited treatment options. However, although in the past decades, for selected early-stage cases, a curative intent surgery is often performed, there is no biomarker to help the selection of patients eligible for surgery. Because previous studies - predominantly from East Asia - showed that high neutrophil to lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) correlate with poor prognosis in several types of tumors including SCLC, the aim of our study was to investigate the prognostic value of NLR and PLR in Caucasian patients with resected SCLC.
Methods:
Consecutive patients with histologically confirmed and surgically resected SCLC evaluated between 2000 and 2013 at the National Koranyi Institute of Pulmonology were analyzed in this retrospective analysis. Patients were divided into "high" and "low" groups according to their NLR and PLR at diagnosis. The cut-off NLR and PLR values were 3 and 110, respectively. Next, we evaluated the associations of preoperative NLR or PLR with vascular involvement, tumor necrosis, peritumoral inflammation, tumor grade, clinicopathological characteristics (including age, gender, stage) and overall survival (OS) in univariate and multivariate analyses.
Results:
There were a total of 65 patients (39 men and 26 women) with a median age of 57.7 years (range, 40-79). The pathological stages were 1, 2 and 3A in 23, 23 and 14 cases by AJCC 7[th] edition (in five patients no pTNM was available). PLR was high (HPLR) in 41 (63%) and low (LPNR) in 24 (37%) patients. NLR was high (HNLR) in 35 (66%) and low (LLNR) in 17 (33%) patients. PLR significantly correlated with pathologic lymph node status (p<0.001) and NLR (p=0.007). HPLR was associated with shorter OS (vs. LPLR, HR, 2.2; 95% CI, 1.13–4.29; p=0.02). There was a non-significant trend towards longer OS in patients with LNLR (vs. HNLR, p=0.078). There were no significant associations between NLR or PLR and age, gender, stage, vascular involvement, tumor necrosis, peritumoral inflammation and tumor grade.
Conclusion:
This is the first study in Caucasian patients with resected SCLC which shows that LPLR (<110) before surgical resection may be a favorable prognostic factor for longer OS. We also conclude that preoperative HPLR may predict lymph node involvement. PLR but not NLR may help in selecting patients for surgery in the future. Further prospective studies are needed to confirm these observations.
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P2.03a - Poster Session with Presenters Present (ID 464)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03a-025 - Randomized, Double-Blind, Phase 3 Study Comparing Biosimilar Candidate ABP 215 with Bevacizumab in Patients with Non-Squamous NSCLC (ID 6068)
14:30 - 15:45 | Author(s): G. Ostoros
- Abstract
Background:
ABP 215 is a biosimilar candidate that is similar to bevacizumab, a VEGF inhibitor, in analytical and functional comparisons. Pharmacokinetic similarity between ABP 215 and bevacizumab has been demonstrated in a phase 1 study. Here we present results from a pivotal phase 3 clinical study in non–small-cell lung cancer (NSCLC).
Methods:
In this double-blind, active-controlled study in adults with non-squamous NSCLC receiving first-line chemotherapy with carboplatin and paclitaxel, subjects were randomized (1:1) to receive investigational product (IP; ABP 215 or bevacizumab 15 mg/kg) Q3W for 6 cycles as an IV infusion. Clinical equivalence was demonstrated by comparing the 2-sided 90% confidence interval (CI) of the risk ratio (RR) of the objective response rate (ORR; primary endpoint) with pre-specified margin of (0.67, 1.5) Secondary endpoints were risk difference (RD) of the ORR, duration of response (DOR), progression-free survival (PFS), treatment-emergent adverse events, and overall survival (OS).
Results:
A total of 642 subjects (ABP 215 [Arm 1], n=328; bevacizumab [Arm 2], n=314) were randomized. Demographic and baseline characteristics were balanced between arms. There were 128 (39.0%) responders in Arm 1 and 131 (41.7%) responders in Arm 2. The RR for ORR was 0.93 (90%CI, 0.80–1.09). The RD for ORR was −2.90% (90%CI, −9.26%–3.45%). Among the responders the estimated median DOR was 5.8 months in Arm 1 versus 5.6 months in Arm 2. The estimated median PFS in Arm 1 was 6.6 months versus 7.9 months in Arm 2; the analysis included all 256 PFS events, 131 (39.9%) in Arm 1 and 125 (39.8%) in Arm 2. The safety population included 324 treated subjects in Arm 1 and 309 in Arm 2; 139 (42.9%) subjects in Arm 1 and 137 (44.3%) in Arm 2 experienced grade ≥3 TEAEs. TEAEs leading to IP discontinuation affected 61 (18.8%) subjects in Arm 1 and 53 (17.2%) in Arm 2; 85 (26.2%) subjects in Arm 1 and 71 (23.0%) in Arm 2 experienced at least one serious AE; 13 (4.0%) in Arm 1 and 11 (3.6%) in Arm 2 had a fatal TEAE. OS analysis included 79 deaths, 43 (13.3%) in Arm 1 and 36 (11.7%) in Arm 2. Binding antibodies developed during the study in 4 (1.4%) subjects in Arm 1 versus 7 (2.5%) in Arm 2; no subject tested positive for neutralizing antibodies.
Conclusion:
The study met the primary and secondary objectives demonstrating that ABP 215 and bevacizumab are clinically equivalent.
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SC13 - Interaction of COPD and Lung Cancer - Consequences for Early Diagnosis and Management (ID 337)
- Event: WCLC 2016
- Type: Science Session
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:A. Meert, K. Zarogoulidis
- Coordinates: 12/06/2016, 11:00 - 12:30, Stolz 1
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SC13.03 - Limitation by COPD for Diagnostic Procedures (ID 6651)
11:00 - 12:30 | Author(s): G. Ostoros
- Abstract
- Presentation
Abstract:
Limitation by COPD for Diagnostic Procedures Ostoros, Gy. Varga, J. and Kerpel-Fronius A. National “Korányi” Institute for Pulmonology Hungary, Budapest Lung cancer and COPD are smoking dependent diseases. Smoking cessation is crucial before and during the diagnostic procedures because of the consequences of smoking (e.g. sputum retention, mucociliary dysfunction and potential other more serious complications after the procedures). Severe obstructive or restrictive pulmonary disorders limit the diagnostic possibilities in patients with malignant pulmonary diseases. The screening of lung cancer with low-dose CT has become the gold standard in the past decade. The two imaging-based phenotypes of COPD can be well distinguished by this technique. CT screening can also help to identify non-diagnosed emphysema patients and may lead to early treatment of the disease. It has been showed that non-smoker emphysema patients have a similar risk of lung cancer as smokers with emphysema. Thus, patients with emphysema may be an eligible subgroup for a more intensive lung cancer screening program. However, once a suspicious lesion is found severe COPD, it can limit the choices available for differential diagnosis seriously - CT guided lung biopsies in COPD patients carry a higher risk of haemorrhage and pneumothorax. Patients with severe COPD and respiratory failure with decreased oxygen saturation limit the indication of diagnostic bronchoscopic procedures as well. The examination of exhaled breath condensate (EBC) is a non invasive process. There are efforts to discriminate lung cancer and COPD with EBC. Lung tumours have influence on lung function. Besides the severity of COPD, the result of the lung function test (LFT) depends on the size and position of the pulmonary tumour as well. In the case of a big central tumour or a huge amount of pleural fluid, the LFT will show rather restrictive than obstructive character. A small peripheral malignancy will not change the shape and volume of the LFT. If the tumour is in the trachea or compresses it's wall, the inspiratory phase of the flow-volume chart could be flat. Sometimes the lung tumours could lead a misdiagnosis of COPD. A centrally located small tumor which is not visible on the chest X-ray but compresses the trachea or any of the pulmonary vessels can cause breathlessness, fatigue and decreased oxygen saturation. A mediastinal conglomerate of lymph nodes can cause similar symptoms. Low physical activity, obesity, smoking and comorbidities are significant negative factors for risk stratification before any pulmonary diagnostic procedure as well. Pulmonary rehabilitation can improve functional reserves if functional capacity is at borderline. Pulmonary rehabilitation has positive effect on cardiovascular function, metabolism, muscle-function and lung mechanics. As for lung function parameters, we need to focus on forced expiratory volume in one second (FEV~1~) and diffusion capacity (DL~CO~). We can follow the common agreement of minimum criteria of the European Society of Chest Surgeon and European Respiratory Society for risk stratification before a diagnostic pleuroscopy. Based on this protocol, FEV~1~ and DL~CO~ need to be >35%pred. In the case of 35%pred< FEV~1 ~and DL~CO~<75%pred, we need to consider VO~2~/kg during a cardiopulmonary exercise test. If VO~2 ~is~ ~<10 ml/kg/min, the patient need a pulmonary rehabilitation program to improve functional reserves. Regarding lung function, we need to focus on lung mechanics and lung kinematics as well. Lung mechanics can be monitored by resting functional reserve capacity (FRC) and residual volume (RV). Lung kinematics can be monitored by chest expansion. Improved resting or dynamic hyperinflation and lung kinematics of the patients with chest physiotherapy and complex pulmonary rehabilitation is also suggested. As a general effect of rehabilitation, training programs can improve the cardiovascular response, oxygen uptake and the metabolism. We may also focus on physical activity, which is a general prognostics marker. Physical activity can be monitored by pedometer. Obesity can influence the complications of the surgical procedure and it has some effect on lung mechanics as well. If we have time, in case of an obese patient we may also consider improving their body composition before the invasive procedure. To sum up, comorbidities have to be considered before an invasive diagnostic procedure of lung cancer. Patients with impaired pulmonary hemodynamics, ischemic heart disease, diabetes or obesity have to be carefully evaluated. de Torres JP. Casanova C. et al. : Exploring the impact of screening with low-dose CT on lung cancer mortality in mild to moderate COPD patients: A pilot study. Respiratory Medicine, 107, 5, 702-707. 2013. Wiener RS. Schwarcz LM. et al. Population-Based Risk of Complications Following Transthoracic Needle Lung Biopsy of a Pulmonary Nodule. Annals of Internal Medicine, 155, 3, 137-144. 2011. GOLD-www.goldcopd.org Brunelli, A. Charloux, A. et al : ERS/ESTS clinical guidelines on fitness for radical therapy in lung cancer patients Eur. Resp. J., 34, 1, 2009.
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